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Background: Many animal models have been used to study the pathophysiology of hydrocephalus; most of these have been rodent models whose lissencephalic cerebral cortex may not respond to ventriculomegaly in the same way as gyrencephalic species and whose size is not amenable to evaluation of clinically relevant neurosurgical treatments. Fewer models of hydrocephalus in gyrencephalic species have been used; thus, we have expanded upon a porcine model of hydrocephalus in juvenile pigs and used it to explore surgical treatment methods., Methods: Acquired hydrocephalus was induced in 33-41-day old pigs by percutaneous intracisternal injections of kaolin (n = 17). Controls consisted of sham saline-injected (n = 6) and intact (n = 4) animals. Magnetic resonance imaging (MRI) was employed to evaluate ventriculomegaly at 11-42 days post-kaolin and to plan the surgical implantation of ventriculoperitoneal shunts at 14-38-days post-kaolin. Behavioral and neurological status were assessed., Results: Bilateral ventriculomegaly occurred post-induction in all regions of the cerebral ventricles, with prominent CSF flow voids in the third ventricle, foramina of Monro, and cerebral aqueduct. Kaolin deposits formed a solid cast in the basal cisterns but the cisterna magna was patent. In 17 untreated hydrocephalic animals. Mean total ventricular volume was 8898 ± 5917 SD mm 3 at 11-43 days of age, which was significantly larger than the baseline values of 2251 ± 194 SD mm 3 for 6 sham controls aged 45-55 days, (p < 0.001). Past the post-induction recovery period, untreated pigs were asymptomatic despite exhibiting mild-moderate ventriculomegaly. Three out of 4 shunted animals showed a reduction in ventricular volume after 20-30 days of treatment, however some developed ataxia and lethargy, from putative shunt malfunction., Conclusions: Kaolin induction of acquired hydrocephalus in juvenile pigs produced an in vivo model that is highly translational, allowing systematic studies of the pathophysiology and clinical treatment of hydrocephalus., (© 2021. The Author(s).)

The effects of cyclophosphamide on 5-hydroxytryptamine (5-HT) synthesis in the intestinal tissue of rats were investigated. Rats received 120 mg/kg cyclophosphamide intraperitoneally as a single administration, and kaolin and food intake was measured by an automatic monitoring apparatus. Ileal tissues were collected at either 24 or 72 h after administration. Cyclophosphamide caused a significant increase in kaolin intake at the acute and the delayed phases and was associated with a decrease in food intake, and body weight. Cyclophosphamide had no significant effect on intestinal mucosal morphology, or inducible nitric oxide synthase and cyclooxygenase-2 expression in the intestine. Cyclophosphamide significantly increased tryptophan hydroxylase 1 (TPH1) mRNA expression, number of anti-TPH antibody-positive cells, and 5-HT content in the intestine. Cyclophosphamide also significantly increased the expression of Tac1 mRNA, encoding preprotachykinin-1, which is a preprotein of substance P, and the number of anti-substance P antibody-positive cells in the intestine. Cyclophosphamide significantly increased Lgr5, Bmi1, and Atoh1 mRNA levels, which are markers for the proliferation and differentiation of stem cells. This study demonstrated that cyclophosphamide induced pica in rats, and potentiated 5-HT synthesis associated with hyperplasia of substance P-containing enterochromaffin cells without causing severe intestinal injury., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

In the current study, hemostatic compositions including a combination of chitosan and kaolin have been developed. Chitosan is a marine polysaccharide derived from chitins, a structural component in the shells of crustaceans. Both chitosan and kaolin have the ability to mediate a quick and efficient hemostatic effect following immediate application to injury sites, and thus they have been widely exploited in manufacturing of hemostatic composites. By combining more than one hemostatic agent (i.e., chitosan and kaolin) that act via more than one mechanism, and by utilizing different nanotechnology-based approaches to enhance the surface areas, the capability of the dressing to control bleeding was improved, in terms of amount of blood loss and time to hemostasis. The nanotechnology-based approaches utilized to enhance the effective surface area of the hemostatic agents included the use of Pluronic nanoparticles, and deposition of chitosan micro- and nano-fibers onto the carrier. The developed composites effectively controlled bleeding and significantly improved hemostasis and survival rates in two animal models, rats and rabbits, compared to conventional dressings and QuikClot ® Combat Gauze. The composites were well-tolerated as demonstrated by their in vivo biocompatibility and absence of clinical and biochemical changes in the laboratory animals after application of the dressings.

The clay minerals are characterized as important minerals due to their specific properties. One of the most important groups of the clay minerals is the kaolinite's group minerals due to their morphology, availability and range of potential applications. Halloysite and kaolinite are investigated here for their pharmaceutical applications and especially for their potential in cancer treatment. This review study is focusing on the potential applications of the kaolinite's group minerals in cancer diagnosis and monitoring, cancer treatment, the avoidance of metastasis, and the relief of cancer pains. Anticancer drug-loaded formulations based on these minerals show high potential for the treatment of various types of cancer as they have been shown to exhibit high anticancer activity in cancer cell lines and cancer animal models, high biocompatibility, low side effects, and high drug bioavailability., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Drought is one of the main serious problems for agriculture production which its intensity is increasing in many parts of the world, hence, improving water use efficiency is a main goal for sustainable agriculture., Results: Growth indices including relative shoot length growth (SL), relative stem diameter increase (SD) and relative trunk cross sectional area growth (TCSA) measured at the start and end of the season decreased by reducing the irrigation level. Chlorophyll index (CI) was decreased at 70% crop evapotranspiration, however water use efficiency (WUE), leaf and fruit total phenolic content (TPC), and fruit anthocyanin content (AC) were among the traits that showed increment by water deficit stress in both cultivars. Shafi-Abadi cultivar showed to be more sensitive to the water stress than 'Golab'. Kaolin treatment improved SL, SD and CI traits, but this increase was statistically significant only for SD at 5% level. Kaolin had no significant effect on yield and water use efficiency (WUE), however, it had negative effect on yield efficiency (YE). Kaolin treatments also significantly increased fruit and leaf TPC (P < 0.01) but had no effect on leaf and fruit total antioxidant activity (AA), as well as fruit anthocyanin content (AC) and soluble proteins (SP)., Conclusions: Irrigation at 85% ETc showed better results than 100% and 70% ETc levels for yield attributes. It seems that the more pronounced effect of kaolin on vegetative traits but not on the fruits, might be attributed to the early ripening and harvest time of the examined cultivars.

Purpose: Kaolin (aluminum silicate) has been used to generate hydrocephalus by direct cisterna magna injection in animal models. The aim of the present study is to compare which method of Kaolin injection into fetal cisterna magna is feasible, safer, and more effective to induce hydrocephalus in fetal lambs., Methods: Twenty-five well-dated pregnant ewes at gestational 85-90 days (E85-90) were used to compare three different kaolin injection puncture techniques into the fetal cisterna magna. Group 1, ultrasound guidance in a maternal percutaneous transabdominal (TA); group 2, without opening the uterus in a transuterine (TU) technique; group 3, by occipital direct access after exteriorizing fetal head (EFH); and group 4, control group, was normal fetal lambs without injection. The fetal lambs were assessed using lateral ventricle diameter ultrasonographic measurements prior the kaolin injection and on the subsequent days. We analyzed the effectivity, mortality, and fetal losses to determine the best technique to create hydrocephalus in fetal lamb., Results: After fetal intracisternal kaolin (2%, 1mL) injection, lateral ventricle diameters increased progressively in the three different interventional groups compared with the normal values of the control group (p ≤ 0.05). We observed that the transabdominal method had a 60% of fetal losses, considering failure of injection and mortality, compared with the 12.5% in the open group (EFH), and 0% for the transuterine group., Conclusions: Based on our study, we believe that both, open uterine (EFH) and transuterine approaches are more effective and safer than the transabdominal ultrasound-guided method to induce hydrocephalus.

