Search

This study introduces a groundbreaking method to enhance the accuracy and reliability of emotion recognition systems by combining electrocardiogram (ECG) with electroencephalogram (EEG) data, using an eye-tracking gated strategy. Initially, we propose a technique to filter out irrelevant portions of emotional data by employing pupil diameter metrics from eye-tracking data. Subsequently, we introduce an innovative approach for estimating effective connectivity to capture the dynamic interaction between the brain and the heart during emotional states of happiness and sadness. Granger causality (GC) is estimated and utilized to optimize input for a highly effective pre-trained convolutional neural network (CNN), specifically ResNet-18. To assess this methodology, we employed EEG and ECG data from the publicly available MAHNOB-HCI database, using a 5-fold cross-validation approach. Our method achieved an impressive average accuracy and area under the curve (AUC) of 91.00 % and 0.97, respectively, for GC-EEG-ECG images processed with ResNet-18. Comparative analysis with state-of-the-art studies clearly shows that augmenting ECG with EEG and refining data with an eye-tracking strategy significantly enhances emotion recognition performance across various emotions.

Researchers suggest that a short video clip, when tagged with a single label, is sufficient for classification into an emotional category. However, when subjects view an emotional film tagged similarly, there is no guarantee that the designated emotion persists throughout the duration, or when exactly the emotion is elicited. This inconsistency adversely affects the performance of emotion recognition (ER) systems. In this study, we propose a multimodal ER system employing an eye-tracking gated strategy to identify the most effective timing for emotional categorization. Initially, common eye-tracking features are extracted and selected using the minimum-redundancy-maximum-relevance (mRMR) method. Subsequently, the most discriminative feature is employed as a threshold to pinpoint the most relevant timing. EEG signals from these moments are then decomposed into five standard frequency bands using the Daubechies wavelet function (order 4). Furthermore, four types of entropy features are extracted from four-second segments of 62 and 32 channels for the SEED-IV and MAHNOB-HCI databases, respectively. The best features, as determined by the mRMR method, are fed into a Sugeno-fuzzy inference system (S-FIS) designed to derive rules for discriminating between the four emotional categories of happiness, fear, sadness, and neutrality. The S-FIS rules were refined using a genetic algorithm (GA), leading to most discriminative rules achieving average accuracies of 94.42% and 85.20% for the alpha frequency bands of the SEED-IV and MAHNOB-HCI databases, respectively. The results of this study demonstrate the effectiveness of fuzzy rule extraction in enhancing the performance of multimodal ER systems

The study was conducted to evaluate the effects of increasing doses: 0 (control), 0.20, 0.40, 0.60, 0.80 and 1.00 % DM of an exogenous fibrolytic enzymes (EFE) cocktail preparation on in vitro gas production (GP), nutrient degradability and fermentation characteristics of oats straw based Total Mixed Ration (TMR) with 60:40 roughage to concentrate ratio using sheep rumen liquor. The chemical composition of all the feed ingredients used for preparation of the experimental TMR (containing 16.63% crude protein and 90.51% organic matter) were within the normal ranges. Increasing the incorporation level of enzyme cocktail linearly as well as quadratically increased net GP, metabolisable energy content, short chain fatty acid concentrations and microbial crude protein production up to 0.60% DM level (L3) with no additional improvement at further higher levels. There were significant improvements in degradability of dry matter, organic matter and neutral detergent fibre up to the enzyme dose of 0.60% DM (L3) with constant values thereafter. Fermentation characteristics response to varying incorporation doses of EFE cocktail also revealed improvements up to 0.60% DM level (L3) with no effect on non-protein nitrogen contents. It is recommended that EFE cocktail incorporation dose of 0.60% DM to be used for efficient utilisation of oats straw based complete feed; however, this requires further testing by in vivo studies.

The present experiment was conducted to evaluate the palatability, growth and economics of the silkworm pupae meal (SWPM) feeding, replacing fish meal (FM) in cattle calves. Crossbred cattle calves (15) around one-month of age were selected for the study and were divided into three equal groups (n=5) viz., T0 (100% FM), T1 (75% FM: 25% SWPM) and T2 (50% FM: 50% SWPM). To estimate the growth parameters fortnightly, a growth trial of 90 days was conducted, and a digestibility trial of 7 days was conducted at the end of experiment. The results revealed non-significant differences between the experimental groups in DMI, OMI, periodical body weight, body weight gain, average daily gain (ADG) (g/d), feed conversion ratio (FCR), feed conversion efficiency (FCE) (%), digestibility coefficients of dry matter (DM), organic matter (OM) and crude protein (CP). Significant differences were observed in digestibility coefficients of crude fibre (CF), ether extract (EE) and nitrogen free extract (NFE) between the groups. The digestible nutrients intake revealed significant difference only in CPI (g/d) with higher values in T0 followed by T1 and T2, but non-significant differences were observed in DDMI, DCPI and TDNI. The economics of feeding showed a decrease in the feed cost and feeding cost per kg body weight gain with increased inclusion of SWPM. Thus, it is concluded that costly FM can be replaced upto 50% level by SWPM without any adverse effect on feed intake, growth and nutrient utilization of crossbred cattle calves.

The effect of Saffron petals (agricultural by-product) on health and production performance was investigated in broiler chicken. In this experiment, 140-day-old chicks were randomly distributed in five groups each having four replicates of seven chicks. The birds of control group (T0) were offered basal diet without feed additives whereas, birds of treatments T1, T2, T3 and T4 were given a basal diet supplemented with ground saffron petals (SP) as feed additive at an inclusion level of 0.5, 1.0, 1.5 and 2.0 g/kg feed on dry matter basis. The overall temperature and humidity of the experimental shed were 23.43 °C & 55.19% during the day and 23.17 °C & 56.01% during the night. The SP as feed additive contained 83% dry matter, 11.94% crude protein, 5.03% ether extract and 7.85% crude fiber. The feed intake during the experiment was not affected, however total body weight gain was significantly (p ≤ 0.05) higher in T3 and T4 as compared to control (T0) with better FER. The SP in the diet improved nutrient digestibility with better economical returns. The study revealed a non-significant change in the overall haematological parameters viz. Hb, PCV, RBC and WBC The plasma glucose increased proportionately with the inclusion level of petals, being significantly (p ≤ 0.05) higher in T2, T3 and T4. The immune parameters reflected a significant (p ≤ 0.05) increase in HI titre at days 21 and 28 in different SP supplemented groups. The response to DNCB (mm) was highest in the birds of T3 group. The SP feeding leads to an increase in the weight of immune organs, significantly (p ≤ 0.05) in Spleen. Similarly, the biochemical parameters indicated an improved lipid profile with cholesterol and triglycerides decreasing significantly (p ≤ 0.05) in the T4 group. The total oxidant status and total antioxidant status showed a significant (p ≤ 0.05) improvement and revealed figures of 6.30 ± 0.12 μmol H2O2 Eq/L and 1.46 ± 0.03 μmol Trolox Eq/L, respectively in T4 group. Likewise, T-BARS in breast and thigh showed a significant (p ≤ 0.05) decline as the SP level increased in ration. Significantly (p ≤ 0.05) improvement dressing percentage was recorded in T3 and T4 treatments as compared to control (T0). The Cutability (%) of Breast, Back, Drumstick, Thighs, Wings, Neck and total Giblet did not differ significantly among treatments as compared to the control. The production cost per kg live weight was least in T4 group and highest in control (T0). The results of this study indicate superior immunity, health, carcass quality and production performance in saffron petal supplemented birds. Hence, its use as a feed additive at 2 g/kg in poultry diets is a viable proposition to improve poultry production performance.

