Effect of subinhibitory exposure to quaternary ammonium compounds on the ciprofloxacin susceptibility of Escherichia coli strains in animal husbandry.

BACKGROUND: Quaternary ammonium compound based disinfectants are commonly used in pig and poultry husbandry to maintain farm hygiene. However, studies have shown that subinhibitory concentrations of these disinfectants may increase antibiotic resistance. Investigation of antibiotic susceptibility is usually assessed via the microbroth dilution method, although this conventional culture-based technique only provides information on the bacteriostatic activity of an antimicrobial agent. Therefore, experiments were performed to investigate the effect of prior benzalkonium chloride (BKC) exposure on the viability of subsequent ciprofloxacin (CIP) treated Escherichia coli. RESULTS: Following CIP treatment, bacterial cell counts were significantly higher after exposure to a subinhibitory BKC concentration than without BKC exposure. The flow cytometric results suggested a BKC-dependent onset of membrane damage and loss of membrane potential. CONCLUSION: Our results indicate a lower bactericidal effect of CIP treatment on BKC-exposed E. coli isolates compared to unexposed E. coli isolates.

α-Lipoic Acid Reduces Iron-induced Toxicity and Oxidative Stress in a Model of Iron Overload.

Iron toxicity is associated with organ injury and has been reported in various clinical conditions, such as hemochromatosis, thalassemia major, and myelodysplastic syndromes. Therefore, iron chelation therapy represents a pivotal therapy for these patients during their lifetime. The aim of the present study was to assess the iron chelating properties of α-lipoic acid (ALA) and how such an effect impacts on iron overload mediated toxicity. Human mesenchymal stem cells (HS-5) and animals (zebrafish, n = 10 for each group) were treated for 24 h with ferric ammonium citrate (FAC, 120 µg/mL) in the presence or absence of ALA (20 µg/mL). Oxidative stress was evaluated by reduced glutathione content, reactive oxygen species formation, mitochondrial dysfunction, and gene expression of heme oxygenase-1b and mitochondrial superoxide dismutase; organ injury, iron accumulation, and autophagy were measured by microscopical, cytofluorimetric analyses, and inductively coupled plasma‒optical mission Spectrometer (ICP-OES). Our results showed that FAC results in a significant increase of tissue iron accumulation, oxidative stress, and autophagy and such detrimental effects were reversed by ALA treatment. In conclusion, ALA possesses excellent iron chelating properties that may be exploited in a clinical setting for organ preservation, as well as exhibiting a good safety profile and low cost for the national health system.

High-Content Assay Multiplexing for Muscle Toxicity Screening in Human-Induced Pluripotent Stem Cell-Derived Skeletal Myoblasts.

Skeletal muscle-associated toxicity is an underresearched area in the field of high-throughput toxicity screening; hence, the potential adverse effects of drugs and chemicals on skeletal muscle are largely unknown. Novel organotypic microphysiological in vitro models are being developed to replicate the contractile function of skeletal muscle; however, the throughput and a need for specialized equipment may limit the utility of these tissue chip models for screening. In addition, recent developments in stem cell biology have resulted in the generation of induced pluripotent stem cell (iPSC)-derived skeletal myoblasts that enable high-throughput in vitro screening. This study set out to develop a high-throughput multiplexed assay using iPSC-derived skeletal myoblasts that can be used as a first-pass screen to assess the potential for chemicals to affect skeletal muscle. We found that cytotoxicity and cytoskeletal integrity are most useful and reproducible assays for the skeletal myoblasts when evaluating overall cellular health or gauging disruptions in actin polymerization following 24 h of exposure. Both assays are based on high-content imaging and quantitative image processing to derive quantitative phenotypes. Both assays showed good to excellent assay robustness and reproducibility measured by interplate and interday replicability, coefficients of variation of negative controls, and Z'-factors for positive control chemicals. Concentration response assessment of muscle-related toxicants showed specificity of the observed effects compared to the general cytotoxicity. Overall, this study establishes a high-throughput multiplexed assay using skeletal myoblasts that may be used for screening and prioritization of chemicals for more complex tissue chip-based and in vivo evaluation.

Antipsychotic-like activity of scopoletin and rutin against the positive symptoms of schizophrenia in mouse models.