This article presents an experimental preparation for establishing conditioned food aversion (CFA) by voluntary wheel running in rats with laboratory chow and water freely available. In Experiment 1, unfamiliar food (raisins) was avoided by rats when they first encountered it. This neophobic food avoidance was habituated by repeated tests; the rats gradually increased their raisin consumption. However, the consumption remained suppressed in rats that accessed the raisins after wheel running. This finding implies that running yielded CFA, which suppressed consumption of the unfamiliar food rather than increasing it. Because running generated kaolin clay ingestion, which is a behavioral marker of nausea, it is suggested that the running-based CFA was mediated by weak gastrointestinal discomfort. Experiment 2 supported the claim that the suppressed consumption is due to running-based CFA by showing the specificity of food suppression. Demonstration of CFA based on voluntary activity in non-deprived rats will contribute to basic research on learning and memory as an alternative technique for studying aversive conditioning with minimized discomfort in animals.

Radial artery occlusion (RAO) occurs in 2% to 18% of patients after transradial access (TRA) cardiac catheterization. Using a kaolin-filled pad (QuikClot) reduces compression time during TRA and might reduce RAO. We examined the RAO risk with the kaolin-filled pad after TRA cardiac catheterization.This was a prospective cross-sectional study of 260 patients who underwent TRA cardiac catheterization in a cardiac ward of a Medical Center from 2012 to 2016. Patients were randomly assigned to 1 of 2 groups: the case group (n = 130) was postoperatively treated with a kaolin-filled pad, and the control group (n = 130) was treated with conventional hemostasis. Color duplex ultrasound was used to evaluate the 24-hour and 1-month postoperative radial artery flow velocity, diameter, patency, and RAO risk.RAO risk was not significantly different between the case and control groups after 24 hours (4.6% vs 5.4%, P = .776) or after 1 month (5.4% vs 6.1%, P = .789), regardless of whether it was a first TRA cardiac catheterization (after 24 hours [P = .153] or after 1month [P = .617], respectively) or a repeated TRA cardiac catheterization (after 24 hours [P = .754] or after 1month [P = .753], respectively).Using a kaolin-filled pad after TRA cardiac catheterization did not significantly reduce RAO risk compared with conventional hemostasis.

Motion sickness (MS) is an acute disorder that occurs in healthy individuals worldwide regardless of gender, age, or ethnicity. Our study used a mouse model to rule out the effects of any psychological factors related to MS and EA. Subjects were randomly separated into four groups, namely the control group (Con), motion sickness inducing group (MS), mentioning sickness inducing with electroacupuncture treatment group (EA) and motion sickness inducing only in TRPV1 knockout mice group (TRPV1 -/- ). The consumption of kaolin, a non-nutrient substance, was measured as a behavior observed response of an emetic reflex in a murine model. This behavior is referred to as pica behavior. Our results showed that pica behavior was observed in the MS group. Moreover, kaolin consumption in the EA group decreased to the average baseline of the control group. A similar result was observed in TRPV1 null mice. We also observed an increase of TRPV1 and related molecules in the thalamus, hypothalamic and brain stem after MS stimulation and a significant decrease in the EA and TRPV1 null groups. This is the first study to demonstrate that TRPV1 pathways are possibly associated with mechanisms of MS, and can be attended through EA or TRPV1 genetic manipulation.

OBJECTIVE To assess effects of buprenorphine hydrochloride (BH), sustained-release buprenorphine (SRB), and high-concentration buprenorphine (HCB) formulations in healthy rats. ANIMALS 8 Sprague-Dawley rats. PROCEDURES In a crossover-design study, rats received BH (0.05 mg/kg), SRB (1.2 mg/kg), HCB (0.30 mg/kg), or 5% dextrose solution (0.2 mL/kg), SC, once. Self-injurious behavior and thermal sensitivity (hind limb withdrawal latencies) were assessed prior to injection (time 0) and 1, 4, 8, 12, and 24 hours after injection. Food intake, kaolin intake, and fecal output were measured over 12-hour light and dark periods before and after each treatment. Values were compared among treatments and time points. RESULTS Self-injurious behavior was detected with all buprenorphine treatments; scores were greater at all time points during the 12 hours after HCB and 24 hours after SRB administration than at time 0. Percentage change in hind limb withdrawal latencies from time 0 was higher with BH and HCB 1 hour after injection than at other time points. Postinjection light-period food intake was higher (BH and HCB) and dark-period food intake was lower (BH, HCB, and SRB), compared with preinjection values for the same treatments. For SRB, postinjection light-period kaolin intake was greater than the preinjection value, and postinjection light- and dark-period kaolin intake was greater than that for other treatments. CONCLUSIONS AND CLINICAL RELEVANCE Hypoalgesic effects were briefly observed after administration of BH or HCB in healthy rats; adverse effects were detected in some rats with all buprenorphine formulations. Studies comparing effects of BH, SRB, and HCB in rats undergoing surgery or other noxious stimuli are indicated to determine clinical benefits in this species.

The foliar exogenous application of kaolin, a radiation-reflecting inert mineral, has proven to be an effective short-term climate change mitigation strategy for Mediterranean vineyards. In this work, we address the hypothesis that kaolin could improve both the hormonal dynamics and physiological responses of grapevines growing in Douro Region, northern Portugal. For this purpose, the leaf water potential, gas exchange and chlorophyll a fluorescence parameters were monitored, as well as the abscisic acid (ABA) and indole-3-acetic acid (IAA) quantification and immunolocalization were assessed. The study revealed a slight decrease in ABA and an increase in IAA in the kaolin treatment, which in turn were associated with the improvement of physiological performance. A month after spraying, kaolin improves the water potential respectively, 30% and 17% in the predawn and midday periods. Besides, plants treated with kaolin showed higher values of stomatal conductance, net CO 2 assimilation rate and intrinsic water use efficiency. Kaolin also ameliorates the effective PSII efficiency (67%), as well as the maximum quantum efficiency of photosystem II and the photosynthetic electron transport rate (>73%). These results were consistent with the higher photochemical quenching and the lower non-photochemical quenching observed in treated leaves and with the better performance obtained by the JIP test parameters. Physiological and hormonal analysis confirmed that kaolin effectively enhance grapevine summer stress tolerance., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Three experiments were conducted showing rats' pica behavior (kaolin clay intake) due to running in activity wheels. The amount of kaolin consumed was a positive function of the available time of voluntary running (20, 40, or 60 min), although this relationship was blunted by a descending (i.e., 60 → 40 → 20 min) test series of execution (Experiment 1). Pica was also generated by forced running in a motorized wheel for 60 min as a positive function of the speed of wheel rotations at 98, 185, or 365 m/h, independent of the order of execution (Experiment 2). Voluntary running generated more pica than did forced running at 80 m/h, although the distance travelled in the former condition was 27% lesser than that in the latter condition (Experiment 3). Because kaolin intake is regarded as a reliable measure of nausea in rats, these results show that wheel running, either voluntary or forced, induces nausea in rats., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Nanoclay can be incorporated into emerging dual functional drug delivery systems (DDSs) to promote efficiency in drug delivery and reduce the toxicity of doxorubicin (DOX) used for thyroid cancer treatment. This paper reports the expansion of the basal spacing of kaolinite nanoclay was expanded from 0.72 nm to 0.85 nm, which could provide sufficiently spacious site for hosting doxorubicin molecules and controlling the diffusion rate. A targeted design for papillary thyroid cancer cells was achieved by introducing KI, which is consumed by the sodium-iodide symporter (NIS). As indicated by MTT assays, confocal laser scanning microscopy and bio-TEM observations, methoxy-intercalated kaolinite (KaolinMeOH) exhibited negligible cytotoxicity against papillary thyroid cancer cells. By contrast, DOX-KaolinMeOH showed dose-dependent therapeutic effects in vitro, and KI@DOX-KaolinMeOH was found to act as a powerful targeted therapeutic drug. Furthermore, active and passive targeting strategies played a role in the accumulation of the drug molecules, as verified by an in vivo bio-distribution analysis.