Background and Purpose To evaluate the ability of cannabidiolic acid ( CBDA) to reduce nausea and vomiting and enhance 5- HT1A receptor activation in animal models. Experimental Approach We investigated the effect of CBDA on (i) lithium chloride ( LiCl)-induced conditioned gaping to a flavour (nausea-induced behaviour) or a context (model of anticipatory nausea) in rats; (ii) saccharin palatability in rats; (iii) motion-, LiCl- or cisplatin-induced vomiting in house musk shrews ( Suncus murinus); and (iv) rat brainstem 5- HT1A receptor activation by 8-hydroxy-2-(di- n-propylamino)tetralin (8- OH-DPAT) and mouse whole brain CB1 receptor activation by CP55940, using [35 S] GTPγ S-binding assays. Key Results In shrews, CBDA (0.1 and/or 0.5 mg·kg−1 i.p.) reduced toxin- and motion-induced vomiting, and increased the onset latency of the first motion-induced emetic episode. In rats, CBDA (0.01 and 0.1 mg·kg−1 i.p.) suppressed LiCl- and context-induced conditioned gaping, effects that were blocked by the 5- HT1A receptor antagonist, WAY100635 (0.1 mg·kg−1 i.p.), and, at 0.01 mg·kg−1 i.p., enhanced saccharin palatability. C BDA-induced suppression of LiCl-induced conditioned gaping was unaffected by the CB1 receptor antagonist, SR141716A (1 mg·kg−1 i.p.). In vitro, CBDA (0.1-100 nM) increased the Emax of 8- OH-DPAT. Conclusions and Implications Compared with cannabidiol, CBDA displays significantly greater potency at inhibiting vomiting in shrews and nausea in rats, and at enhancing 5- HT1A receptor activation, an action that accounts for its ability to attenuate conditioned gaping in rats. Consequently, CBDA shows promise as a treatment for nausea and vomiting, including anticipatory nausea for which no specific therapy is currently available. [ABSTRACT FROM AUTHOR]

Background. Oral direct-acting antivirals (DAAs) provide an exceptional opportunity to treat hepatitis C virus (HCV) infection. Goals. We compared the treatment outcomes between specialty and primary care physician (PCP) clinics for patients treated with DAAs. Methods. We performed a retrospective analysis of patients treated for HCV in our PCP clinics and specialty; liver and gastroenterology clinics and gastroenterology clinics. We used the two-sided t-test and the chi-square test to compare the means of continuous and categorical variables, respectively. Results. Data from a total of 377 patients was analyzed (PCP clinic: n=185 and specialty clinic: n=192). There was no significant difference between age, race, and gender. Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) scores were comparable at baseline. Greater than 90% of the patients achieved sustained virological response (SVR) with no difference between the groups. Conclusions. Uncomplicated patients can be treated for hepatitis C by their PCPs with DAAs with similar treatment outcomes to specialty clinics. There should be explicit guidelines on patient eligibility for treatment by PCPs vs. specialists.

Mysterious aspects of the long presumed to be well-known hepatitis E virus (HEV) have recently surfaced that distinguish it from other hepatotropic viruses. It is a cause of chronic hepatitis in immunosuppressed patients. It has human to human transmission through blood and mantains high seroprevalence in blood donors. HEV has also been found to occur more frequently in the West in those without a history of travel to endemic countries. It has varied extrahepatic manifestations and has multiple non-human reservoirs including pigs and rats. Considering these recent discoveries, it appears odd that HEV is not sought more frequently when working up acute and chronic hepatitis patients. The disease is particularly severe among pregnant women and has a high attack rate in young adults. What adds to its ambiguity is the absence of a well-established diagnostic criteria for its detection and that there is no specific antiviral drug for hepatitis E, except for isolated cases where ribavirin or pegylated interferon alpha has been used with occasional success. This review paper discusses the recent advances in the knowledge of the virus itself, its epidemiology, diagnostic approach and prevention, and the treatment options available.

Aim: Cannabis-based medication has recently been made available in the NHS for reducing pain and spasticity in patients with multiple sclerosis (MS). The currently available preparation of Sativex (nabiximols) contains a combination of botanical cannabis extracts with cannabidiol (CBD) and tetrahydrocannabinol (THC) with almost equal amounts in addition to minor cannabinoids and terpenoids and is delivered via an oro-mucosal spray. The present study aims to examine the use and trends in prescribing cannabinoid-based Sativex to control pain in patients diagnosed with MS., Methods: Primary care prescribing data for cannabinoid-based Sativex (2013-2022) from the Prescription Cost Analysis were extracted and analysed. Linear regression analyses were performed to examine prescription trends and prescription costs (average change per year)., Results: There was a general increasing trend in the number of prescriptions each year, from 4.42 items dispensed per 100,000 people in 2013 to 5.15 in 2022. Overall, prescription items for cannabinoid-based Sativex increased by 0.34% per year (95% CI:-3.98, 4.67, p  = 0.860) on average between 2013 and 2022. On average, a 2.43% (95% CI: -5.78, 0.92, p  = 0.133) increase per year was observed for the costs of cannabinoid-based Sativex from 2013 to 2022., Conclusion: The results suggested that cannabinoid-based Sativex should be considered an option due to its effectiveness, acceptable tolerance, and safety profile in the prescribing of Sativex., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Cannabinoids have been shown to induce anti-tumor activity in a variety of carcinoma cells such as breast, prostate, and brain. The aim of the present study is to investigate the anti-tumor activity of cannabinoids, CBD (cannbidiol), and CBG (cannabigerol) in ovarian carcinoma cells sensitive and resistant to chemotherapeutic drugs. Sensitive A2780 cells and resistant A2780/CP70 carcinoma cells and non-carcinoma cells were exposed to varying concentrations of CBD, CBG, carboplatin or CB 1 and CB 2 receptor antagonists, AM251 and AM630, respectively, alone or in combination, at different exposure times and cytotoxicity was measured by MTT assay. The mechanism of action of CBD and CB in inducing cytotoxicity was investigated involving a variety of apoptotic and cell cycle assays. Treatment with CBD and CBG selectively, dose and time dependently reduced cell viability and induced apoptosis. The effect of CBD was stronger than CBG in all cell lines tested. Both CBD and CBG induced stronger cytotoxicity than afforded by carboplatin in resistant cells. The cytotoxicity induced by CBD was not CB 1 or CB 2 receptor dependent in both carcinoma cells, however, CBG-induced cytotoxicity may involve CB 1 receptor activity in cisplatin-resistant carcinoma cells. A synergistic effect was observed when cannabinoids at sublethal doses were combined with carboplatin in both carcinoma cells. The apoptotic event may involve loss of mitochondrial membrane potential, Annexin V, caspase 3/7, ROS activities, and cell cycle arrest. Further studies are required to investigate whether these results are translatable in the clinic. Combination therapies with conventional cancer treatments using cannabinoids are suggested., (© 2023 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