In an earlier report, we demonstrated an antipsychotic-like activity of a methanolic extract of Morinda citrifolia Linn fruit in mouse models and postulated the contribution of its bioactive principles, scopoletin and rutin. Moreover, the antidopaminergic activities of scopoletin and rutin were reported in isolated vas deferens preparations. In the present study, scopoletin and rutin were assessed for antipsychotic-like activity using apomorphine-induced climbing behavior and methamphetamine-induced stereotypy in mice. The results of this study revealed that scopoletin and rutin (0.05, 0.1, 0.5, and 1 mg/kg, p.o.) had a "U-shaped" dose-dependent effect on climbing and stereotyped behaviors induced by apomorphine and methamphetamine, respectively, in mice. A significant reduction in climbing and stereotyped behaviors caused by scopoletin and rutin was observed only at a dose 0.1 mg/kg. This study suggests that scopoletin and rutin can alleviate positive symptoms of schizophrenia only at a specific dose. Further studies evaluating the effects of scopoletin and rutin on animal models for negative symptoms of schizophrenia are required for a novel drug discovery in the treatment of neuropsychiatric diseases.

Chitosan Derivatives Active against Multidrug-Resistant Bacteria and Pathogenic Fungi: In Vivo Evaluation as Topical Antimicrobials.

The continuous rise of antimicrobial resistance and the dearth of new antibiotics in the clinical pipeline raise an urgent call for the development of potent antimicrobial agents. Cationic chitosan derivatives, N-(2-hydroxypropyl)-3-trimethylammonium chitosan chlorides (HTCC), have been widely studied as potent antibacterial agents. However, their systemic structure-activity relationship, activity toward drug-resistant bacteria and fungi, and mode of action are very rare. Moreover, toxicity and efficacy of these polymers under in vivo conditions are yet to be established. Herein, we investigated antibacterial and antifungal efficacies of the HTCC polymers against multidrug resistant bacteria including clinical isolates and pathogenic fungi, studied their mechanism of action, and evaluated cytotoxic and antimicrobial activities in vitro and in vivo. The polymers were found to be active against both bacteria and fungi (MIC = 125-250 µg/mL) and displayed rapid microbicidal kinetics, killing pathogens within 60-120 min. Moreover, the polymers were shown to target both bacterial and fungal cell membrane leading to membrane disruption and found to be effective in hindering bacterial resistance development. Importantly, very low toxicity toward human erythrocytes (HC50 = >10000 µg/mL) and embryo kidney cells were observed for the cationic polymers in vitro. Further, no inflammation toward skin tissue was observed in vivo for the most active polymer even at 200 mg/kg when applied on the mice skin. In a murine model of superficial skin infection, the polymer showed significant reduction of methicillin-resistant Staphylococcus aureus (MRSA) burden (3.2 log MRSA reduction at 100 mg/kg) with no to minimal inflammation. Taken together, these selectively active polymers show promise to be used as potent antimicrobial agents in topical and other infections.

Laxatives for the management of constipation in people receiving palliative care.

BACKGROUND: This article describes the second update of a Cochrane review on the effectiveness of laxatives for the management of constipation in people receiving palliative care. Previous versions were published in 2006 and 2010 where we also evaluated trials of methylnaltrexone; these trials have been removed as they are included in another review in press. In these earlier versions, we drew no conclusions on individual effectiveness of different laxatives because of the limited number of evaluations. This is despite constipation being common in palliative care, generating considerable suffering due to the unpleasant physical symptoms and the availability of a wide range of laxatives with known differences in effect in other populations. OBJECTIVES: To determine the effectiveness and differential efficacy of laxatives used to manage constipation in people receiving palliative care. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library), MEDLINE, EMBASE, CINAHL and Web of Science (SCI & CPCI-S) for trials to September 2014. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating laxatives for constipation in people receiving palliative care. DATA COLLECTION AND ANALYSIS: Two authors assessed trial quality and extracted data. The appropriateness of combining data from the studies depended upon clinical and outcome measure homogeneity. MAIN RESULTS: We identified five studies involving the laxatives lactulose, senna, co-danthramer, misrakasneham, docusate and magnesium hydroxide with liquid paraffin. Overall, the study findings were at an unclear risk of bias. As all five studies compared different laxatives or combinations of laxatives, it was not possible to perform a meta-analysis. There was no evidence on whether individual laxatives were more effective than others or caused fewer adverse effects. AUTHORS' CONCLUSIONS: This second update found that laxatives were of similar effectiveness but the evidence remains limited due to insufficient data from a few small RCTs. None of the studies evaluated polyethylene glycol or any intervention given rectally. There is a need for more trials to evaluate the effectiveness of laxatives in palliative care populations. Extrapolating findings on the effectiveness of laxatives evaluated in other populations should proceed with caution. This is because of the differences inherent in people receiving palliative care that may impact, in a likely negative way, on the effect of a laxative.