Background: Previous work with 3-week hydrocephalic rats showed that white matter damage could be reduced by the calcium channel antagonist magnesium sulfate (MgSO4). We hypothesized that MgSO4 therapy would improve outcomes in ferrets with hydrocephalus induced with kaolin at 15 days., Methods: MRI was performed at 29 days to assess ventricle size and stratify ferrets to treatment conditions. Beginning at 31 days age, they were treated daily for 14 days with MgSO4 (9 mM/kg/day) or sham saline therapy, and then imaged again before sacrifice. Behavior was examined thrice weekly. Histological and biochemical ELISA and myelin enzyme activity assays were performed at 46 days age., Results: Hydrocephalic ferrets exhibited some differences in weight and behavior between treatment groups. Those receiving MgSO4 weighed less, were more lethargic, and displayed reduced activity compared to those receiving saline injections. Hydrocephalic ferrets developed ventriculomegaly, which was not modified by MgSO4 treatment. Histological examination showed destruction of periventricular white matter. Glial fibrillary acidic protein content, myelin basic protein content, and myelin enzyme activity did not differ significantly between treatment groups., Conclusion: The hydrocephalus-associated disturbances in juvenile ferret brains are not ameliorated by MgSO4 treatment, and lethargy is a significant side effect.

Chitosan, a natural biopolymer, obtained by alkaline deacetylation of chitin, exhibits excellent biological properties such as biodegradability, immunological and antibacterial activity. Recently, there has been a growing interest in the chemical modification of chitosan in order to widen its applications. The chemical modification of chitosan has been achieved via grafting of monomer, 2-hydroxyethyl methacrylate (HEMA) in the presence of the initiator, ammonium persulfate (APS) and kaolin was added to improve the mechanical strength of the newly developed nanocomposites hydrogel. The so prepared grafted nanocomposites hydrogel was characterized by FTIR, XRD, SEM, TEM and TGA. The equilibrium water content (EWC) of the samples were measured at different pH ranges 6.5-8.0 and found optimum at pH 7.5 for biomedical applications. Further, the biodegradability of the samples was studied at different time intervals from 15 days to 1 year but, the kaolin based nanohydrogels exhibited good biodegradability., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Hydrocephalus is a common neurological disease in humans, but a uniform and particularly effective hydrocephalic animal model amenable to proper appraisal and deep study has not yet been established. In this study, we attempted to construct a high-efficiency model of hydrocephalus via intraventricular kaolin injection. Adult male Sprague-Dawley rats were randomly divided into 2 groups: the control group (n = 15) and the experimental group (n = 30). Kaolin was injected into the lateral ventricle of experimental animals. Control rats underwent the same procedure but received sterile saline injection instead of kaolin. All animals with kaolin injection into the lateral ventricle developed hydrocephalus according to magnetic resonance imaging (MRI) results (success rate up to 100%). Also, the Morris water maze (MWM) test demonstrated disturbed spatial learning and memory. Furthermore, there were significant differences between groups with respect to the histological changes in the periventricular tissue. Our results indicate that experimental hydrocephalus induced by lateral ventricle injection of kaolin in adult rats is feasible and may be widely used.

Voluntary running in an activity wheel establishes aversion to paired taste in rats. A proposed mechanism underlying this taste aversion learning is gastrointestinal discomfort caused by running. We tested this hypothesis by measuring the pica behavior (kaolin clay intake) of rats, because it is known that rats engage in pica behavior after various nausea-inducing treatments including irradiation, motion sickness, and injection of emetic drugs such as lithium chloride (LiCl). Following a demonstration of the already-known phenomenon of LiCl-based pica in Experiment 1, we successfully showed running-based pica behavior in Experiment 2 where the running treatment was compared with a non-running control treatment (i.e., confinement in a locked wheel). These results suggest that not only LiCl but also running induces nausea in rats, supporting the gastrointestinal discomfort hypothesis of running-based taste aversion learning., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The main postoperative complications after tonsillectomy are due to bleeding, and effective hemostasis may lead to a reduction of overall postoperative morbidity. This study was undertaken to determine the efficacy and safety of a novel kaolin-based hemostatic dressing in tonsillectomy., Methods: A pilot, single-blind, open label study was performed in patients aged 3-20 y with history of chronic or hypertrophic tonsillitis. Cold dissection tonsillectomy (CDT) + ligature was performed by the same surgeon. Hemostasis on each tonsillar fossa was achieved using kaolin-impregnated gauze (KG; study group) or standard surgical cotton gauze (CG; control). Time to complete hemostasis, operative time, intraoperative blood loss, pain score, analgesic use, and return to normal diet and activity were recorded for all children., Results: A total of 230 patients with a mean age of 8.0 y (138 in the study group and 92 in the control group) were included in the study. Both operative time and intraoperative blood loss were significantly reduced in the KG group (P < 0.0001) versus the CG group. At 5 min, 84.8% patients using the KG successfully achieved complete hemostasis versus 34.8% in the CG group where standard gauze controlled bleeding only partially. Results show significantly less pain for the KG group at 6- and 12-h postoperative when compared with the CG group (P < 0.0001). Also, the KG group required less analgesic medications, returned to normal diet and normal activities faster than the CG group (P < 0.01)., Conclusions: Preliminary findings show that the KG is effective and safe in managing surgical bleeding after tonsillectomy. In addition to rapid bleeding control, the dressing causes minimal inflammation and pain and allows patients to quickly return to normal activities. This novel dressing is a promising tool for ear, nose and throat surgical hemostasis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The effects of methotrexate on 5-hydroxytryptamine (5-HT) metabolism in the intestinal tissue of rats were investigated during the delayed phase after a single administration. Rats were i.p. injected with methotrexate or with saline as a control, and kaolin and food intakes were measured by an automatic monitoring apparatus. At 96 h after administration, dissected-out ileal tissue was frozen rapidly in liquid nitrogen for further analysis or fixed for immunohistochemical staining. Methotrexate at a dose of 50 mg/kg caused a time-dependent increase in kaolin intake lasting up to 72 h after administration, which returned to the control level at 96 h after administration. This dose of methotrexate caused a gradual decrease in body weight, food intake, and water intake lasting up to 72 h, which approached the control level at 96 h. Methotrexate caused pathologic changes, including a moderate inflammatory response in the ileal tissue and an increase in the number of L-tryptophan hydroxylase (TPH)-expressing cells in the ileal mucosa. Methotrexate also caused a significant increase in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) content and in TPH1 mRNA expression in the ileal tissues. It had no significant effects on mRNA expression of serotonin transporter, COX-1, or COX-2 or on myeloperoxidase activity. This study demonstrated, for the first time, that methotrexate caused a change in the ileal 5-HT metabolism associated with hyperplasia of mucosal enterochromaffin cells., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Skin protective creams (PCs) are used widely in industrial work environments to prevent irritant contact dermatitis. However, workplace studies remain equivocal in terms of their effectiveness, which may be partly owing to whether the PC remains on the skin., Objectives: To assess the practicability of using skin occlusion testing in a workplace as a method to determine whether PCs applied under controlled conditions can reduce skin damage against known irritants. This study also compares two methods of skin evaluation: clinical dermatological assessment and bioengineering techniques., Methods: Daily occlusion testing for 1 h (over two consecutive weeks) was conducted in an engineering company on the volar forearm of 21 healthy volunteer engineers with sodium lauryl sulfate (SLS) and a PC that was used on site. The engineers conducted their normal work activities during the occlusion testing period. The skin areas tested were assessed using transepidermal water loss (TEWL), Chroma Meter and by visual dermatological scoring., Results: Testing with PC and SLS together showed that PC does not prevent irritant contact dermatitis but significantly reduced skin damage compared with SLS alone (P < 0.01). The changes in skin were evident earlier with the biophysical measurements when compared with the dermatological assessment., Conclusions: Occlusion testing is a useful method for assessing the potential effectiveness of protective creams and can be used in a workplace without affecting work practices. TEWL and the Chroma Meter provide useful objective information and should be used in combination with dermatological examinations., (© 2014 British Association of Dermatologists.)

