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This ex vivo study aimed to measure the performance of an electronic apex locator (EAL) in the presence of sodium hypochlorite irrigants with different concentrations. Two EALs (Root ZX Mini and Locapex 6) were used to locate the apical foramen in 10 extracted single-rooted teeth in the presence of 0.5%, 2.5% and 5% sodium hypochlorite. Visual working lengths were also determined using #10 K-file under a microscope before the electronic measurements were made. The performance of both EALs was compared for the electronic working lengths determined under the different concentrations of sodium hypochlorite. A multiple-way ANOVA and PLSD Fisher's test with an α risk fixed at 5% were conducted. There were no statistical differences in the working lengths determined by both EALs between the three groups with different concentrations of sodium hypochlorite and their visual control measurements. When a ± 0.5 mm margin was applied, the Root ZX Mini and the Locapex 6 presented 88% and 83% accuracy, respectively. Sodium hypochlorite concentration in irrigants does not affect the accuracy and reliability of either the Root ZX Mini or the Locapex 6. Electronic apex locators are reliable with any concentration of sodium hypochlorite irrigants.

Cancer treatments with cytotoxic drugs have been shown to cause bone loss. However, effects on bone are less clear for ErbB-targeting tyrosine kinase inhibitors or their combination use with cytotoxic drugs. This study examined the effects of individual or combination treatments with breast cancer drugs lapatinib (a dual ErbB1/ErbB2 inhibitor) and paclitaxel (a microtubule-stabilizing cytotoxic agent) on bone and bone marrow of rats. Wistar rats received lapatinib (240 mg/kg) daily, paclitaxel (12 mg/kg) weekly, or their combination for 4 weeks, and effects on bone/bone marrow were examined at the end of week 4. Microcomputed tomographical structural analyses showed a reduction in trabecular bone volume in tibia following the lapatinib, paclitaxel or their combination treatments ( P < 0.05). Histomorphometry analyses revealed marked increases in bone marrow adipocyte contents in all treatment groups. Reverse transcription polymerase chain reaction gene expression studies with bone samples and cell culture studies with isolated bone marrow stromal cells showed that the all treatment groups displayed significantly reduced levels of osterix expression and osteogenic differentiation potential but increased expression levels of adipogenesis transcription factor peroxisome proliferator-activated receptor γ. In addition, these treatments suppressed the expression of Wnt10b and/or increased expression of Wnt antagonists (secreted frizzled-related protein 1, Dickkopf-related protein 1 and/or sclerostin). Furthermore, all treatment groups showed increased numbers of bone-resorbing osteoclasts on trabecular bone surfaces, although only the lapatinib group displayed increased levels of osteoclastogenic signal (receptor activator of nuclear factor κΒ ligand/osteoclastogenesis inhibitor osteoprotegrin expression ratio) in the bones. Thus, inhibiting ErbB1 and ErbB2 by lapatinib or blocking cell division by paclitaxel or their combination causes significant trabecular bone loss and bone marrow adiposity involving a switch in osteogenesis/adipogenesis potential, altered expression of some major molecules of the Wnt/β-catenin signalling pathway, and increased recruitment of bone-resorbing osteoclasts., (© 2018 Wiley Periodicals, Inc.)

Background: Gastrointestinal (GI) mucositis caused by chemotherapy is associated with diarrhoea and intestinal barrier disruption caused by apoptosis, immune dysfunction and microbiome alterations. Serum-derived bovine immunoglobulin/protein isolate (SBI) has been shown to manage HIV-associated enteropathy and irritable bowel syndrome with diarrhoea (IBS-D). We investigated in a rat model whether SBI was effective in alleviating symptoms of irinotecan-induced GI mucositis., Methods: Animals were gavaged with 250 or 500 mg/kg of SBI twice daily for 4 days, before intraperitoneal administration of 200 mg/kg irinotecan. Twice daily gavaging of SBI continued for 6 days post-irinotecan. Animals were monitored for bodyweight changes and incidence of diarrhoea and clinical symptoms of stress. Tissues and blood samples were collected at necropsy 6 h, and 2, 4 and 6 days post-irinotecan. H&E-stained colon and jejunum were analysed for histological damage., Results: The overall incidence, severity and duration of diarrhoea, and clinical symptoms of mucositis were decreased in irinotecan-treated animals that had received SBI. Animals receiving 500 mg/kg SBI also tended to lose less bodyweight than animals treated only with irinotecan (P > 0.10). SBI-gavaged animals had less pronounced irinotecan-induced changes in neutrophil (P = 0.04959) and lymphocyte (P = 0.0035) levels, and lower tissue damage scores than those receiving irinotecan alone (P < 0.0001)., Conclusions: Twice daily oral gavage of SBI was well-tolerated and reduced the incidence, severity and duration of irinotecan-induced mucositis. SBI was associated with less pronounced changes in inflammatory cell levels and tissue damage to colon and jejunum. Ongoing experiments aim to investigate the mechanisms of SBI-associated gastrointestinal protection.