A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease.

Therapies that target leukocyte trafficking pathways can reduce disease activity and improve clinical outcomes in multiple sclerosis (MS). Experimental autoimmune encephalomyelitis (EAE) is a widely studied animal model that shares many clinical and histological features with MS. Chemokine-like receptor-1 (CMKLR1) is a chemoattractant receptor that is expressed by key effector cells in EAE and MS, including macrophages, subsets of dendritic cells, natural killer cells and microglia. We previously showed that CMKLR1-deficient (CMKLR1 KO) mice develop less severe clinical and histological EAE than wild-type mice. In this study, we sought to identify CMKLR1 inhibitors that would pharmaceutically recapitulate the CMKLR1 KO phenotype in EAE. We identified 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) as a CMKLR1 small molecule antagonist that inhibits chemerin-stimulated ß-arrestin2 association with CMKLR1, as well as chemerin-triggered CMKLR1+ cell migration. α-NETA significantly delayed the onset of EAE induced in C57BL/6 mice by both active immunization with myelin oligodendrocyte glycoprotein peptide 35-55 and by adoptive transfer of encephalitogenic T cells. In addition, α-NETA treatment significantly reduced mononuclear cell infiltrates within the CNS. This study provides additional proof-of-concept data that targeting CMKLR1:chemerin interactions may be beneficial in preventing or treating MS.

Iron decreases biological effects of ozone exposure.

CONTEXT: Ozone (O3) exposure is associated with a disruption of iron homeostasis and increased availability of this metal which potentially contributes to an oxidative stress and biological effects. OBJECTIVE: We tested the postulate that increased concentrations of iron in cells, an animal model and human subjects would significantly impact the biological effects of O3 exposure. RESULTS: Exposure to 0.4 ppm O3 for 5 h increased mRNA for both Superoxide Dismutase-1 (SOD1) and Cyclooxygenase-2 (COX2) in normal human bronchial epithelial (NHBE) cells. Pre-treatment of NHBE cells with 200 µM ferric ammonium citrate (FAC) for 4 h diminished changes in both SOD1 and COX2 following O3 exposure. mRNA transcript levels and associated protein release of the pro-inflammatory mediators IL-6 and IL-8 were increased by O3 exposure of NHBE cells; changes in these endpoints after O3 exposure were significantly decreased by FAC pre-treatment of the cells. Exposure of CD-1 mice to 2 ppm O3 for 3 h significantly increased lavage indices of inflammation and airflow limitation. Pre-treatment of the animals with pharyngeal aspiration of FAC diminished the same endpoints. Finally, the mean loss of pulmonary function in 19 healthy volunteers exposed to 0.3 ppm O3 for 2 h demonstrated significant correlations with either their pre-exposure plasma ferritin or iron concentrations. DISCUSSION AND CONCLUSION: We conclude that greater availability of iron after O3 exposure does not augment biological effects. On the contrary, increased available iron decreases the biological effects of O3 exposure in cells, animals and humans.

A comparison of the biological activities of human osteoblast hFOB1.19 between iron excess and iron deficiency.

Bone metabolism has a close relationship with iron homeostasis. To examine the effects of iron excess and iron deficiency on the biological activities of osteoblast in vitro, human osteoblast cells (hFOB1.19) were incubated in a medium supplemented with 0-200 µmol/L ferric ammonium citrate and 0-20 µmol/L deferoxamine. The intracellular iron was measured by a confocal laser scanning microscope. Proliferation of osteoblasts was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Apoptotic cells were detected using annexin intervention V/PI staining with a flow cytometry. Alkaline phosphatase (ALP) activity was measured using an ALP assay kit. The number of calcified nodules and mineral area was evaluated by von Kossa staining assay. The expressions of type I collagen and osteocalcin of cultured osteoblasts were detected by reverse transcriptase polymerase chain reaction and Western blot. Intracellular reactive oxygen species (ROS) was measured using the oxidation-sensitive dye 2,7-dichlorofluorescin diacetate by flow cytometry. The results indicated that excessive iron inhibited osteoblast activity in a concentration-dependent manner. Low iron concentrations, in contrast, produced a biphasic manner on osteoblasts: mild low iron promoted osteoblast activity, but serious low iron inhibited osteoblast activity. Osteogenesis was optimal in certain iron concentrations. The mechanism underlying biological activity invoked by excessive iron may be attributed to increased intracellular ROS levels.