It is known that gynecological cancers remain a worldwide problem and as shown by the statistics, there is a need for new gynecological cancer treatments. Cannabinoids, the pharmacologically active compounds of the Cannabis sativa plant, have been used for many centuries by individuals as a symptomatic treatment to alleviate pain, nausea, vomiting, and to help stimulate appetite. Research has revealed that cannabinoids also exert anti-cancer activity such as anti-proliferative and pro-apoptotic effects through a variety of mechanisms. There is significant value in the development of these compounds as anti-cancer therapies in clinical practice as they do not produce the typical toxic side effects that exist with conventional therapies and recent clinical trials have shown their great tolerability by patients at high doses. Cannabinoids can induce psychoactive effects that could limit their progression. Therefore, non-psychoactive cannabinoids are attracting pharmacological interest due to their inability to produce psychological effects. Recent studies have focussed on non-psychoactive cannabinoids in ovarian cancer and have revealed promising pre-clinical results that indicate that these compounds may have potential benefits in the treatment of these cancers. However, there are still unanswered questions and research gaps that need to be addressed. This review summarizes the current understanding of this topic and identifies the current gaps in knowledge that provide a useful direction for future work., (© 2023 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Background: Electronic repeat dispensing (eRD) has been part of the community pharmacy contact since 2005 and a requirement in the General Medical Services contract since 2019. NHS England highlights benefits of eRD as increased efficiency in general practice of 2.7 million hours annually if 80% of all repeat prescriptions are issued as eRD. Despite clear benefits to patients, community pharmacies and general practices, the uptake of eRD remains low and variable across general practices in West Yorkshire, UK., Objectives: To investigate the impact of COVID-19 on eRD in general practice and understand the key enablers to its uptake., Methods: A 19-item questionnaire was developed and piloted during cognitive interviews. A cross-sectional survey was conducted via emails to general practices in West Yorkshire, UK, between July 2020 and November 2020., Results: Sixty-seven complete responses were received (23 pharmacists, 21 practice managers, 11 general practitioners, seven pharmacy technicians, four advanced practitioners, one prescription clerk). 59% of respondents were aware of eRD uptake in their surgery (mean value 4.56% ± 0.229%). Higher uptake of eRD was demonstrated where the general practice integrated eRD into routine workflows during the repeat prescription reauthorisation process (P < 0.001) and where an eRD service lead is nominated (P = 0.04)., Conclusion: Utilising eRD in the respective practices should be considered due to potential efficiency gains and the increase in average eRD utilisation observed in the study participating general practices was from 7.2% average uptake in March 2020 to 10.4% November 2020, as the response to COVID-19. The stated benefits of eRD by NHS England of 2.7 million hours per annum predates the roll out of electronic transmission of prescriptions suggesting further research is needed to quantify the efficiency gains in present NHS general practice environments., (© 2023. The Author(s).)

Attempts were made to review the literature on diabetic patients who experience complications when they contract COVID-19, and to determine whether ethnicity and other risk factors play an important role in the development of symptoms and their severity, as well as responding to medications. A literature search was performed using five keywords, namely COVID-19, diabetes, ethnicity, medications, and risk factors between January 2019 and December 2020 using electronic databases such as PubMed, Science Direct, Google Scholar, Springer Link, and Scopus. Forty studies were included. The review indicated that diabetes was a significant risk factor for poorer outcomes and increased mortality associated with COVID-19. There were several risk factors for diabetic patients that increased their likelihood of poorer outcomes associated with COVID-19. These included black and Asian ethnicity, male sex with high BMI. In conclusion, patients with diabetes of black or Asian origin with high BMI, male sex, and older age had an increased risk of poorer outcomes associated with COVID-19. This highlights the importance of considering the history of the patient in prioritising care and treatment., (© 2023. The Author(s).)

Gynaecological cancers continue to present a significant health burden upon the health of the global female population. This deficit is most prominent with ovarian cancer which possesses the lowest survival rate compared to all other cancers occurring within this anatomical region, with an annual UK-mortality of 7,300. The poor tolerability and selectively of the treatment options that are currently available is likely to have contributed to this high mortality rate thus, demonstrating the need for the development of enhanced therapeutic approaches. Aptamer technology would involve the engineering of specifically sequenced oligonucleotide chains, which bind to macromolecular targets with a high degree of affinity and selectively. Recent in-vitro studies conducted upon the clinical utility of this technique have supported its superiority in targeting individual therapeutic drug targets compared to various other targeting moieties currently within therapeutic use such as, monoclonal antibodies. For this reason, the employment of this technique is likely to be favourable in reducing the incidence of non-specific, chemotherapy-associated adverse effects. Kisspeptin is a naturally expressed polypeptide with an established role in the development of the reproductive system and other proposed roles in influencing the ability of ovarian cancer growths to exhibit the metastasis hallmark. This distinctive feature would indicate the potential for the manipulation of this pathway through the application of aptamer structures in developing a novel prophylactic strategy and improve the long-term outcome for ovarian cancer patients., (Copyright © 2022. Published by Elsevier B.V.)