Objectives: The aims of the study were to 1) determine the effectiveness of QuikClot Combat Gauze (QCG); 2) determine the arterial blood pressure at which rebleeding occurs; 3) determine how much intravenous fluid could be administered before hemorrhage reoccurred, and 4) determine the number extremity movement on rebleeding when QCG was used., Design: This was a prospective, randomized, experimental study., Subjects: Adult Yorkshire pigs were randomly assigned to two groups QCG (n = 10) or control (n = 10)., Intervention: After the swine were anesthetized, the investigators transected the femoral artery and vein. After 1 minute of uncontrolled bleeding, QCG was placed in the wound followed by standard wound packing. The control group underwent the same procedures without QCG. After 5 minutes of firm, manual pressure, a pressure dressing was applied. Following 30 minutes, the dressings were removed and blood loss was calculated. If hemostasis occurred, phenylephrine was administered until there was rebleeding. If no bleeding, up to 5 L of IV crystalloid was administered until there was hemorrhage. If no bleeding, the extremity on the side of the hemorrhage was moved through flexion, extension, abduction, and adduction 10 times or until rebleeding occurred., Main Outcomes: QCG compared to a control was more effective in controlling hemorrhage, withstanding increases in systolic blood pressure, more latitude in resuscitation fluid, and movement (p < 0.05).

We have previously shown that kaolinite slowed down gastric emptying and intestinal transit and induced changes in enteric mechanical activities. As gastric emptying and intestinal transit have been shown to be regulated by nitric oxide (NO), the effect of an imposed ingestion of kaolinite on enteric nitrergic innervation was determined. Kaolinite has also been shown to increase plasmatic levels of leptin. Therefore, the responses of enteric neurons in the presence of leptin after kaolinite ingestion were determined, and a possible role of nitrergic neurons was evaluated in rats using organ bath technique. Our results showed that kaolinite modulates activities of enteric nerves at 14 days of ingestion. Exogenous l-NNA produced a decrease in nerve stimulation (NS)-induced relaxation in both jejunum and colon of control groups. At 14 days of kaolinite ingestion, this effect of l-NNA was significantly reduced only in the jejunum. Although l-NNA did not affect NS-induced contraction in jejunum and colon of control animals, it increased the amplitude of the NS-induced contraction in the colon of rats at 14 days of kaolinite ingestion. Leptin inhibitory effects on ENS in the jejunum were also altered at 14 days of ingestion. These differences were masked in the presence of l-NNA. Our data give evidence that changes in mechanical activities induced by kaolinite might be due to alterations in inhibitory (nitrergic and/or other) innervation at 14 days of kaolinite ingestion and to modifications of leptin effects on the responses to intramural nerve stimulation., (© 2013 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Background and Purpose: Although substance P (SP) and neurokinin NK1 receptors have been reported to be involved in cisplatin-induced acute and delayed emesis, their precise roles remain unclear. Pica, the consumption of non-nutrient materials such as kaolin in rats, can be used as a model of nausea in humans. We investigated the time-dependent changes in cisplatin-induced pica and the involvement of SP and NK1 receptors in this behaviour., Experimental Approach: Rats were administered cisplatin with or without a daily injection of a 5-HT3 receptor antagonist (granisetron) or an NK1 receptor antagonist (aprepitant), and kaolin intake was then monitored for 5 days. The effects of granisetron on the cisplatin-induced expression of preprotachykinin-A (PPT-A) mRNA, which encodes mainly for SP, and on SP release in the medulla, measured by in vivo brain microdialysis, were also investigated., Key Results: Cisplatin induced pica within 8 h of its administration that continued for 5 days. Granisetron inhibited the acute phase (day 1), but not the delayed phase (days 2-5), of pica, whereas aprepitant abolished both phases. Within 24 h of the injection of cisplatin, PPT-A mRNA expression and SP release in the medulla were significantly increased; these findings lasted during the observation period and were inhibited by granisetron for up to 24 h., Conclusions and Implications: The profiles of cisplatin-induced pica in rats are similar to clinical findings for cisplatin-induced emesis in humans, and we showed that SP production in the medulla and activation of NK1 receptors are involved in this cisplatin-induced pica., (© 2014 The British Pharmacological Society.)

Tranexamic acid suppresses post-partum haemorrhage and idiopathic menorrhagia through its anti-fibrinolytic action. Although it is clinically useful, it is associated with high risks of side effects such as emesis. Understanding the mechanisms underlying tranexamic acid-induced emesis is very important to explore appropriate anti-emetic drugs for the prevention and/or suppression of emesis. In this study, we examined the receptors involved in tranexamic acid-induced kaolin intake in rats, which reflects the drug's clinical emetogenic potential in humans. Further, we examined the brain regions activated by administration of tranexamic acid and elucidated pivotal pathways of tranexamic acid-induced kaolin intake. We examined the effects of ondansetron, a 5-hydroxytryptamine 3 receptor antagonist, domperidone, a dopamine 2 receptor antagonist, and aprepitant, a tachykinin neurokinin 1 (NK1) receptor antagonist, on tranexamic acid-induced kaolin intake in rats. Then, we determined the brain regions that showed increased numbers of c-Fos immunoreactive cells. Finally, we examined the effects of an antagonist(s) that reduced tranexamic acid-induced kaolin intake on the increase in c-Fos immunoreactive cells. Aprepitant significantly decreased tranexamic acid-induced kaolin intake. However, neither ondansetron nor domperidone decreased kaolin intake. Tranexamic acid significantly increased c-Fos immunoreactive cells by approximately 5.5-fold and 22-fold in the area postrema and nucleus of solitary tract, respectively. Aprepitant decreased the number of c-Fos immunoreactive cells in both areas. Tranexamic acid induced kaolin intake possibly via stimulation of tachykinin NK1 receptors in rats. The tachykinin NK1 receptor could be targeted to prevent and/or suppress emesis in patients receiving tranexamic acid., (© 2013 Published by Elsevier B.V.)