Development and preclinical safety evaluation of a new therapeutic HIV-1 vaccine based on 18 T-cell minimal epitope peptides applying a novel cationic adjuvant CAF01.

Therapeutic immunization of HIV-1-infected individuals with or without anti-retroviral therapy is a new promising disease prevention. To induce a new cytotoxic T(CD8) lymphocyte (CTL) immunity during chronic HIV-1 infection 15 infrequently targeted but conserved HLA-supertype binding CTL epitopes from Gag, Pol, Nef, Env, Vpu and Vif were identified. The 15 T(CD8) and three T(CD4) helper peptides were GMP synthesised and formulated with a new adjuvant CAF01 which is a synthetic two-component liposomic adjuvant comprising the quaternary ammonium dimethyl-dioctadecyl-ammonium (DDA) and the immune modulator trehalose 6,6'-dibehenate (TDB). Using IFN-γ ELISPOT assay, T-cell immune induction by the vaccine was found to both CD4 and CD8 T-cell restricted peptides in HLA-A2 transgenic mice. Comprehensive toxicity studies of the CAF01 adjuvant-alone and together with different vaccines showed that CAF01 when tested at human dose levels was safe and well tolerated with only local inflammation at the site of injection and no systemic reactions. No pharmacological safety issues were observed in Beagle dogs. The HIV-1 vaccine toxicity study in the Göttingen Minipig(®) showed no systemic toxicity from five repetitive i.m. injections, each with a 2-week interval, of either the 18 HIV-1 peptide antigen solution (AFO18) or the AFO18-CAF01, in which the 18 HIV-1 peptides were formulated with the CAF01 adjuvant. Distinct inflammatory responses were observed in the injected muscles of the AFO18-CAF01 vaccine treated animals as a result of the immune stimulating effect of the adjuvant on the vaccine. The results of the toxicity studies provide optimism for phase I clinical trials evaluating the therapeutic HIV-1 T-cell vaccination approach using multiple subdominant minimal epitope peptides applying the novel cationic adjuvant CAF01.

Identification of quaternary ammonium compounds as potent inhibitors of hERG potassium channels.

The human ether-a-go-go-related gene (hERG) channel, a member of a family of voltage-gated potassium (K(+)) channels, plays a critical role in the repolarization of the cardiac action potential. The reduction of hERG channel activity as a result of adverse drug effects or genetic mutations may cause QT interval prolongation and potentially leads to acquired long QT syndrome. Thus, screening for hERG channel activity is important in drug development. Cardiotoxicity associated with the inhibition of hERG channels by environmental chemicals is also a public health concern. To assess the inhibitory effects of environmental chemicals on hERG channel function, we screened the National Toxicology Program (NTP) collection of 1408 compounds by measuring thallium influx into cells through hERG channels. Seventeen compounds with hERG channel inhibition were identified with IC(50) potencies ranging from 0.26 to 22µM. Twelve of these compounds were confirmed as hERG channel blockers in an automated whole cell patch clamp experiment. In addition, we investigated the structure-activity relationship of seven compounds belonging to the quaternary ammonium compound (QAC) series on hERG channel inhibition. Among four active QAC compounds, tetra-n-octylammonium bromide was the most potent with an IC(50) value of 260nM in the thallium influx assay and 80nM in the patch clamp assay. The potency of this class of hERG channel inhibitors appears to depend on the number and length of their aliphatic side-chains surrounding the charged nitrogen. Profiling environmental compound libraries for hERG channel inhibition provides information useful in prioritizing these compounds for cardiotoxicity assessment in vivo.

Laxatives or methylnaltrexone for the management of constipation in palliative care patients.

