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This article describes the design, synthesis, and biological screening of a new series of diarylurea and diarylamide derivatives including quinoline core armed with dimethylamino or morpholino side chain. Fifteen target compounds were selected by the National Cancer Institute (NCI, USA) for in vitro antiproliferative screening against a panel of 60 cancer cell lines of nine cancer types. Compounds 1j-l showed the highest mean inhibition percentage values over the 60-cell line panel at 10 μM with broad-spectrum antiproliferative activity. Subsequently, compounds 1j-l were subjected to a dose-response study to measure their GI

Method We examined faecal samples, using the GA-map™ Dysbiosis Test, to associate gut microbiota composition with Crohn’s disease (CD) and ulcerative colitis (UC) and to identify markers for future biomarker identification. We conducted a prospective case-control study (EU-ref. no. 305676) in an inception cohort of 324 individuals (64 CD, 84 UC, 116 symptomatic non-IBD controls and 44 healthy controls) across five European centres and examined 54 predetermined bacterial markers. We categorized patients according to the Montreal Classification and calculated the dysbiosis index (DI). Non-parametric tests were used to compare groups and the Bonferroni correction to adjust for multiple comparisons. Results The fluorescent signals (FSSs) for Firmicutes and Eubacterium hallii were lower in inflammatory bowel disease (IBD) vs. symptomatic controls (p

Although vestibular symptoms are amongst the most frequent reasons for seeking emergency medical help, many patients remain undiagnosed.In this cross-sectional study, we investigated the spectrum of vertigo and dizziness in a tertiary ear, nose, and throat (ENT) emergency department (ED). Furthermore, we investigated the attendant symptoms, clinical signs, and the diagnostic tests performed.We screened all ED reports from 01/2013 to 12/2013 for adult patients with vestibular symptoms referred to the ENT department.In total, we found 2596 cases with reported vestibular symptoms in the ED as a main or accompanying complaint. Of these, 286 were referred to the ENT specialist directly (n = 98) or via other major medical specialties (n = 188). Benign paroxysmal positional vertigo (BPPV) was the most frequent diagnosis in our study (n = 46, 16.1%), followed by vestibular neuritis (n = 44, 15.4%), otitis media (n = 20, 7%), and 9 patients (3.1%) had an ischemic stroke or a transient ischemic attack. In 70 (24.5%) cases, dizziness was not further specified.BPPV is the most frequent diagnosis seen in the ED; however, physicians need to document nystagmus more precisely and perform diagnostic tests systematically, in order to make an accurate diagnosis. To avoid misdiagnoses, ED physicians and ENT specialists should be able to recognize central signs in patients with an acute vestibular syndrome. Every fourth patient does not receive a definitive diagnosis. Diagnostic ED workup for patients with dizziness needs further improvement.