The aim of the present study was to investigate the cytotoxicity induced by an omega-3 derivative, didocosahexaenoin (Dido) on human prostate carcinoma cells and to compare the cytotoxicity to that of docosahexaenoic acid (DHA). Different carcinoma- and non-carcinoma cells were exposed to various concentrations of omega-3 compounds at varying exposure times and the cytotoxicity was measured by MTT assay. The mechanism of Dido-induced apoptosis was investigated in prostate carcinoma cells. Dido induced stronger cytotoxicity than DHA in human prostate carcinoma cells in a dose- and time-dependent manner. Dido was also more selective and potent in inducing cytotoxicity in prostate carcinoma cells than other carcinoma cell lines tested. Pre-treatment with Dido increased the level of reactive oxygen species (ROS) in prostate carcinoma cells. Pre-treatment with various antioxidants reduced the cytotoxicity induced by Dido. Pre-treatment with Dido ≥30 ​μM also induced apoptosis which was suggested to involve an externalisation of phosphatidyl serine, a significant increase in the mitochondrial membrane potential (p ​< ​0.01) and the level of activated caspase 3/7 (p ​< ​0.05) in prostate carcinoma cells. This study is the first to show that Dido induced cytotoxicity with high selectivity and higher potency than DHA in human prostate carcinoma cells. The mechanism of action is likely to involve an increase in the level of ROS, loss in the mitochondrial membrane potential as well as externalisation of phosphatidyl serine and increase in the caspase 3/7 activity. Dido may have potential to be used for the adjuvant therapy or combination therapy with conventional chemotherapeutic drugs., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Glenn Robinson reports financial support was provided by Dr Brian Whittle Ltds., (Crown Copyright © 2022 Published by Elsevier B.V.)

Background and Objective: The present survey was a preliminary to a European research project on the attitude and knowledge of healthcare professionals towards the use of medical cannabis. The objective was to evaluate the readability, understandability, and relevance of a first version of the study questionnaire before preparing the finalized questionnaire, which will be subsequently proposed to European healthcare professionals on a large scale., Methods: A cross-sectional study was conducted between December 2019 and May 2020. We established an electronic evaluation questionnaire relating to the study questionnaire. This evaluation questionnaire was proposed to multidisciplinary experts from all over Europe. Feedback from the evaluation questionnaire was considered for improving and finalizing the study questionnaire., Results: 66 evaluation questionnaires were collected from nine European countries (Cyprus, France, Germany, Italy, Lithuania, Portugal, Spain, Sweden, United Kingdom), which corresponded to a participation rate of 41.5%. Most participants were women (65.2%, n = 43). The mean age was 39.5 years ± 11.6. Each participant could specify several occupations. There were 25 pharmacologists, 24 physicians, ten pharmacists, four university teachers, three epidemiologists or public health experts, one nurse, one biotechnologist, one microbiologist, and one police researcher. Overall, 84.8% of participants were interested in the topic of the survey on the knowledge and attitudes of healthcare professionals towards recreational and medical cannabis across Europe. Participants were satisfied with all but six of the proposed questions. In addition, two additional questions were subject for comments despite a high level of satisfaction. Consequently, the concerned questions (n = 8) were modified., Conclusion: This evaluation survey was a necessary step to improve the quality of the future research project. The positive feedback encourages the authors to proceed with the project on a European scale, scheduled for 2021., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To determine the frequency of beta s globin gene haplotypes in Nigerian patients with sickle cell disease (SCD) and to measure their correlation with clinical and haematological characteristics., Methods: This study enrolled patients with SCD and collected their peripheral blood for restriction fragment length polymorphism analysis in order to identify five polymorphic sites in the β-globin gene cluster., Results: A total of 245 homozygous SCD patients (490 alleles) were included in the study. Among the analysed alleles, 426 (86.9%) had the Benin (BEN) haplotype; 19 (3.9%) had the Senegal (SEN) haplotype; 31 (6.3%) had the Cameroon haplotype; five (1.0%) had the Bantu/Central African Republic haplotype; and nine 9 (1.8%) had atypical haplotypes. No significant association was observed between the haplotypes and haematological events, although patients with the BEN/SEN haplotype showed improved red blood cell counts, haemoglobin levels and red blood cell width index. No significant association was observed between the haplotypes and the three clinical manifestations, although patients with the BEN/SEN haplotype showed a four-fold lower frequency of painful episodes., Conclusion: These findings suggest that the SEN haplotype combined with the BEN haplotype might contribute toward a better haematological profile and milder clinical severity in SCD.

Fluoxetine has been shown to induce anti-tumour activity. The aim of this study was to determine the effect of fluoxetine on HCT116+/+ and p53 gene-depleted HCT116-/- human colorectal cancer cells and the mechanisms, including potential p53-dependence, of its action. Fluoxetine-induced apoptosis was investigated by mitochondrial membrane potential assay, Annexin V assay, two-step cell cycle analysis using NC-3000™ system and pharmacological inhibition assays. Fluoxetine induced very selectively concentration-dependent apoptosis in human colorectal cancer cells by altering mitochondrial membrane potential and inducing translocation of phosphatidylserine to the outer membrane layer. Further evidence of the preponderance of apoptosis in fluoxetine-induced cell death is provided by the finding that the cell death was not blocked by inhibitors of parthanatos, a form of cell death that results from overactivation of the enzyme poly (ADP-ribose) polymerase (PARP) but is different from apoptosis. Data obtained indicate fluoxetine caused cell cycle event at Sub-G1 and G0/G1 phases in both cell lines. In terms of apoptosis, there is no significant difference between the responses of the two cell lines to fluoxetine. In conclusion, fluoxetine's cytotoxicity induces mainly apoptosis and causes DNA fragmentation in human colorectal cancer cells, which seemed to be independent of the p53 protein, as no significant difference in death profiles in response to fluoxetine treatment was observed in both the p53-intact and the p53-deleted cell lines. Fluoxetine, therefore, has potential for being repurposed as a drug for the treatment of colon cancer and thus deserves further investigations in this context., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Traditional cytotoxic agents which act through a DNA-alkylating mechanism are relatively non-specific, resulting in a small therapeutic window and thus limiting their effectiveness. In this study, we evaluate a panel of 24 non-alkylating Strathclyde Minor Groove Binders (S-MGBs), including 14 novel compounds, for in vitro anti-cancer activity against a human colon carcinoma cell line, a cisplatin-sensitive ovarian cancer cell line and a cisplatin-resistant ovarian cancer cell line. A human non-cancerous retinal epithelial cell line was used to measure selectivity of any response. We have identified several S-MGBs with activities comparable to cis-platin and carboplatin, but with better in vitro selectivity indices, particularly S-MGB-4, S-MGB-74 and S-MGB-317. Moreover, a comparison of the cis-platin resistant and cis-platin sensitive ovarian cancer cell lines reveals that our S-MGBs do not show cross resistance with cisplatin or carboplatin and that they likely have a different mechanism of action. Finally, we present an initial investigation into the mechanism of action of one compound from this class, S-MGB-4, demonstrating that neither DNA double strand breaks nor the DNA damage stress sensor protein p53 are induced. This indicates that our S-MGBs are unlikely to act through an alkylating or DNA damage response mechanism., (This journal is © The Royal Society of Chemistry 2019.)