Background: Severe hepatic injuries may be highly lethal, and perihepatic packing remains the mainstay of treatment. This is not always successful, particularly in the setting of hypothermia and coagulopathy. Kaolin-impregnated Combat Gauze (CG) is an effective hemostatic dressing used primarily to treat external wounds. The objective of this study was to determine the ability of CG to control severe hemorrhage in hypothermic, coagulopathic swine with a high-grade hepatic injury., Methods: Anesthetized animals underwent splenectomy and were cooled to 32°C while undergoing a 60% exchange transfusion with Hextend. A grade V liver injury was created in the left middle hepatic lobe. Animals were allowed to freely bleed for 30 s and then randomized to treatment with CG or plain gauze laparotomy pads (PG) applied to the injury site. Animals were then resuscitated with warmed Hextend., Results: There was no difference between groups in preinjury hemodynamic or laboratory values. Animals packed with CG had less blood loss when compared with standard packing (CG = 25 mL/kg versus PG = 58 mL/kg, P = 0.05). There was a trend towards lower hetastarch resuscitation requirements in the CG group (CG = 7 mL/kg versus PG = 44 mL/kg, P = 0.06) but no statistically significant difference in mortality (CG = 13% versus PG = 50%, P = 0.11). Histology of the injury sites revealed more adherent clot in the CG group, but no inflammation, tissue necrosis, or residual material., Conclusion: In pigs with severe hepatic injury, Combat Gauze reduced blood loss and resuscitation requirements when compared with plain laparotomy pads. Combat Gauze may be safe and effective for use on severe liver injuries., (Published by Elsevier Inc.)

Context: Nausea and vomiting are considered as the foremost unpleasant side effects of chemotherapy experienced by 20-90% of cancer patients., Objective: In the present study, the effects of Korean Panax ginseng C.A. Meyer (Araliaceae) (RG), ginseng saponin (GS) and non-saponin (GNS) on cisplatin (CP)-induced pica and gastric damage in rats were investigated., Material and Methods: Rats were treated with RG (25, 50, 100 mg/kg b.wt.), GS (5 and 10 mg/kg 100 mg/kg b.wt.) and GNS (50 and 100 mg/kg b.wt.) before or after a single intraperitoneal injection of CP (6 mg/kg b.wt.). Kaolin together with normal food intake, normal food alone, body weight, histological examination of stomach and small intestine were used as indices of CP-induced pica in rats., Results: Pre-treatment with RG (50 and 100 mg/kg b.wt.) attenuated CP-induced kaolin intake at 24 h. CP-induced kaolin intake decreased upon post-treatment of rats with RG (50 and 100 mg/kg b.wt.) at 48 h. The incidence of body weight reduction at 48 and 72 h diminished in rats post-treated with RG (50 mg/kg b.wt.). Pre-treatment with GS (5 and 10 mg/kg b.wt.) and GNS (50 and 100 mg/kg b.wt.) attenuated CP-induced kaolin intake while normal food intake was not improved in 24 and 48 h., Discussion and Conclusion: The gastro-protective effects of RG, GS and GNS were further confirmed by histopathological (damage in glandular portion and villi with dilated appearance) findings. The study indicates that both the red GS and GNS improve feeding behavior against CP-induced pica in rats.

Extracts from the immature fruit of Citrus aurantium are often used for weight loss but are reported to produce adverse cardiovascular effects. Root extracts of Rhodiola rosea have notable antistress properties. The hypothesis of these studies was that C aurantium (6% synephrine) and R rosea (3% rosavins, 1% salidroside) in combination would improve diet-induced obesity alterations in adult male Sprague-Dawley rats. In normal-weight animals fed standard chow, acute administration of C aurantium (1-10 mg/kg) or R rosea (2-20 mg/kg) alone did not reduce deprivation-induced food intake, but C aurantium (5.6 mg/kg) + R rosea (20 mg/kg) produced a 10.5% feeding suppression. Animals maintained (13 weeks) on a high-fat diet (60% fat) were exposed to 10-day treatments of C aurantium (5.6 mg/kg) or R rosea (20 mg/kg) alone or in combination. Additional groups received vehicle (2% ethanol) or were pair fed to the C aurantium + R rosea group. Although high-fat diet intake and weight loss were not influenced, C aurantium + R rosea had a 30% decrease in visceral fat weight compared with the other treatments. Only the C aurantium group had an increased heart rate (+7%) compared with vehicle. In addition, C aurantium + R rosea administration resulted in an elevation (+15%) in hypothalamic norepinephrine and an elevation (+150%) in frontal cortex dopamine compared with the pair-fed group. These initial findings suggest that treatments of C aurantium + R rosea have actions on central monoamine pathways and have the potential to be beneficial for the treatment of obesity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to compare standard gauze (SG) and advanced hemostatic dressings in use by military personnel in a no-hold model., Methods: A randomized, controlled trial was conducted using 36 swine. Animals underwent femoral arteriotomy, followed by 60 seconds of uncontrolled hemorrhage. After hemorrhage, packing with 1 of 3 dressings-SG, Combat Gauze (CG), or Celox Rapid gauze (XG)-and a 500-mL bolus of Hextend were initiated. Pressure was not held after packing, and animals were followed for 120 minutes. Physiologic parameters were monitored continuously, and electrolyte and hematologic laboratory assessments were performed before injury and 30 and 120 minutes after injury. Dressing failure was determined if bleeding occurred outside the wound., Results: All animals survived to study end. Baseline characteristics were similar between groups. No statistical difference was seen in initial blood loss or dressing success rate (SG, 10 of 12; CG, 10 of 12; and XG, 12 of 12). Secondary blood loss was significantly less with XG (median, 12.8 mL; interquartile range, 8.8 to 39.7 mL) compared with SG (median, 44.7 mL; interquartile range, 17.8 to 85.3 mL; P = .02) and CG (median, 31.9 mL; interquartile range, 18.6 to 69.1 mL; P = .05). Packing time was significantly shorter with XG (mean, 37.1 ± 6.2 seconds) compared with SG (mean, 45.2 ± 6.0 seconds; P < .01) and CG (mean, 43.5 ± 5.6 seconds; P = .01)., Conclusions: XG demonstrated shorter application time and decreased secondary blood loss in comparison with both SG and CG. These differences may be of potential benefit in a care-under-fire scenario., (Copyright © 2013 Elsevier Inc. All rights reserved.)

HIV infected patients are frequently exposed to anaemia, due to antiretroviral agents and/or prophylactic treatment of opportunistic infections. Anemia due to PICA, unusually evoked in our western countries, could be a more frequent situation than imagined. We report two cases of fluctuating anemia with no HIV or iatrogenic origin, observed in two HIV infected women, 47 years old and 33 years old respectively, coming from Africa and treated with antiretroviral agents. The anemia was explained by a culturally sanctioned practice of kaolin ingestion, in the broader context of PICA and resolved after the withdrawal of kaolin ingestion. PICA, and in particular kaolin ingestion, must be investigated when HIV infected patients came from Africa and presented significative unexplained anemia., (© 2013 Société Française de Pharmacologie et de Thérapeutique.)

Introduction: Although hemostatic agents may be effective at stopping hemorrhage, they may fail because of hemodilution from intravenous fluids. The purpose of this study was to investigate the effects of QuikClot Combat Gauze (QCG) on rebleeding in a class II hemorrhage in the presence of hemodilution in a lethal femoral injury., Methods: This was a prospective experimental, between swine subjects design. Pigs were assigned to one of two groups: QCG (n=15) or control (n=15). Thirty percent of the pig's blood was exsanguinated and then a 3:1 ratio of ringers lactate was administered. A groin injury was created by transecting the femoral artery and vein to simulate a battlefield injury and allowed to bleed for one minute. After one minute of hemorrhage, proximal pressure was applied to the injury, and QCG was placed into the wound followed by standard wound packing. The control group underwent the same procedures with the exception of the hemostatic agent. For both groups, 5 minutes of direct pressure was applied to the wound followed by a standard pressure dressing. Dressings were removed after 30 minutes, and the amount of hemorrhage was calculated in milliliters for each group for a period of 5 minutes. An activated clotting time was used to exclude any pigs with coagulation pathology., Results: A multivariate analysis of variance indicated that there were no significant differences in the groups relative to weight, amount of one minute hemorrhage, fluid deficit replacement, blood volume, and the activated clotting time (P>.05) indicating that the groups were equivalent on these parameters. A t test indicated that there was significantly less bleeding (P=.002) in the QCG group (36 mL±112 mL) compared to the control group (340 mL±297 ml)., Conclusion: QCG produces a robust clot that can more effectively tolerate hemodilution compared to a control group.