Introduction: Diarrhoea caused by treatment with receptor tyrosine kinase inhibitors (TKI) targeting Epidermal Growth Factor Receptors (EGFR) is an important clinical toxicity in oncology that remains poorly understood. This study aimed to identify histological and molecular changes within the intestine following lapatinib to elucidate mechanisms of diarrhoea related to treatment with this dual EGFR TKI., Methods and Materials: Male albino Wistar rats were orally gavaged lapatinib at 100, 240 or 500 mg/kg daily for 4 weeks and assessed for indicators of gastrointestinal injury at the end of each week. Lapatinib in combination with weekly paclitaxel (9 mg/kg i.p.) was also assessed for cumulative injury. At each time point, blood was collected for biochemical analysis. Sections or jejunum and colon were also collected and underwent immunohistochemistry and RT-PCR to detect markers of EGFR pathway signalling, and morphometric analysis to assess changes in mucosal architecture., Results: Lapatinib (with or without paclitaxel co-treatment) caused dose-dependent changes in crypt length, mitotic rate and goblet cell morphology. Jejunal crypt expression of EGFR and ErbB2 were decreased, whilst no changes in Erk1/2 were observed. Markers of apoptosis (caspase-3) and proliferation (Ki-67) were only significantly altered in rats treated with both lapatinib and paclitaxel., Conclusions: In our novel rat model of lapatinib-induced diarrhoea we have shown that changes in small intestinal morphometry and expression of EGFR are associated with diarrhoea. Further research is required to test intervention agents for the prevention of diarrhoea.

Chemotherapy-induced mucositis represents a significant burden to quality of life and healthcare costs, and may be improved through enhanced nutritional status. We first determined the safety of two nutritional drinks (plus placebo), and then potential gut protection in tumor-bearing rats in a model of methotrexate-induced mucositis. In study 1, animals were fed one of two test diets (or placebo or control chow pellets) for a total of 60 days and were monitored daily. All diets were found to be safe to administer. In study 2, after seven days of receiving diets, a Dark Agouti Mammary Adenocarcinoma (DAMA) was transplanted subcutaneously. Ten days after starting diets, animals had 2 mg/kg intramuscular methotrexate administered on two consecutive days; after this time, all animals were given soaked chow. Animals were monitored daily for changes in bodyweight, tumor burden and general health. Animals were killed 10, 12 and 16 days after initially starting diets, and tissues were collected at necropsy. In study 1, animals receiving diets had gained 0.8% and 10.8% of their starting bodyweight after 60 days, placebo animals 4.4%, and animals fed on standard chow had gained 15.1%. In study 2, there was no significant influence of test diet on bodyweight, organ weight, tumor burden or biochemical parameters. Only animals treated with MTX exhibited diarrhea, although animals receiving Diet A and Diet C showed a non-significant increase in incidence of diarrhea. Administration of these nutritional drinks did not improve symptoms of mucositis.

Orally administered small molecule receptor tyrosine kinase inhibitors (RTKIs) are increasingly common treatments for cancer, both alone and in combination with chemotherapy. However, their side effect profiles and the underlying mechanisms of such are not yet fully elucidated. Management of their most common dose limiting side effect, diarrhea, has been hampered by a lack of suitable animal models. We aimed to develop a clinically relevant rat model of RTKI-induced diarrhea that could be utilized for investigating supportive care interventions and pharmacokinetics. Albino Wistar rats were treated daily for 4 weeks with various concentrations of lapatinib to determine the optimal dose for development of diarrhea. This was then followed by an experiment with addition of paclitaxel once weekly for 4 weeks to observe effects of combination drug treatment on diarrhea. Data regarding animal tolerance to the treatment, organ weights, circulating lapatinib concentration and histopathology were collected weekly. Lapatinib caused diarrhea in rats that was dose-dependent. Diarrhea occurred without causing significant intestinal histopathology. Follow up experiments are currently underway to determine the exact pathogenesis and mechanisms of lapatinib-induced diarrhea and potential protective strategies.

This paper presents a first attempt to develop a prospective paradigm to test Rachman's (Behav. Res. Ther. 15 (1977) 375) theory of fear acquisition for social fears. Following the prospective paradigm for animal fears developed by Field et al. (Behav. Res. Ther. 39 (2001) 1259) an attempt is made to adapt this paradigm to look at the effect of fear information in the development of social fears. A large group of normal children (N=135) who were at an age (10-13 years) at which social concerns are most pertinent were tested using this paradigm. They were given positive, negative or neutral information about three social situations: public speaking, eating in public, and meeting a new group of children. Children's fear beliefs were measured before and after the information was given and the information was given by a teacher, a same age peer or no information was given (a control). The results indicate that although information can change social fear beliefs it is dependent upon the type of social activity and who provides the information. The implications of these initial results for our understanding of both the role of fear information in the development of social fear beliefs, and the limitations of this current paradigm are discussed.