5-HT receptors are implicated in many gastrointestinal disorders. However, the precise role of 5-HT in mediating GI responses in Suncus murnius is still unclear. Therefore in this study, the effects of 5-HT and its agonists were investigated in Suncus. The involvement of 5-HT 2C receptors in mediating emesis was also investigated. The ability of 5-HT and its agonists/antagonists at 5-HT 1A and 5-HT 2 to modify GI motility was investigated in vitro and in vivo. WAY100635 (a 5-HT 1A antagonist) inhibited the contraction response to 5-HT in the proximal segments without affecting the maximum response; whilst enhancing the contraction to 5-HT (>30.0nM) in the distal intestine. The selective 5-HT 2A and 5-HT 2B receptor antagonists MDL-100907 and RS-127445 attenuated 5-HT-induced contractions (<10.0µM) in the distal segments. RS-127445 also attenuated 5-HT-induced contractions in the central segments. The selective 5-HT 2C receptor antagonist SB-242084, attenuated the responses to 5-HT (> 3.0nM) in the proximal and central but not the distal regions. 8-OH-DPAT-induced relaxation was resistant to the antagonism by 5-HT 1A/7 antagonists. DOI in the presence of 5-HT 1A/2A/2B/2C antagonists induced greater contraction responses (>1.0µM) in most tissues, whilst RS-127445, or SB-242084, reduced the responses to DOI (< 1.0µM) in some tissues. SB-242084 also suppressed emesis-induced by motion and intragastric CuSO 4 . In conclusion, within different regions of intestine, 5-HT 2 receptors are differently involved in contraction and emetic responses and that 8-OH-DPAT induces relaxation via non-5-HT 1A/7 receptors. Suncus could provide a model to investigate these diverse actions of 5-HT., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cannabinoids have been used for many centuries to ease pain and in the past decade, the endocannabinoid system has been implicated in a number of pathophysiological conditions, such as mood and anxiety disorders, movement disorders such as Parkinson's and Huntington's disease, neuropathic pain, multiple sclerosis, spinal cord injury, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity, and osteoporosis. Several studies have demonstrated that cannabinoids also have anti-cancer activity and as cannabinoids are usually well tolerated and do not produce the typical toxic effects of conventional chemotherapies, there is considerable merit in the development of cannabinoids as potential anticancer therapies. Whilst the presence of psychoactive effects of cannabinoids could prevent any progress in this field, recent studies have shown the value of the non-psychoactive components of cannabinoids in activating apoptotic pathways, inducing anti-proliferative and anti-angiogenic effects. The aforementioned effects are suggested to be through pathways such as ERK, Akt, mitogen-activated protein kinase (MAPK) pathways, phosphoinositide 3-kinase (PI3K) pathways and hypoxia inducible factor 1 (HIF1), all of which are important contributors to the hallmarks of cancer. Many important questions still remain unanswered or are poorly addressed thus necessitating further research at basic pre-clinical and clinical levels. In this review, we address these issues with a view to identifying the key challenges that future research needs to address., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Sixteen new isothiazoloisoxazole 1,1-dioxides, one new isothiazolotriazole and one new isothiazolopyrazole have been synthesised by using 1,3-dipolar cycloadditions to isothiazole 1,1-dioxides. One sub-set of these isothiazoloisoxazoles showed low μM activity against a human breast carcinoma cell line, whilst a second sub-set plus the isothiazolotriazole demonstrated an interesting restricted rotation of sterically hindered bridgehead substituents. A thiazete 1,1-dioxide produced from one of the isothiazole 1,1-dioxides underwent conversion into an unknown 1,2,3-oxathiazolin-2-oxide upon treatment with Lewis acids, but was inert towards 1,3-dipoles and cyclopropenones. Six supporting crystal structures are included.

The present study used the whole isolated urinary bladder of Suncus murinus, to investigate the effect of exogenously added serotonin (5-HT) and electrical field stimulation (EFS) in the absence and presence of methysergide, a 5-HT1/2/7 receptor antagonist or the selective 5-HT7 receptor antagonist, SB269970. Further experiments investigated the involvement of potassium channel, cholinergic and purinergic systems in mediating the contractile response to EFS. Pre-treatment with methysergide reduced and increased the contractile responses to 5-HT and EFS, respectively. Pre-treatment with SB269970 increased the responses to 5-HT without modifying the EFS-induced contractions. EFS-induced contractions were not modified by pre-treatment with atropine (10μM), α-β-methylene ATP or glibenclamide. EFS-induced contractions were attenuated by cromakalim (10µM) or atropine (0.1 µM). In conclusion, the 5-HT2 receptors are likely to play a role in mediating the contractile response to 5-HT in detrusor muscle. Furthermore, EFS-induced contractions are mediated through cholinergic and an unknown neurotransmitter which is modulated by K(ATP) channels in the detrusor muscle of Suncus murinus., (© 2013 Published by Elsevier B.V.)