Clay consumption is a spontaneous behavior currently observed in animals and humans, particularly during undernutrition. Often regarded as intestinal care products, ingested clays also enhance food efficiency, notably by increasing intestinal lipid uptake. Clay complementation could then optimize the reconstitution of energy reserves in animals with low lipid stocks consecutive to intensive fasting. The aim of this study was therefore to observe the effects of voluntarily kaolinite complementation during the refeeding of fasted rats to determine whether body mass, food uptake, lipid and mineral contents as intestinal morphology and protein profile were modified. This study examined two types of refeeding experiments after prolonged fasting. Firstly, rats with ad libitum access to food were compared to rats with ad libitum access to food and kaolinite pellets. Animals were randomly put into the different groups when the third phase of fasting (phase III) reached by each individual was detected. In a second set of experiments, rats starting phase III were refed with free access to food and kaolinite pellets. When animals had regained their body mass prior to fasting, they were euthanized for chemical, morphological, and proteomic analyses. Although kaolinite ingestion did not change the time needed for regaining prefasting body mass, daily food ingestion was seen to decrease by 6.8% compared with normally refed rats, without affecting lipid composition. Along the intestinal lining, enterocytes of complemented animals contained abundant lipid droplets and a structural modification of the brushborder was observed. Moreover, the expression of two apolipoproteins involved in lipid transport and satiety (ApoA-I and ApoA-IV) increased in complemented rats. These results suggest that kaolinite complementation favors intestinal nutrient absorption during refeeding despite reduced food uptake. Within the intestinal lumen, clay particles could increase the passive absorption capacity and/or nutrient availability that induce mucosal morphological changes. Therefore, clay ingestion appears to be beneficial for individuals undergoing extreme nutritional conditions such as refeeding and limited food supplies., (© 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.)

Geophagia is found in various animal species and in humans. We have previously shown that spontaneously ingested kaolinite interacts with the intestinal mucosa modifies nutrient absorption and slows down gastric emptying and intestinal transit in rats in vivo. However, the precise mechanisms involved are not elucidated. The aim of this work was to investigate the effects of controlled kaolinite ingestion on food intake, gut morphology and in vitro motility in rats. Male Wistar rats were fed with 5% kaolinite in standard food pellets during 7, 14 and 28 days. Body mass and food consumption were measured daily. Intestinal morphological and proteomic analyses were conducted. The length of mucosal lacteals was evaluated. Plasmatic levels of leptin and adiponectin were determined. Finally, organ bath studies were conducted to evaluate smooth muscle contractility. Food consumption was significantly increased during the first two weeks of kaolinite ingestion without any mass gain compared to controls. Kaolinite induced weak variations in proteins that are involved in various biological processes. Compared to control animals, the length of intestinal lacteals was significantly reduced in kaolinite group whatever the duration of the experiment. Leptin and adiponectin plasmatic levels were significantly increased after 14 days of kaolinite consumption. Changes in spontaneous motility and responses to electrical nerve stimulation of the jejunum and proximal colon were observed at day 14. Altogether, the present data give evidence for a modulation by kaolinite-controlled ingestion on satiety and anorexigenic signals as well as on intestinal and colonic motility., (© 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.)

Panax ginseng is an indigenous medicinal herb and has traditionally been used among Asian population for relief of many human ailments. We investigated the prophylactic role of Korean P. ginseng extract (KG) against X-ray irradiation-induced emesis in an acute rat pica model. Rats were treated with KG (12.5, 25, 50 mg/kg orally at -48, -24 and 0 h) prior to X-ray irradiation (6 Gy), and intake of kaolin and normal food and body weight changes examined as an index of the acute emetic stimulus. Levels of serotonin in small intestine tissue were assessed and histopathology of gastric tissue, small intestine and colon examined specific staining. Pre-treatment with KG (12.5 and 25 mg/kg) reduced X-ray irradiation-induced kaolin intake at 24h. Normal food intake was improved in rats treated with 25 mg/kg KG. The anti-emetic effect of KG was further confirmed on the basis of serotonin release, histopathological findings. Our findings collectively indicate that KG protects against X-ray irradiation-induced acute pica to a moderate extent, leading to improved feeding behavior in rats., (Copyright © 2012. Published by Elsevier B.V.)

Background: Bleeding and vascular access site complications are an important cause of morbidity after percutaneous femoral procedures. Together with collagen-based and suture-based vascular closure devices, new hemostatic dressings have been developed to control heavy bleeding., Aim of Study: To evaluate safety and efficacy results of the first clinical QuikClot Interventional Hemostatic Bandage use for femoral artery closure after diagnostic or interventional procedures., Methods: The first European safety study was performed at the Centro Cardiologico Monzino in Milan, Italy, on January 2010. Forty consecutive patients (75% male, mean age 68 ± 11years) undergoing diagnostic angiography (62%) or PCI (38%) by femoral approach with a 6- (90%) or 7-Fr (10%) size introducer, received arterial sheath removal with the QuikClot Interventional gauze use. The mean ACT value at hemostasis time was 138 ± 24s (range 95-186s). Hemostasis was achieved in a mean time of 4.9 ± 0.5 min. Only one hemostasis failure occurred requiring prolonged mechanical compression. Neither major bleeding, re-bleeding nor hematoma occurred after early (4h after procedure) ambulation., Conclusions: QuikClot Interventional Bandage obtained prompt hemostasis and allowed for an early ambulation without clinical complications., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

We previously reported that motion sickness was prevented in rats with amygdala lesion and that provocative motion stimuli increased the number of Fos-positive neurons in the amygdala, suggesting that the amygdala is one of the neural substrates involved in the development of motion sickness. NK-1 receptors in the brain stem and amygdala are thought to play an important role in emesis and affective disorders, respectively. In the present study, to elucidate a role of substance P neuronal system and NK-1 receptors in the brain stem and amygdala in the development of motion sickness, we measured changes in gene expression of NK-1 receptors and preprotachykinin, a precursor of substance P, using quantitative real-time PCR methods in solitary tract nucleus and amygdala in rats after provocative motion stimuli induced by 2G hypergravity load. Effects of systemic administration of CP-99,994, an antagonist for NK-1 receptors, on hypergravity-induced motion sickness were also examined using pica behavior, eating non-nutritive substances such as kaolin, as an index of motion sickness in rats. Hypergravity-induced motion sickness was inhibited by CP-99,994 with a dose-dependent and enantioselective manner. Preprotachykinin mRNA expression was increased in basolateral nucleus of amygdala and solitary tract nucleus after hypergravity load for 3h, whereas NK-1 receptor mRNA expression was not changed by hypergravity in amygdala and solitary tract nucleus. Present results suggest that 2G hypergravity load activated the substance P neuronal system in amygdala as well as in the brain stem and this activation would be related to the development of motion sickness., (Copyright © 2011 Elsevier B.V. All rights reserved.)