BACKGROUND: Constipation is common in palliative care; it can generate considerable suffering due to the unpleasant physical symptoms. In the first Cochrane Review on effectiveness of laxatives for the management of constipation in palliative care patients, published in 2006, no conclusions could be drawn because of the limited number of evaluations. This article describes the first update of this review. OBJECTIVES: To determine the effectiveness of laxatives or methylnaltrexone for the management of constipation in palliative care patients. SEARCH STRATEGY: We searched databases including MEDLINE and CENTRAL (The Cochrane Library) in 2005 and in the update to August 2010. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating laxatives for constipation in palliative care patients. In the update we also included RCTs on subcutaneous methylnaltrexone; an opioid-receptor antagonist that is now licensed for the treatment of opioid-induced constipation in palliative care when response to usual laxative therapy is insufficient. DATA COLLECTION AND ANALYSIS: Two authors assessed trial quality and extracted data. The appropriateness of combining data from the studies depended upon clinical and outcome measure homogeneity. MAIN RESULTS: We included seven studies involving 616 participants; all under-reported methodological features. In four studies the laxatives lactulose, senna, co-danthramer, misrakasneham, and magnesium hydroxide with liquid paraffin were evaluated. In three methylnaltrexone.In studies comparing the different laxatives evidence was inconclusive. Evidence on subcutaneous methylnaltrexone was clearer; in combined analysis (287 participants) methylnaltrexone, in comparison with a placebo, significantly induced laxation at 4 hours (odds ratio 6.95; 95% confidence interval 3.83 to 12.61). In combined analyses there was no difference in the proportion experiencing side effects, although participants on methylnaltrexone suffered more flatulence and dizziness. No evidence of opioid withdrawal was found. In one study severe adverse events, commonly abdominal pain, were reported that were possibly related to methylnaltrexone. A serious adverse event considered to be related to the methylnaltrexone also occurred; this involved a participant having severe diarrhoea, subsequent dehydration and cardiovascular collapse. AUTHORS' CONCLUSIONS: The 2010 update found evidence on laxatives for management of constipation remains limited due to insufficient RCTs. However, the conclusions of this update have changed since the original review publication in that it now includes evidence on methylnaltrexone. Here it found that subcutaneous methylnaltrexone is effective in inducing laxation in palliative care patients with opioid-induced constipation and where conventional laxatives have failed. However, the safety of this product is not fully evaluated. Large, rigorous, independent trials are needed.

The role of opioid receptor antagonists in the treatment of opioid-induced constipation: a review.

Opioid-induced constipation (OIC) is associated with negative impact of opioid analgesics on opioid receptors located in the gut wall. Until recently, OIC was treated symptomatically only, with different laxatives which did not target the pathophysiology of OIC. Recently, several opioid receptor antagonists have been introduced in the treatment of OIC. Methylnaltrexone (MNTX) is a peripheral mu-opioid receptor antagonist for subcutaneous administration, which does not evoke symptoms of opioid abstinence. MNTX is indicated for patients with OIC who are not amenable to therapy with oral laxatives. In clinical trials, the effectiveness of MNTX assessed as its ability to induce spontaneous bowel movement, is 50%-60% of treated patients; MNTX demonstrates significant superiority over placebo. Another product is combination of oral formulation of prolonged release oxycodone and prolonged release naloxone (PR oxycodone/PR naloxone), indicated for patients who require opioid administration for chronic pain and have already developed OIC, and for those who need opioid therapy and take the drug to prevent OIC. Naloxone administered orally displays local, antagonist effects on opioid receptors in the gut wall, negligible systemic bioavailability, and significantly reduces the oxycodone constipating effect. PR oxycodone/PR naloxone has similar analgesic efficacy, but causes less constipation and less laxative consumption in comparison with patients treated with oxycodone alone. Both products are expensive, therefore their administration should be carefully considered. On the other hand, uncontrolled OIC and the necessity to perform rectal invasive procedures (enema, manual evacuation) lead not only to increased health care costs, but most importantly, cause severe patient suffering.

Effects of ammonium hexafluorosilicate concentration on dentin tubule occlusion and composition of the precipitate.