Paradoxically, erythromycin is associated with nausea when used as an antibiotic but at lower doses erythromycin activates motilin receptors and is used to treat delayed gastric emptying and nausea. The aim of this study was to characterise pro- and anti-emetic activity of erythromycin and investigate mechanisms of action. Japanese House musk shrews (Suncus murinus) were used. Erythromycin was administered alone or prior to induction of emesis with abnormal motion or subcutaneous nicotine (10mg/kg). The effects of erythromycin and motilin on vagal nerve activity and on cholinergically mediated contractions of the stomach (evoked by electrical field stimulation) were studied in vitro. The results showed that erythromycin (1 and 5mg/kg) reduced vomiting caused by abnormal motion (e.g., from 10.3 ± 1.8 to 4.0 ± 1.1 emetic episodes at 5mg/kg) or by nicotine (from 9.5 ± 2.0 to 3.1 ± 2.0 at 5mg/kg), increasing latency of onset to emesis; lower or higher doses had no effects. When administered alone, erythromycin 100mg/kg induced vomiting in two of four animals, whereas lower doses did not. In vitro, motilin (1, 100 nM) increased gastric vagal afferent activity without affecting jejunal afferent mesenteric nerve activity. Cholinergically mediated contractions of the stomach (prevented by tetrodotoxin 1 μM or atropine 1 μM, facilitated by l-NAME 300 μM) were facilitated by motilin (1-100 nM) and erythromycin (10-30 μM). In conclusion, low doses of erythromycin have anti-emetic activity. Potential mechanisms of action include increased gastric motility (overcoming gastric stasis) and/ or modulation of vagal nerve pathways involved in emesis, demonstrated by first-time direct recording of vagal activation by motilin., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Cannabidiol (CBD) has been shown to inhibit gastrointestinal (GI) transit in pathophysiologic in vivo models, while having no effect in physiologic controls. The actions of the precursor of CBD, cannabidiolic acid (CBDA), have not been investigated in the GI tract. The actions of these phytocannabinoids on the contractility of the GI tract of Suncus murinus were investigated in the current study. The effects of CBDA and CBD in resting state and pre-contracted isolated intestinal segments, and on the contractile effects of carbachol and electrical field stimulation (EFS) on the intestines of S. murinus were examined. CBDA and CBD induced a reduction in resting tissue tension of isolated intestinal segments which was not blocked by the cannabinoid CB1 receptor antagonist, AM251, the CB(2) receptor antagonist AM630, or tetrodotoxin. CBDA and CBD reduced the magnitude of contractions induced by carbachol and the tension of intestinal segments that were pre-contracted with potassium chloride. In tissues stimulated by EFS, CBDA inhibited contractions induced by lower frequencies (0.1-4.0 Hz) of EFS, while CBD inhibited contractions induced by higher frequencies (4.0-20.0 Hz) of EFS. The data suggest that CBDA and CBD have inhibitory actions on the intestines of S. murinus that are not neuronallymediated or mediated via CB(1) or CB(2) receptors.

The relevance of age on serotonergic involvement in the control of alimentary contractility has not been pharmacologically described. Experiments were performed to investigate the effects of acetylcholine, atropine, 5-hydroxytryptamine (5-HT) and its related drugs on intestinal segments taken from the neonatal and adult ileum. 5-HT induced concentration-dependent contractions of ileum irrespective of age; however, these contractions were diminished by pretreatment with atropine only in neonatal tissues. In tissues taken from both the neonatal and adult ileum, methysergide (5-HT(1/2/5-7) receptor antagonist), ritanserin (5-HT(2) receptor antagonist), and RS23597-190/SB204070 (5-HT(4) receptor antagonists) all differentially reduced 5-HT-induced contractions at a concentration <100 μmol/l. At higher concentrations, the contractions were comparable to those in control tissues. Granisetron and ondansetron (5-HT(3) receptor antagonists) significantly reduced contractions induced by 5-HT at concentrations >30 μmol/l in both neonatal and adult ileum. Combined treatments with ritanserin, granisetron, plus RS23597-190 reduced or abolished contraction responses induced in neonatal ileum by 5-HT. SB269970A (5-HT(7) receptor antagonist) and WAY100635 (5-HT(1A) receptor antagonist) failed to influence contractile responses induced by 5-HT or 5-HT receptor agonists. Pretreatments with WAY100635 and SB267790A also had no influence on the contractile responses induced by 5-HT(1A/7) receptor agonist, 5-CT, and 5-HT(1A) receptor agonist, 8-OH-DPAT, which itself failed to induce a measurable response. It is concluded that the 5-HT-induced contractions in segments taken from both the neonatal and adult rat ileum were mediated via 5-HT(2) receptors, 5-HT(3) receptors and 5-HT(4) receptors. However, the effect of atropine on the neonatal rat intestine indicates that the mechanism of serotonergic involvement in ileal contractility is influenced by age., (Copyright © 2011 S. Karger AG, Basel.)

The effects of fluoxetine, a serotonin reuptake inhibitor, were studied in the isolated rat small intestine. Electrical field stimulation (EFS) triggered relaxant and/or contractile responses that were sensitive to tetrodotoxin and fluoxetine at 1.0-10.0 μM. In 0.1 mM hexamethonium-treated tissues, fluoxetine (1.0 μM) induced a relaxant response at 10.0 Hz, while it decreased the attenuation of the contractile responses to EFS. In PCPA pretreated rat jejunum and ileum, 1.0 μM of fluoxetine induced a greater relaxation response to EFS and significantly attenuated the contractile responses to EFS (10.0 Hz) in the duodenum. In a separate experiment, the application of reboxetine (1.0-10.0 μM), a noradrenergic reuptake inhibitor, reduced the contraction and increased the relaxation responses to EFS at 10.0 Hz in most regions. In the presence of hexamethonium (0.1 mM) the application of 10.0 μM reboxetine reduced contractile responses to ESF while enhancing the relaxant responses to EFS at 10.0 Hz. The data suggest that the effects of fluoxetine appear to be related to the selected region of the intestine and may contribute to a better understanding of the serotonergic and cholinergic transmitter mechanisms involved in ileal activity and the gastrointestinal discomfort associated with the clinical use of fluoxetine., (Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.)

Attempts were made to develop a simplified procedure for long-term cryopreservation of intestinal smooth muscle cells (ISMC). ISMC were collected from the ileum of Sprague-Dawley neonatal rats through cellular dissociation in trypsin. Cryopreservation method comprised of a rapid 1-step (protocol 1) and a slow 3-step (protocol 2) freezing of ISMC for 1week. Preparations were thawed and single ISMC were assessed via the comet assay and damaged DNA was quantified through comet tail moment. The control unfrozen ISMC exhibited DNA damage of 2.34+/-0.35 compared to ISMC cooled via protocol 2 (2.62+/-0.36) and protocol 1 (10.15+/-0.72). Thereafter, protocol 2 freezing method was adopted and ISMC were cryopreserved for 1-week, 1-month, and 4-months to analyse the temporal and long-term cryopreservation of ISMC. This revealed a DNA damage of 2.62+/-0.36 (1-week), 3.81+/-0.72 (1-month), and 5.1+/-0.9 (4-months). Gradual cooling is suitable for continuing storage of ISMC and although fluctuation in cryoinjury is observed with time this is considered to reflect cell-to-cell variability.