It is known that pica, the consumption of non-nutritive substances such as kaolin, can be induced by administration of toxins or emetic agents in rats. In the present study, we examined the effects of intraperitoneal (i.p.) administration of cyclophosphamide on pica behavior and on the concentration of 5-hydroxyindoleacetic acids (5HIAA) in cerebrospinal fluid (CSF) in the following five strains of adult male rats: Sprague Dawley (SD), Wistar, Fischer 344 (F344), Wistar-Imamichi (WI) and Long Evans (LE). Cyclophosphamide (25 mg or 50 mg/kg) was injected (i.p.) into the rats and kaolin and food intake were measured at 24 hr after injection. The animals were anesthetized with urethane (1 g/kg) at 3 hr after injection of cyclophosphamide, and CSF was collected from the cisterna magna. WI and LE rats clearly showed pica behavior as compared with the other strains. In LE rats, the concentration of 5HIAA in CSF also increased in a dose-dependent manner of cyclophosphamide. The pretreatment with ondansetron (5-HT(3) antagonist) restored both changes (kaolin consumption and 5HIAA levels) induced by cyclophosphamide. These results suggest that the LE rat is sensitive to cyclophosphamide, that pica induced by cyclophosphamide mimics many aspects of emesis including the serotonergic response in the central nervous system and that use of the pica model would be a practical method for evaluating the effects of antiemetic drugs in addition to the mechanism of emesis.

Object: Hydrocephalus is a pathological enlargement of the ventricles of the brain, which can result from various diseases of the central nervous system. Patients with hydrocephalus frequently show motor abnormalities, such as abnormal gait and posture, as well as intellectual and emotional impairment. The present study was designed to investigate anxiety responses in rats with kaolin-induced hydrocephalus., Methods: A total of 26 Sprague-Dawley rats were used for this study. Hydrocephalus was induced in 14 Sprague-Dawley rats by injecting 0.1 ml of 20% kaolin solution into the cisterna magna; 12 rats were administered the same volume of saline in the same fashion and served as controls. Seven of the rats that were injected with kaolin and 6 of the rats injected with saline were killed 3 days after injection (Group 1); the remaining rats were killed 4 weeks after injection (Group 2) to evaluate effects related to acute and chronic hydrocephalus. The rats were tested in an elevated plus maze after induction of hydrocephalus by kaolin injection. After the animals were killed, brain sections were immunostained for cholecystokinin and neuropeptide Y. In addition, tyrosine hydroxylase immunoreactivity in the ventral tegmental area was evaluated by immunohistological staining., Results: The rats with acute hydrocephalus showed decreased entry into and spent less time in the open arms of the elevated plus maze as compared with the control rats. The hydrocephalic rats had significantly more cholecystokinin-immunoreactive neurons and fewer neuropeptide Y-immunoreactive neurons in their brains. In addition, hydrocephalus progress in this model was positively correlated with the anxiety response. The numbers of tyrosine hydroxylase-immunoreactive neurons were decreased significantly in the hydrocephalic rats as compared with the control rats., Conclusions: These results suggest that the rat model of hydrocephalus is characterized by increased anxiety response and is associated with the functional impairment of the central dopamine system.

Introduction: We have reported that pica, kaolin ingestion behavior, correlates with nausea and vomiting in rats and the amount of kaolin intake is related to the severity of symptoms. However, the time course of the behavior is still unclear, because kaolin intake has been measured 24h after administration of an emetic stimulus. It is quite difficult and troublesome to determine kaolin intake manually at short time intervals without affecting the animal's behavior. In the present study, we investigated the time course of radiation or chemotherapeutic agent-induced pica in rats using an automatic feeding monitoring system (FDM700SW)., Methods: Rats received total body X-ray irradiation (4 Gy), or i.p. administration of cisplatin (6 mg/kg) or cyclophosphamide (120 mg/kg) with or without pretreatment of 5-HT(3) receptor antagonist, granisetron (0.1mg/kg, i.p.), then their kaolin and food intake were monitored hourly for 24h after the emetic stimuli., Results: Total body irradiation and i.p. injection of cisplatin or cyclophosphamide induced pica within 3h of the administration and the pica persisted for 12, 8 and 16 h after the emetic stimuli, respectively. Granisetron delayed the latency and inhibited the amount of kaolin intake. X-ray and chemotherapeutic agents induced anorexia in all rats, but anorexia was not recovered by pretreatment with granisetron., Discussion: These results suggested that both the latency and the duration of pica are similar to the clinical evidence of radiation or chemotherapy-induced nausea and vomiting in human patients and this monitoring system is useful to evaluate the emetogenic potential of drugs and other medical intervention in preclinical studies., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Standard gauze field dressings and direct pressure occasionally are inadequate for the control of hemorrhage. QuikClot® Combat Gauze™ (QCG) combines surgical gauze with an inorganic material and is approved by the Food and Drug Administration and by the Israeli Standards Institute for external hemorrhage control. The purpose of this article is to report clinical use of this dressing during Operation Cast Lead in the Gaza strip during January 2009., Methods: QuikClot Combat Gauze and the QCG guidelines were issued to advanced life support (ALS) providers during the preparations for the Operation. All cases of injuries involving hemorrhage were reviewed, as well as interviews with the ALS providers (physicians and paramedics) and injured soldiers., Results: Fourteen uses of QCG were reported and reviewed (out of a total of 56 hemostatic interventions in 35 cases). Dressings were applied to injuries to the head, neck, axilla, buttocks, abdomen, back, and pelvis in 10 cases, and to extremities in four cases. In 13 cases (93%), injuries were caused by blast or gunshot mechanisms. The success rate was reported as 79% (11/14). Failure to control hemorrhage was reported in three cases in three different locations: neck, buttock, and thigh. All failures were attributed to severe soft tissue and vascular injuries. No complications or adverse events were reported., Conclusions: This report on the clinical field use of the QCG dressing by ALS providers suggests that it is an effective and safe product, and applicable for prehospital treatment of combat casualties. This report further suggests that QCG should be issued to medics as well as ALS providers. Larger clinical investigations are needed to confirm these findings.

Background: In 2007, a potent procoagulant mineral called WoundStat (WS), consisting of smectite granules, received clearance from the Food and Drug Administration for marketing in the United States for temporary treatment of external hemorrhage. Previously, we found that microscopic WS particles remained in the injured vessels that were treated, despite seemingly adequate wound debridement. Thus, we investigated the thromboembolic risk of using WS when compared with kaolin-coated gauze, Combat Gauze (CG); or regular gauze, Kerlix (KX) to treat an external wound with vascular injuries in pigs., Methods: The right common carotid artery and external jugular vein of pigs were isolated and sharply transected (50%). After 30 seconds of free bleeding, the neck wounds were packed with WS, CG, or KX and compressed until hemostasis was achieved (n = 8 per group). Wounds were debrided after 2 hours, and vascular injuries were primarily repaired with suture. Blood flow was restored after infusing 1 L of crystalloid (no heparin or aspirin) and the wounds were closed. Two hours later, computed tomographic angiography was performed, and the wounds were reopened to harvest the vessels. The brains and lungs were recovered for gross and microscopic examination after euthanasia., Results: No differences were found in baseline measurements. Thrombelastography showed similar hypercoagulability of the final blood samples when compared with baselines in all groups. All vessels treated with KX or CG were patent and had no thrombus or blood clot in their lumen. In contrast, seven of eight carotid arteries and six of eight jugular veins treated with WS developed large occlusive red thrombi and had no flow. Small clots and WS residues were also found in the lungs of two pigs. Histologically, significant endothelial and transmural damage was seen in WS-treated vessels with luminal thrombi and embedded WS residues., Conclusion: WS granules caused endothelial injury and significant transmural damage to the vessels that render them nonviable for primary surgical repair. The granules can enter systemic circulation and cause distal thrombosis in vital organs. More relevant in vitro and in vivo safety tests should be required for clearance of new hemostatic agents.