UNLABELLED: Ammonium hexafluorosilicate [SiF: (NH(4))(2)SiF(6)] was prepared in order to overcome the tooth discoloration caused by diamine silver fluoride [AgF: (NH(3))(2)AgF] application. We employed a single concentration of SiF solution in our previous study; therefore, it is still unclear how the concentration of SiF solution affects the occlusion of dentin tubules and composition of the precipitate. OBJECTIVE: The aim of this study was to evaluate the effects of changing the concentration of SiF on its clinical use as a dentin hypersensitivity treatment. METHODS: To simulate dentin tubules subject to dentin hypersensitivity, dentin disks were treated with EDTA for 2 min. Then, the disks were treated with several concentrations of SiF solution (from 100 to 19,400 ppm) for 3 min. The occlusion of dentin tubules was evaluated using scanning electron microscopy (SEM), and the composition of the precipitate formed in the tubules after SiF treatment was assessed using energy dispersive X-ray analysis (EDXA). RESULTS: SEM photographs demonstrated that dentin tubules after treatment with SiF were occluded homogeneously and fully regardless of the concentration of SiF solution. The Ca/P molar ratio of the precipitate formed in dentin tubules after SiF treatment was increased with the concentration of SiF solution. SIGNIFICANCE: It was concluded that the capacity to occlude dentin tubules was the same regardless of the concentration of SiF solution. However, the composition of the precipitate formed in the tubules was dependent on the concentration of SiF solution.

Tratamento da pitiríase do couro cabeludo com champô de lactato de amónio, cetoconazol e piroctonalonamina / Treatment of dandruff with a shampoo containing ammonium lactate, ketoconazole and piroctone olamine

Objectivo: Neste trabalho pretendeu-se avaliar a eficácia e a agradabilidade cosmética de um champô de lactato de amónio a 6 por ciento, cetoconazol a 1 por ciento e piroctonalonamina a 0,5 por ciento* no tratamento da pitiríase do couro cabeludo.Método: Utilizou-se o champô durante quatro semanas, em 30 doentes, 16 do sexo masculino e 14 do feminino, duas ou três vezes por semana, com uma só aplicação de 1 a 2 ml, em massagem ligeira, durante dois minutos. A acção do champô foi estudada na redução da extensão e da intensidade da descamação, do eritema e do prurido. Resultados: Na avaliação final feita por cinco médicos, catorze (48,2 por ciento) doentes foram classificados com muito bom, treze (44,7 por ciento) com bom e dois (6,9 por ciento) com regular, enquanto que na avaliação dos doentes, nove (31,0 por ciento) deram a classificação de muito bom, dezasseis (55,2 por ciento) a de bom e quatro (13,8 por ciento) a de regular. Em nenhum caso se verificou a classificação de mau. A diminuição da área da pitiríase observou-se sobretudo nos casos em que, na consulta inicial, era superior a 50 cm2. Como efeitos secundários, dois doentes referiram acentuação da oleosidade, um, queda de cabelo e, outro, dermite irritativa.Conclusões: o champô revelou-se eficaz e bem tolerado no controle da pitiríase do couro cabeludo, nas condições prescritas, durante um mês. (AU) - Pt

Effect of medium change on the development of in vitro matured and fertilized bovine oocytes cultured in medium containing amino acids.

Bovine in vitro matured and fertilized oocytes were cultured for 153 hr in groups of 3 or 30 in 30 microl of modified synthetic oviduct fluid medium supplemented with amino acids. The concentration of ammonium in culture medium at 153 hr of culture was significantly decreased by medium change at 72 hr of culture. However, regardless of embryo density, medium change had no beneficial or detrimental effect on the development of bovine embryos. Increase in the development to blastocysts and production of ammonium were observed when embryos were cultured in groups of 30. These results indicated that the ammonium concentration detected in this culture system has a negligible effect on the development of bovine embryos to blastocysts.

In vitro screening of antitumour agents for cardiotoxicity by means of isolated mouse left atria.

Cardiotoxicity, a side-effect that can occur after treatment with an anticancer drug, has severe clinical implications. Therefore, a model is desired to screen new anticancer drugs or drug combinations for possible cardiotoxic side-effects. In the present study we tested the applicability of the electrically stimulated isolated mouse left atrium model using a wide range of anticancer drugs with known cardiotoxicity. It appeared that the cardiotoxicity observed in our model, i.e. the negative or positive inotropic effects of the drugs on the isolated atrium, corresponded with the observed cardiotoxicity in animals and/or humans. It is therefore concluded that our model can be used to wam for possible cardiotoxic side-effects of anticancer drugs in vivo.