The effect of cannabinoids on motion-induced emesis is unknown. The present study investigated the action of phytocannabinoids against motion-induced emesis in Suncus murinus. Suncus murinus were injected intraperitoneally with either cannabidiol (CBD) (0.5, 1, 2, 5, 10, 20 and 40 mg/kg), Delta(9)-tetrahydrocannabinol (Delta(9)-THC; 0.5, 3, 5 and 10 mg/kg) or vehicle 45 min. before exposure to a 10-min. horizontal motion stimulus (amplitude 40 mm, frequency 1 Hz). In further investigations, the CB(1) receptor antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM 251; 5 mg/kg), was injected 15 min. prior to an injection of Delta(9)-THC (3 mg/kg). The motion stimulus was applied 45 min. later. The number of emetic episodes and latency of onset to the first emetic episode were recorded. Pre-treatment with the above doses of CBD did not modify the emetic response to the motion stimulus as compared to the vehicle-treated controls. Application of the higher doses of Delta(9)-THC induced emesis in its own right, which was inhibited by AM 251. Furthermore, pre-treatment with Delta(9)-THC dose-dependently attenuated motion-induced emesis, an effect that was inhibited by AM 251. AM 251 neither induced an emetic response nor modified motion-induced emesis. The present study indicates that Delta(9)-THC, acting via the CB(1) receptors, is anti-emetic to motion, and that CBD has no effect on motion-induced emesis in Suncus murinus.

This paper reports on the development of an entirely new intestinal smooth muscle cell (ISMC) culture model using rat neonates for use in pharmacological research applications. Segments of the duodenum, jejunum and ileum were obtained from Sprague-Dawley rat neonates. The cell extraction technique consisted of ligating both ends of the intestine and incubating (37 degrees C) in 0.25% trypsin for periods of 30-90 min. Isolated cells were suspended in DMEM-HEPES, plated and allowed to proliferate for 7 days. Cell culture quality was assessed via a series of viability tests using the dye exclusion assay. In separate experiments, tissues were exposed to trypsin for varying durations and subsequently histological procedures were applied. Cell purification techniques included differential adhesion technique for minimizing fibroblasts. Selective treatments with neurotoxin scorpion venom (30 microg mL(-1)) and anti-mitotic cytosine arabinoside (6 microm) were also applied to purify respectively ISMC and myenteric neurones selectively. The different cell populations were identified in regard to morphology and growth characteristics via immunocytochemistry using antibodies to smooth muscle alpha-actin, alpha-actinin and serotonin-5HT3 receptors. Based on both viability and cell confluence experiments, results demonstrated that intestinal cells were best obtained from segments of the ileum dissociated in trypsin for 30 min. This provided the optimum parameters to yield highly viable cells and confluent cultures. The finding was further supported by histological studies demonstrating that an optimum incubation time of 30 min is required to isolate viable cells from the muscularis externae layer. When cell cultures were treated with cytosine arabinoside, the non-neuronal cells were abolished, resulting in the proliferation of cell bodies and extended neurites. Conversely, cultures treated with scorpion venom resulted in complete abolition of neurones and proliferation of increasing numbers of ISMC, which were spindle-shaped and uniform throughout the culture. When characterized by immunocytochemistry, neurones were stained with antibody to 5HT3 receptors but not with antibodies to alpha-smooth muscle actin and alpha-actinin. Conversely, ISMC were stained with antibodies to alpha-smooth muscle actin and alpha-actinin but not with antibody to 5HT3 receptors. The present study provides evidence that our method of dissociation and selectively purifying different cell populations will allow for pharmacological investigation of each cell type on different or defined mixtures of different cell types.

In the present study we evaluated the role of 5-HT(1A) receptors in mediating the inhibitory action of 8-OH-DPAT, a 5-HT(1A) receptor agonist, in motion sickness in Suncus murinus. 8-OH-DPAT (0.1 mg/kg, i. p) attenuated motion-induced emesis which was associated with an increase in the latency of the onset to the first emetic episode. Pre-treatment with methysergide (a 5-HT(1/2/7) receptor antagonist, 1.0 mg/kg, i. p.), WAY-100635 (a 5-HT(1A) receptor antagonist, 1.0 mg/kg, i. p.), SB269970A (a 5-HT(7) receptor antagonist, 1.0 and 5.0 mg/kg, i. p.), ondansetron (a 5-HT(3) receptor antagonist, 1.0 mg/kg, i. p) or GR13808 (a 5-HT(4) receptor antagonist, 0.5 mg/kg, i. p) failed to modify the inhibitory action of 8-OH-DPAT on motion sickness. Furthermore, the application of either methysergide, WAY-100635, SB269970A, ondansetron or GR13808 alone had no effect on motion sickness in its own right. These data indicate that neither 5-HT(1A) nor any 5-HT(2) receptor subtypes, 5-HT(3), 5-HT(4) and 5-HT(7) receptors are likely to be involved in the inhibition of motion-induced emesis mediated by 8-OH-DPAT.

In the present study, we investigated the effect of 5-hydroxytryptamine (5-HT) and 5-HT receptor agonists and antagonists on motion sickness in Suncus murinus, and the possibility that the emetic stimulus of 5-HT can alter the sensitivity of the animals to the different emetic stimulus of motion sickness. 5-HT (1.0, 2.0, 4.0 and 8.0 mg/kg ip) induced emesis and that was antagonised by methysergide (1.0 mg/kg ip), the 5-HT(4) receptor antagonist sulphamate[1-[2-[(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl-5-fluoro-2-methoxy-1H-indole-3-carboxylate (GR125487D; 1.0 mg/kg ip) and granisetron (0.5 mg/kg ip). Pretreatment with 5-HT caused a dose-related attenuation of the emetic response induced by a subsequent motion stimulus, which was not significantly modified by methysergide, granisetron or GR125487D pretreatment. (+)-1-(2,5-Dimethoxy-4-iodophenyl)-2-amino-propane (DOI; 0.5 and 1.0 mg/kg ip), 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT; 0.1 mg/kg ip) but not methysergide, GR125487D or granisetron, attenuated motion-induced emesis, and that was not affected by pretreatment with ketanserin (2.0 mg/kg, ip) or N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrocholoride (WAY-100635; 1.0 mg/kg ip), respectively. Indeed, ketanserin alone (0.1, 0.3, 1.0 and 2.0 mg/kg ip) attenuated motion sickness. These data indicate that 5-HT(1/2), 5-HT(3) and 5-HT(4) receptors are involved in the induction of 5-HT-induced emesis. However, agonist action at the 5-HT(1A/7) and 5-HT(2) receptors, and antagonist action at the 5-HT(2A) receptors can attenuate motion sickness in S. murinus.