Background Patients with malignant tumours may suffer from nausea as a side-effect of chemo-/radiotherapy. Antiemetic drugs can cause dizziness, which may lead to falls and decrease quality of life. Complementing research on painkiller-associated dizziness [1], we now focus on dizziness in association with antiemetic drugs. Methods A systematic review is provided on dizziness in association with antiemetic drugs. A PubMed literature search was carried out for all articles in core clinical journals until 30 June 2019. Results A total of 411 articles were identified. No study evaluated dizziness caused by antiemetic drugs as a primary endpoint. A focus on dizziness as a secondary endpoint revealed four studies with class 1a (meta-analysis) or 1b (randomized controlled trial) level of evidence (LoE). In cisplatin-based chemotherapy, there is LoE 1b that the 5-hydroxytryptamine 3 receptor antagonists (5-HT(3)RA) ondansetron [2] or the combination of tropisetron and dexamethasone [3] are better in terms of antiemetic potential and dizziness than metoclopramide [2] or metoclopramide plus dexamethasone plus diphenhydramine [3]. Among 5-HT(3)RAs, a meta-analysis with over 6000 patients [4] revealed that palonosetron had the lowest incidence of nausea and dizziness (LoE 1a). The neurokinin-1 receptor rolapitant was associated with less nausea than ondansetron plus dexamethasone in a randomized controlled trial (LoE 1b) including 454 patients and had a descriptively but not significantly higher incidence of dizziness [5]. Conclusions 5-HT(3)RAs, particularly palonosetron, have an advantage with regard to antiemetic efficacy and frequency of reported dizziness when compared to metoclopramide [2-4]. The neurokinin-1 receptor rolapitant is a possible alternative [5]. References: 1. Spiegel R, et al. Ann Oncol. 2018 Oct;29(suppl_8):1793P. doi: 10.1093/annonc/mdy300.107 2. Tsavaris N, et al. Acta Oncol. 1995;34(2):243-6. doi: 10.3109/02841869509093962 3. Chua DT, et al. Br J Clin Pharmacol. 1996 May;41(5):403-8. doi: 10.1046/j.1365-2125.1996.03268.x 4. Popovic M, et al. Support Care Cancer. 2014 Jun;22(6):1685-97. doi: 10.1007/s00520-014-2175-6 5. Rapoport B, et al. Support Care Cancer. 2015 Nov;23(11):3281-8. doi: 10.1007/s00520-015-2738-1. Legal entity responsible for the study The first author and the last author. Funding Has not received any funding. Disclosure S.I. Rothschild: Honoraria (institution), Honoraria for advisory boards to the institution: AbbVie; Honoraria (institution), Honoraria for advisory boards to the institution: AstraZeneca; Honoraria (institution), Honoraria for advisory boards to the institution: Boehringer Ingelheim; Honoraria (institution), Honoraria for advisory boards to the institution: BMS; Honoraria (institution), Honoraria for advisory boards to the institution: Eisai; Honoraria (institution), Honoraria for advisory boards to the institution: Eli Lilly; Honoraria (institution), Honoraria for advisory boards to the institution: Merck; Honoraria (institution), Honoraria for advisory boards to the institution: MSD; Honoraria (institution), Honoraria for advisory boards to the institution: Novartis; Honoraria (institution), Honoraria for advisory boards to the institution: Pfizer; Honoraria (institution), Honoraria for advisory boards to the institution: Roche; Honoraria (institution), Honoraria for advisory boards to the institution: Takeda; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): BMS; Research grant / Funding (self): Eisai. R. Kalla: Research grant / Funding (self), Grant #320030_173081: National Science Foundation of Switzerland. All other authors have declared no conflicts of interest.

ZusammenfassungDer menschliche Hippocampus spielt eine wichtige Rolle für verschiedene Aspekte des episodischen Gedächtnisses und auch beim räumlichen Gedächtnis sowie der Navigation. In tierexperimentellen Untersuchungen zeigte sich, dass die Stimulation des vestibulären Systems die Aktivität der „place cells” im Hippocampus moduliert, welche ein neuronales Substrat dieser räumlichen Repräsentation darstellen. Das Ziel der hier vorgestellten Untersuchungen war es festzustellen, ob Patienten mit beidseitiger oder einseitiger Durchtrennung des Gleichgewichtsnerven Defizite der räumlichen Orientierung zeigen bzw. ob diese mit Volumenänderungen im Hippocampus einhergehen. Die hier beschriebenen Ergebnisse unterstreichen die Hypothese, dass vestibuläre Informationen, die den Hippocampus erreichen, eine wichtige Funktion für das räumliche Gedächtnis spielen und eine essenzielle Voraussetzung für die erfolgreiche räumliche Orientierung und Navigation darstellen. In Zukunft wird sich zeigen, inwieweit die Ergebnisse klinische und alltagsrelevante Auswirkungen haben und die Behandlung von Patienten mit vestibulären Defiziten in der Praxis beeinflussen.Der menschliche Hippocampus spielt eine wichtige Rolle für verschiedene Aspekte des episodischen Gedächtnisses und auch beim räumlichen Gedächtnis sowie der Navigation. In tierexperimentellen Untersuchungen zeigte sich, dass die Stimulation des vestibulären Systems die Aktivität der “place cells” im Hippocampus moduliert, welche ein neuronales Substrat dieser räumlichen Repräsentation darstellen. Das Ziel der hier vorgestellten Untersuchungen war es festzustellen, ob Patienten mit beidseitiger oder einseitiger Durchtrennung des Gleichgewichtsnerven Defizite der räumlichen Orientierung zeigen bzw. ob diese mit Volumenänderungen im Hippocampus einhergehen. Die hier beschriebenen Ergebnisse unterstreichen die Hypothese, dass vestibuläre Informationen, die den Hippocampus erreichen, eine wichtige Funktion für das räumliche Gedächtnis spielen und eine essenzielle Voraussetzung für die erfolgreiche räumliche Orientierung und Navigation darstellen. In Zukunft wird sich zeigen, inwieweit die Ergebnisse klinische und alltagsrelevante Auswirkungen haben und die Behandlung von Patienten mit vestibulären Defiziten in der Praxis beeinflussen.