Consumption by animals and humans of earthy materials such as clay is often related to gut pathologies. Our aim was to determine the impact of kaolinite ingestion on glucose and NEFA transport through the intestinal mucosa. The expression of hexose transporters (Na/glucose co-transporter 1 (SGLT1), GLUT2, GLUT5) and of proteins involved in NEFA absorption (fatty acid transporter/cluster of differentiation 36 (FAT/CD36), fatty acid transport protein 4 (FATP4) and liver fatty acid binding protein (L-FABP)) was measured (1) in rats whose jejunum was perfused with a solution of kaolinite, and (2) in rats who ate spontaneously kaolinite pellets during 7 and 28 d. Also, we determined TAG and glucose absorption in the kaolinite-perfused group, and pancreatic lipase activity, gastric emptying and intestinal transit in rats orally administered with kaolinite. Glucose absorption was not affected by kaolinite perfusion or ingestion. However, kaolinite induced a significant increase in intestinal TAG hydrolysis and NEFA absorption. The cytoplasmic expression of L-FABP and FATP4 also increased due to kaolinite ingestion. NEFA may enter the enterocytes via endocytosis mainly since expression of NEFA transporters in the brush-border membrane was not affected by kaolinite. After uptake, rapid binding of NEFA by L-FABP and FATP4 could act as an intracellular NEFA buffer to prevent NEFA efflux. Increased TAG hydrolysis and NEFA absorption may be due to the adsorption properties of clay and also because kaolinite ingestion caused a slowing down of gastric emptying and intestinal transit.

Although some of the effects of clay ingestion by humans and animals, such as gastrointestinal wellness and the increase in food efficiency are well known, the underlying mechanisms are not yet fully understood. Therefore, the interactions between the intestinal mucosa and kaolinite particles and their effects on mucosal morphology were observed using light microscopy (LM), transmission electron microscopy (TEM), conventional (CSEM) and environmental (ESEM) scanning electron microscopy combined with an EDX micro-analysis system. Kaolinite consumption, given with free access to rats, varied considerably from one animal to the other but was regular through time for each individual. Some kaolinite particles appeared chemically dissociated in the lumen and within the mucus barrier. Aluminium (Al) originating from ingested clay and present in the mucus layer could directly cross the intestinal mucosa. A significant increase in the thickness of the villi with large vacuoles at the base of the mucosal cells and a decrease in the length of enterocyte microvilli characterized complemented animals. The proteomic analyses of the intestinal mucosa of complemented rats also revealed several modifications in the expression level of cytoskeleton proteins. In summary, kaolinite particles ingested as food complement interact with the intestinal mucosa and modify nutrient absorption. However, these data, together with the potential neurotoxicity of Al, need further investigation.

We evaluated long-term dynorphin A-immunoreactivity in the rat area postrema (AP) after the administration of cisplatin. First, rats were given 1, 5 and 10mg/kg body weight cisplatin (i.p.) and their behavior was monitored for 72h. We observed a delayed increase in pica 24-72h after injection, compared to the 24h before injection. We attributed this to the cisplatin injection. Pica was defined as an increase in the intake of non-nutritional matter such as kaolin. Administration of 1, 5 and 10mg/kg cisplatin led to an increase in kaolin intake on day 1. Administration of 5 and 10mg/kg of cisplatin led to decreased intake of laboratory chow (MF) on days 1-3, but 10mg/kg cisplatin causes an excessive aggravation of their condition. Following this behavioral experiment, we immunohistochemically examined the induction of dynorphin A in the AP at 24, 48 and 72h post-administration of 1 and 5mg/kg cisplatin. Administration of 5mg/kg cisplatin caused dynorphin A to accumulate gradually in the neurosoma of the AP neurons, and the numbers of positive AP neurosomata at 48 and 72h post-administration were higher than following an equal dosage of 0.9% NaCl. These findings suggest that dynorphin A increases in the central nervous system for a long time following administration, and causes certain behavioral and clinical changes, including those related to appetite and nausea.

Cancer chemotherapy is frequently accompanied by severe emesis. The anti-cancer drugs are classified according to their clinical emetogenic potential. We have already found that kaolin ingestion behavior "pica" is analogous to emesis in rats. The aim of this study was to examine the effects of the clinical emetogenic potential of anti-cancer drugs on the induction of the pica in rats. Rats were housed in individual cages with free access to food and kaolin pellets and the daily food and kaolin intakes were measured for 3 days after the intraperitoneal administration of anti-cancer drugs (cisplatin, cyclophosphamide, actinomycin D, 5-fluorouracil and vincristine). The drugs with high potential for inducing emesis, such as cisplatin and cyclophosphamide, induced pica in all animals on the day of administration and the behavior lasted during the observation period. The drugs with moderate emetogenic potential, i.e. actinomycin D and 5-fluorouracil, also induced pica on the first and second day after the drug administration but the kaolin intake was less than that of the drugs with high potential. Vincristine, a drug with low emetogenic potential, slightly increased the kaolin intake in rats on the only first day of the administration. Cyclophosphamide, actinomycin D and vincristine induced anorexia and decreased their body weight during the observation period. These results suggested that the both amounts of kaolin intake and duration of behavior in the anti-cancer drug-induced pica are related to the clinical emetogenic potential of the drugs and the incidence of the anorexia is not related to their emetogenic potential.

Background: Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents., Objective: To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity., Methods and Results: High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 microg/kg/day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 microg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 microg/kg/day (P<0.05). Decreased body weight gain was associated with a significant decrease in fat mass (P<0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (P<0.05). Exenatide at 10 microg/kg significantly reduced food intake (P<0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity., Conclusion: Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.

In animals without the emetic reflex, several emetogenic stimuli induce pica, an altered feeding behaviour consisting of the ingestion of non-nutritive substances. The development of pica in response to an emetogenic stimulus has been proposed to be useful as an indirect marker of nausea in the rat. In fact, like nausea and emesis in humans, it is accompanied by serotonin release from the enterochromaffin cells, increased c-fos labelling in the area postrema and the nucleus tractus solitarius, and a delay in gastric emptying. Furthermore, pica, measured as kaolin intake, is reduced by anti-emetic drugs. Pica has been demonstrated after single doses of cisplatin, the most emetogenic chemotherapeutic drug. However, cisplatin, as other antineoplastic drugs, is generally given in cycles, where conventional anti-emetics tend to lose efficiency. The aim of this work was to evaluate the pica induced by long-term treatment with cisplatin. Saline or cisplatin was administered once a week for 5 consecutive weeks, and temperature, body weight, food ingestion and kaolin intake were measured on a daily basis. The influence of isolation (pica is necessarily studied in isolated animals) and exposure to kaolin (basal kaolin intake could modify pica itself and other parameters) on temperature, body weight and daily food ingestion was negligible in saline-treated rats. Cisplatin administered at 3 mg/kg/week was too toxic: it produced hypothermia, weight drop and anorexia in both grouped and isolated rats, and 50% mortality in isolated animals. Toxicity associated with cisplatin administered at 1 mg/kg/week was acceptable, with a slower rate of weight gain being the major effect. In these rats, each cisplatin injection produced both acute anorexia and rebound hyperphagic responses. In addition, each administration induced both acute pica and an increase in basal kaolin intake, resembling the development of nausea in humans. This model could be useful for studying both the mechanisms leading to nausea associated with a long-term antineoplastic treatment and the efficiency of new anti-emetic drugs.