Otilonium bromide in irritable bowel syndrome: a double-blind, placebo-controlled, 15-week study.

AIM: To evaluate the efficacy of otilonium bromide, a spasmolytic agent, in the treatment of irritable bowel syndrome using modern and validated diagnostic criteria. METHODS: Three hundred and seventy-eight patients with irritable bowel syndrome were enrolled in the study. At entry, endoscopy/barium enema, clinical examination and laboratory tests were used to rule out organic diseases. After a 2-week placebo run-in, 325 patients were randomly assigned to receive either otilonium bromide 40 mg t.d.s. or placebo for 15 weeks. Abdominal pain, abdominal distension and disturbed defecation were scored at the beginning of the study and every 5 weeks. A global determination of well-being by visual analogue scale and the tenderness of the sigmoid colon were also scored. RESULTS: The reduction in the number of abdominal pain episodes was significantly higher (P < 0.01) in otilonium bromide patients (55.3%) than in those taking placebo (39.9%) as was the severity of abdominal distension (42.0%, vs. 30.2%; P < 0.05). Bowel disturbance improved in both groups. but without any statistically significant difference. The visual analogue scale of well-being revealed a significant improvement (P < 0.05) in patients taking otilonium bromide. The investigators' global positive assessment was in favour of otilonium bromide (65.2%) compared with placebo (49.6%) (P < 0.01). CONCLUSIONS: Otilonium bromide may represent an effective treatment for irritable bowel syndrome because it reduces its predominant symptom (abdominal pain/ discomfort) more than placebo does.

Evaluation of oral contrast agents for abdominal magnetic resonance imaging.

We evaluated the efficacy of six available oral contrast agents in improving visualization of bowel and surrounding structures on magnetic resonance imaging of the abdomen and pelvis. Five volunteers were examined without oral contrast (baseline) and, on separate occasions, after ingestion of 600-900 cc of two positive contrasts [12.5% weight-to-volume (w/v) corn oil emulsion (COE), Redi Cat (EZ-Em Corp., Westbury, NY) mixed with 1% ferric ammonium citrate (FAC)] and four negative contrasts [220%, 105%, 85%, 60% w/v barium sulfate (Liquid HD, Liquid Polybar Plus, HD 85, reconstituted EZ Pake; EZ-Em Corp., Westbury, NY)]. Spin-echo axial and coronal T1-weighted and axial T2-weighted images were obtained in the abdomen and pelvis. Three radiologists blindly graded the images for improved visualization of bowel and surrounding structures. Data were analyzed for statistical significance using the General Linear Models algorithm. In the upper abdomen (stomach, duodenum, liver, and pancreas), COE yielded the highest mean scores (p < .0001), followed by 220% w/v barium. For the lower abdomen (ileum, colon), 220% w/v barium yielded the highest scores (p < .0001) and COE was much worse. The higher density barium preparations (220% and 105% w/v) yielded higher scores than their lower density counterparts (85% and 60%). All contrasts improved visualization of the retroperitoneum and spleen, but no one agent was best. All agents tested are superior to no agent at all. For visualization of the upper abdomen, 12.5% COE performed best. For visualization of the lower abdomen, 220% w/v barium performed best. For concurrent evaluation of both areas with one agent, 220% w/v barium performed best.

Effects of high iron and sulfate ion concentrations on dry matter digestion and volatile fatty acid production by ruminal microorganisms.

The inhibitory effects of iron- and sulfate-containing compounds on the in vitro digestion of a balanced forage diet by mixed populations of ruminal microorganisms were examined in batch cultures. Compounds containing ferrous and ferric cations consistently inhibited DM digestion by up to 36% when added Fe concentrations in cultures were between 100 and 1,000 mg/L. Increased sulfate concentrations of up to 200 mg/L or chloride concentrations of up to 635 mg/L were not associated with decreased DM digestion. Ammonium sulfate additions that provided 200 mg/L of added sulfur increased (P less than .05) digestibility by 10%. Sulfate-containing iron salts tended to be less inhibitory than chloride salts and were associated with increased gas production during digestion. Ferric chloride inhibited (P less than .05) microbial activities at lower concentrations than ferrous chloride. Data suggest that excessive iron supplementation or contamination of feeds with iron-containing pollutants may decrease microbial activities in the rumen.