Background Patients with downbeat nystagmus syndrome suffer from oscillopsia, which leads to an unstable visual perception and therefore impaired visual acuity. The aim of this study was to use real-time computer-based visual feedback to compensate for the destabilizing slow phase eye movements. Methods The patients were sitting in front of a computer screen with the head fixed on a chin rest. The eye movements were recorded by an eye tracking system (EyeSeeCam®). We tested the visual acuity with a fixed Landolt C (static) and during real-time feedback driven condition (dynamic) in gaze straight ahead and (20°) sideward gaze. In the dynamic condition, the Landolt C moved according to the slow phase eye velocity of the downbeat nystagmus. The Shapiro-Wilk test was used to test for normal distribution and one-way ANOVA for comparison. Results Ten patients with downbeat nystagmus were included in the study. Median age was 76 years and the median duration of symptoms was 6.3 years (SD +/- 3.1y). The mean slow phase velocity was moderate during gaze straight ahead (1.44°/s, SD +/- 1.18°/s) and increased significantly in sideward gaze (mean left 3.36°/s; right 3.58°/s). In gaze straight ahead, we found no difference between the static and feedback driven condition. In sideward gaze, visual acuity improved in five out of ten subjects during the feedback-driven condition (p = 0.043). Conclusions This study provides proof of concept that non-invasive real-time computer-based visual feedback compensates for the SPV in DBN. Therefore, real-time visual feedback may be a promising aid for patients suffering from oscillopsia and impaired text reading on screen. Recent technological advances in the area of virtual reality displays might soon render this approach feasible in fully mobile settings.

Monensin, a carboxylic ionophore, is well known for Na(+)/H(+) exchanger activity across biological membranes. It is also used in the poultry industry for its useful effects as a food additive. The present study has been designed to investigate the effects of monensin on some oxidative stress-related parameters in rat testis. Monensin was administered intratesticularly (5 mug/testis) to both testes by a single dose to Wistar rats for different time periods. After the completion of the respective treatments, various parameters reflecting the antioxidant defense system of the tissue were monitored and marked changes were found in the activities of various enzymes as well as in the levels of reduced glutathione and lipid peroxidation. After 1, 2, 3, and 4 days of monensin treatment, the activity of superoxide dismutase was found to be unaltered. However, after 2 days of monensin treatment, glutathione-S-transferase and catalase showed inhibition in their activities along with the depletion of glutathione (reduced) accompanied by a marked increase in lipid peroxidation. The increase in lipid peroxidation was noticeable even after 1 day of monensin administration. The inhibition in glutathione-S-transferase and glutathione peroxidase activities was also observed along with an increase in lipid peroxidation at the end of the 3-day posttreatment period, while, the 4-day posttreatment schedule caused an increase in the activity of glutathione reductase and glutathione peroxidase that was also accompanied by an inhibition of catalase. The findings of the present study are indicative of the potential of monensin in testicular tissue in contraceptive intervention.

In this paper we describe Bare Metal Linux (BML), a cut-down version of Linux® 2.6 that requires no firmware, has an in-memory root file system, and runs without a virtualization layer. We designed and implemented BML in order to accelerate the bring up of POWER5TM-based systems. The use of BML allows testing and validation of the POWERS-based system to be conducted in parallel with the standard path, which involves the bring up of a hypervisor, the partition firmware, and the operating system. BML, which has fast boot times and can be modified quickly, is used in fault detection during chip manufacturing, POWER5 chip verification, system-board verification, and benchmarking for performance. BML is also used to reproduce and resolve problems in Linux.

Expression patterns of chimeric gusA reporter genes encoding bacterial β-glucuronidase (GUS) with four differentially regulated promoters from Arabidopsis thaliana were assessed in transgenic white clover ( Trifolium repens ) plants generated by Agrobacterium -mediated transformation. Molecular analysis of independent white clover transformants confirmed the stable integration of T-DNAs containing the various promoter- gusA reporter genes. Histochemical staining of plant tissues and organs revealed that the atmyb32 promoter directed gusA expression in leaf and root vascular tissue including lateral roots and nodules with low levels of expression in reproductive organs. Wound-response of the atmyb32 promoter in white clover leaves and stolons was also shown. The adh promoter showed anaerobic stress and dehydration stress response. The xero2 promoter directed strong expression in roots, leaf vascular tissue, inflorescences, anther filaments and pollen grains, while the A. thaliana SAG12 promoter resulted in senescence-associated gusA expression in white clover leaves.