The aim of the present study was to investigate an opioid receptor involvement in the adaptation response to motion sickness in Suncus murinus. Different groups of animals were treated intraperitoneally with either saline, morphine (0.1 and 1.0 mg/kg), naloxone (1.0, 10.0 and 5.0 mg/kg) or a combination of naloxone plus morphine in the absence or 30 min prior to a horizontal motion stimulus of 1 Hz and 40 mm amplitude. For the study of adaptation, different groups received saline on the first trial, and in subsequent trials (every 2 days) they received either saline, naloxone (1.0 and 10.0 mg/kg, i.p.) or morphine (0.1 mg/kg, i.p.) 30 min prior to the motion stimulus. Pretreatment with morphine caused a dose-related reduction in emesis induced by a single challenge to a motion stimulus. Pretreatment with naloxone alone did not induce emesis in its own right nor did it modify emesis induced by a single challenge to a motion stimulus. However, pretreatment with naloxone (5.0 mg/kg, i.p.) revealed an emetic response to morphine (P<.001) (1.0 mg/kg, i.p.) and antagonised the reduction of motion sickness induced by morphine. In animals that received saline or naloxone (1.0 mg/kg), a motion stimulus inducing emesis decreased the responsiveness of animals to a second and subsequent motion stimulus challenge when applied every 2 days for 11 trials. However, the animals receiving naloxone 10.0 mg/kg prior to the second and subsequent challenges showed no significant reduction in the intensity of emesis compared to the first trial. The data are revealing of an emetic potential of morphine when administered in the presence of a naloxone pretreatment. The administration of naloxone is also revealing of an additional inhibitory opioid system whose activation by endogenous opioid(s) may play a role in the adaptation to motion sickness on repeated challenge in S. murinus.

The involvement of 5-HT2 receptor subtypes in mediating a contraction response in the isolated intestine of Suncus murinus was investigated using DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane, a 5-HT2 receptor agonist) which produced a bell-shaped concentration response curve that was significantly (p < 0.05) reduced by methysergide (a 5-HT1/2 receptor antagonist, 1 microM) but not ketanserin (a 5-HT2A receptor antagonist, 1 microM), yohimbine (a 5-HT2B receptor antagonist, 1 microM) or a combination of ondansetron (a 5-HT3 receptor antagonist, 1 microM) plus SB204070 (8-amino-7-chloro(N-butyl-4-piperidyl) methylbenzo-1,4-dioxan-5-carboxylate hydrochloride, a 5-HT4 receptor antagonist, 1 nM). The contraction response to the lower concentrations of DOI (10 nM-0.3 microM) was reduced in the presence of SB206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole, a 5-HT2B/2C receptor antagonist, 1 microM), whilst conversely, the reducing response to the higher concentrations of DOI (1-30 microM) was prevented. A repeated challenge with 3 microM DOI produced a smaller response (desensitisation) and also reduced the response to 5-HT (5-hydroxytryptamine, 0.3 microM) that was inhibited by SB206553 (1 microM). Data indicate that 5-HT2C receptors are likely candidates to mediate the contractile response to DOI and demonstrate desensitisation to repeated challenges.

The aim of the present study was to investigate the effect of different frequency and amplitude of horizontal movements to induce motion sickness and to identify gender differences and adaptation to motion stimulus in adult Suncus murinus. Each animal was subjected to a horizontal motion stimulus of 3, 7, 13, or 40 mm amplitude at a frequency of 0.5, 1, 2, or 3 Hz. The number of vomiting episodes and the latency of onset were recorded over a 10-min period. For the study of adaptation, different groups of males were exposed to repeated motion sickness (using 0.5 or 1 Hz frequency and the amplitude of 40 mm) either every 2 days for a period of 30 days, or once every week for a period of 28 days. In all animals the number of emetic episodes obtained at 1 and 2 Hz were significantly higher by 40-80% than those at 0.5 and 3 Hz using either 13 or 40 mm amplitude of movements; this was followed by shorter latency of emesis. Age-matched females were shown to be more responsive to the emetic stimuli than males as the number of emetic episodes at 1, 2, and 3 Hz (amplitude of 40 mm) were significantly higher by 33%, 42%, and 75%, respectively, than in males; this also was followed by a shorter latency of emetic response. In the study of adaptation, when used once every 2 days, by the second challenge (at 0.5 Hz) the number of emetic episodes was reduced by 62%, and to subsequent challenges emesis was absent or greatly reduced. Also, a reduction in responsiveness was observed at 1 Hz, which attained a maximum effect by the third challenge. The present results indicated that Suncus murinus is sensitive to horizontal motion stimulus, the emetic episodes were significantly greater at 1 and 2 Hz than at either a lower or higher frequency, a repeated challenge once every 2 days but not weekly reduced the number of emetic episodes, and in all experiments, age-matched female animals were more responsive than males to motion stimulus and in some experiments this achieved significance.

1. The effects of 5-HT and 5-HT agonists to induce contraction and the 5-HT receptors mediating these effects were investigated in the proximal, central and terminal intestinal segments of Suncus murinus. 2. The contraction curves to 5-HT (3 nM - 30 microM) were shifted to the right by methysergide (1 microM) and ritanserin (0.1 microM), without affecting the maximum response. 3. In the central and terminal segments (but not the proximal segments) ondansetron (1 microM) and atropine (1 microM) significantly attenuated the contractions to higher concentrations of 5-HT. The selective 5-HT4 receptor antagonist SB204070 (1 nM), failed to modify 5-HT induced contractions in any segment examined. 4. 5-carboxamidotryptamine, alpha-methyl-5-HT and 5-methoxytryptamine (0.003 - 3.0 microM) induced contractions but unlike 5-HT, higher concentrations of these three agents failed to increase the response or were associated with a decrease in response. 2-methyl-5-HT (0.03 - 1.0 microM) was ten times less potent than 5-HT to induce contraction but achieved the same maximum response. 5. The contractions induced by the lower concentrations of 2-methyl-5-HT (0.03 - 1.0 microM) in all segments were markedly reduced or abolished by methysergide (1.0 microM); the response to the higher concentrations of 2-methyl-5-HT (3 - 30.0 microM) were markedly reduced by atropine (1.0 microM) and ondansetron (1.0 microM). 6. In all segments examined, tetrodotoxin (1 microM) significantly reduced the 5-HT-induced contraction. 7. It is concluded that the 5-HT-induced contraction was mediated via 5-HT2 (ritanserin sensitive) receptors in all regions of the intestine, with 5-HT3 (ondansetron sensitive) receptors mediating an additional major component in the central and terminal regions.