A highly efficient and robust procedure for plant regeneration from cotyledonary explants was developed for a range of clovers ( Trifolium species) including T. repens , T. pratense , T. subterraneum , T. michelianum and T. isthmocarpum and medics ( Medicago species) including alfalfa ( M. sativa ), M. polymorpha , M. truncatula , M. litoralis and M. tonata . Efficient and reproducible protocols for Agrobacterium -mediated transformation of T. repens , T. pratense and T. subterraneum , using different selectable marker genes, were developed based on the established genotype-independent regeneration procedure. Detailed molecular analysis confirmed the transgenic nature of plants recovered for three clover species tested. Stable meiotic transmission of transgenes was demonstrated for selected transgenic plants carrying single T-DNA inserts. The optimised protocol developed for regeneration and genetic transformation of pasture legumes was refined to demonstrate its application to the production of transgenic and untransformed control plants in otherwise isogenic genetic background from individual pairs of cotyledons.

The present study was undertaken to explore the effects of monensin, a potent Golgi disturbing agent on male fertility.Male Wistar rats were administered monensin at the dose levels of 2.5, 5, and 10 mg/kg b wt. Animals were sacrificed after 67 days of the treatment. The activities of lactate dehydrogenase (LDH), ATPase, acid phosphatase and thiamine pyrophosphatase (TPPase) were measured in the testis. Cytochemical assay of Golgi body marker enzyme, thiamine pyrophosphatase was also performed. Ultrastructural changes in testis were studied by Transmission electron microscopy. Sperm number and motility were also examined.The alterations in the activities of above mentioned enzymes indicate the pronounced effect of the drug on the functioning of spermatogenic cells. The findings from electron microscopy such as membrane disruption, swelling and disintegration of Golgi apparatus strongly suggest the interference of monensin with the functioning of Golgi apparatus in the spermatogenic cells. Data from the sperm number and motility as well as the fertility studies and the resulted litter size further points towards the antifertility effects of monensin in male rats.The findings from the present study strongly indicated the effects of monensin on the testis, involving alterations in key enzyme activities and changes at the ultrastructural level.

Proximity Extension Assay technology identifies novel serum biomarkers for predicting Inflammatory Bowel Disease : IBD Character Consortium

Studies were carried out to determine the antifertility and reversibility effect of pyrimethamine (PYR) in adult male mice. The parameters mainly included sperm count and motility, fertility, histoarchitecture of testis and testicular cell kinetics quantitatively following oral administration of PYR (50 mg/kg body weight per day) for 30 days. The same parameters were also studied in PYR-treated animals which were allowed to recover for 45 days (recovery group). The results suggest that sperm motility as well as counts were significantly decreased in PYR-treated animals, and the fertility rate fell to zero. Testicular histology as well as germ cell kinetics were altered. However, in the animals of the recovery group, all the parameters studied were more or less similar to those of control animals. The study demonstrates the antifertility as well as reversible efficacy of PYR.

Summary This paper reviews recent data from our laboratories on the early phases of endosperm development in barley. First, we provide a description of endosperm morphogenesis based on immunohistochemical studies using the confocal laser scanning microscope. In the second part, the barley Ltp2 gene, which is exclusively expressed in the aleurone layer of developing grains, is characterized. In the last part, we describe the barley gene encoding the small subunits of the AGPase in the starchy endosperm and leaf tissue.

Proximity extension assay immunoassay technology identifies novel serum biomarkers that can diagnose and classify inflammatory bowel diseases : IBD Character Consortium

Viral diseases, such as Alfalfa mosaic virus (AMV), cause significant reductions in the productivity and vegetative persistence of white clover plants in the field. Transgenic white clover plants ectopically expressing the viral coat protein gene encoded by the sub-genomic RNA4 of AMV were generated. Lines carrying a single copy of the transgene were analysed at the molecular, biochemical and phenotypic level under glasshouse and field conditions. Field resistance to AMV infection, as well as mitotic and meiotic stability of the transgene, were confirmed by phenotypic evaluation of the transgenic plants at two sites within Australia. The T(0) and T(1) generations of transgenic plants showed immunity to infection by AMV under glasshouse and field conditions, while the T(4) generation in an agronomically elite 'Grasslands Sustain' genetic background, showed a very high level of resistance to AMV in the field. An extensive biochemical study of the T(4) generation of transgenic plants, aiming to evaluate the level and composition of natural toxicants and key nutritional parameters, showed that the composition of the transgenic plants was within the range of variation seen in non-transgenic populations.

To elucidate the molecular aspects of cereal endosperm development, a good understanding of the histo-differentiation process is necessary. Reviewing the extensive history of lightand electron-microscopic investigations has revealed similarities between cereals with respect to cell ontogeny. Thus, using barley as a model and taking into account many developmental mutants in this and other species, a model for endosperm differentiation is proposed. Based on this model, molecular studies on endosperm gene-regulation are discussed and the available techniques for further investigations are considered.

Nystagmus causes blurred vision due to oscillopsia, as well as impaired balance. Depending on etiology, additional cerebellar and brain stem signs may occur. We present the current pharmacotherapy of the most common forms of central nystagmus: downbeat nystagmus (DBN), upbeat nystagmus (UBN), acquired pendular nystagmus (APN), and congenital nystagmus (CGN). Recommended medical therapies are aminopyridines (4-AP) for DBN and UBN, gabapentin and memantine for CGN and APN, and baclofen for periodic alternating nystagmus (PAN).

The effect of monensin, a Na+-specific ionophore on the oxidative defense system in rat testis was studied. Monensin mixed in the animal diet was administered at the dose levels of 2.5, 5 and 10 mg/kg b.w. to Wistar rats for a period of 67 days. A marked inhibition in the activities of different oxidative defense enzymes such as catalase, glutathione peroxidase, glutathione-S-transferase, superoxide dismutase and glutathione reductase was noticed, which indicates the possible involvement of free radicals in the antispermatogenic effects of monensin in rat testis. This was further substantiated by a significant increase in the generation of lipid peroxides along with the depletion of reduced glutathione. The drug treatment resulted in a significant change in apoptotic cell death as seen by an elevated fragmentation in the testicular genomic DNA. Monensin treatment also resulted in marked degenerative changes in the histoarchitecture of testis, such as depletion of different germ cell populations, vacuole formation and disorganization of seminiferous tubules. The results are indicative of the potential antispermatogenic effects of monensin in the rat.

Monensin, a sodium specific ionophore was evaluated for its in vitro effects on rat testis by studying changes at biochemical parameters as well as at the DNA level. It was observed that monensin produced marked alterations in the activities of various enzymes associated with the testicular functions. The significant inhibition of different enzymes of oxidative defense system points toward the generation of reactive oxygen species (ROS) by monensin treatment. The significant depletion of reduced glutathione and elevation in the level of lipid peroxidation further support the above findings. The significant inhibition of the activities of lactate dehydrogenase and adenosine triphosphatase shows the interference of monensin with the normal energy supply in spermatogenesis. Moreover, the significant increase in the activities of acid phosphatase and thiamine pyrophosphatase demonstrates the interference of monensin with the Golgi-lysosomal complex of the rat testis. Induced DNA fragmentation indicates towards the impact of monensin on the DNA integrity and apoptosis. Further studies are needed to understand the important molecular mechanisms responsible for these effects.

Viral diseases such as alfalfa mosaic virus (AMV) cause significant reductions in dry matter yield and persistency of white clover (Trifolium repens L.). Transgenic white clover plants expressing the AMV coat protein (AMV-CP) gene and showing immunity to AMV infection were evaluated in multi-site small-scale field releases. Two transformation events showing field immunity to aphid-mediated AMV infection This article outlines the development of transgenic elite white clover germplasm with AMV immunity, involving the world’s first breeding nursery for transgenic white clover.were selected for elite transgenic germplasm development. Following top crosses with elite parental breeding lines, diallel crosses of heterozygous offspring plants and identification of AMV-CP homozygous T2 lines through quantitative PCR-based high-throughput screening, a breeding nursery with 1,300 transgenic white clover plants was established. Agronomically superior transgenic white clover plants were selected as parents for the production of world’s first AMV immune transgenic white clover cultivars.

Significant advances in the establishment of the methodologies required for the molecular breeding of temperate forage grasses (Lolium and Festuca species) and legumes (Trifolium and Medicago species) are reviewed. Examples of current products and approaches for the application of these methodologies to forage grass and legume improvement are outlined. The plethora of new technologies and tools now available for high-throughput gene discovery and genome-wide expression analysis have opened up opportunities for innovative applications in the identification, functional characterisation and use of genes of value in forage production systems and beyond. Selected examples of our current work in pasture plant genomics, xenogenomics, symbiogenomics and microarray-based molecular phenotyping are discussed.

Introduction Anti-Tumour Necrosis Factor alpha antibodies (anti-TNFs) are widely used for the treatment of severe and fistulising Crohn’s Disease (CD). They are, however, associated with a number of adverse events (AEs) including infections, neutropenia, malignancy, demyelinating disease and infusion reactions. We aimed to evaluate the safety profiles Adalimumab (Al) and Infliximab (Ifx) amongst patients with CD at Central Manchester University Hospitals. Methods 217 CD pts were identified retrospectively from our anti-TNF database; data was retrieved from clinic letters. A probit regression was used to correlate AEs and pt characteristics. Results Median age of pts was 41 (range 20–79) yrs. Total lifetime yrs on anti-TNFs was 740.6 (331.2 on Ifx, 409.4 on Al) yrs. 133 pts were treated with Ifx (75 females), 4 had previously been on Al. Median length of Rx with Ifx was 20 (range 1 dose-still on at 140) months. 98 (73.6%) pts on Ifx were on a concomitant immunomodulator drug. 141 pts were treated with Al (79 females), 53 had previously been on Ifx. Median length of Rx with Al was 33 (range 54 (40.6%) pts had AEs whilst on Ifx (see Table 1 for severity), including lymphoma (2 pts), solid organ tumours (3), pulmonary TB (2), infusion reaction (13), cutaneous side effects (SEs) (7), other infections (12). 33 pts were still on Ifx at the time of this study. 30 pts (22.6%) stopped Ifx due to AEs. 13 pts had an infusion reaction. Pts were most likely to have an infusion reaction at infusion 2 (6 pts). Overall, 57 (39.7%) pts suffered from AEs on Al (see Table 1 for severity), including solid organ tumours (2 pts), cutaneous SEs (10), neurological symptoms (3) and other viral/bacterial infections (28). 88 pts were still on Al at the time of this study. 21 pts (14.9%) stopped Al due to AEs. Pts were more likely to suffer from an AE with increasing age (p = 0.041 for Ifx, p = 0.016 for Al). Patients over 50 yrs were more likely to suffer from an AE than those less than 50 (p = 0.015 for Ifx, p = 0.015 for Al). Pts over 70 yrs were more likely to suffer from a moderate or severe AE on Al (p = 0.009), there was no relationship for Ifx. Gender, smoking status and use of immunomodulators had no effect on AEs. No significant relationship found between length of Rx and development of AEs. No statistically significant difference found in AEs frequency between Ifx and Al. Conclusion This study found that AEs are independent of the length of time on anti-TNFs, but are associated with increasing age of the patient. Patients over 50 yrs are more likely to have an AE on Ifx and Al. Patients over 70 yrs are more likely to have a moderate or severe AE on Al. Disclosure of Interest None Declared.

Reference(s) [1] Stephane Paul, Emilie Del Tedesco, Hubert Marotte, et al. (2013), Therapeutic Drug Monitoring of Infliximab and Mucosal Healing in Inflammatory Bowel Disease: A Prospective Study, Inflammatory Bowel Disease. [2] Filip Baert, Maja Noman, Severine Vermeire, et al. (2003), Influence of Immunogenicity on the Long-Term Efficacy of Infliximab in Crohn’s Disease, The New England Journal of Medicine.

Activation of microglia is among the first cellular changes in the injured CNS. However, little is known about their specific contribution to secondary damage or repair processes in neighboring neurons and nonneuronal cells or to the immune surveillance of the damaged tissue. Animal models with defective microglial response such as osteopetrosis provide an approach to explore these effects. Osteopetrosis (op) is an autosomal recessive mutation with a complete deficiency of the macrophage-colony stimulating factor (MCSF; CSF-1), an important mitogen for brain microglia. In the current study we examined the effects of this MCSF deficiency on the microglial reaction and the overall cellular response to nerve injury in the mouse axotomized facial motor nucleus. In the brain, MCSF receptor immunoreactivity was found only on microglia and was strongly up-regulated following injury. MCSF deficiency led to a failure of microglia to show a normal increase in early activation markers (thrombospondin, MCSF receptor, alpha M beta 2- and alpha 5 beta 1-integrins), to spread on the surface of axotomized motoneurons, and to proliferate after injury. Early recruitment of CD3(+) T-lymphocytes to the facial nucleus 24 hours after injury was reduced by 60%. In contrast, the neuronal and astrocyte response was not affected. There was a normal increase in the neuropeptides calcitonin gene-related peptide and galanin, neuronal c-JUN, and NADPH-diaphorase and a decrease in choline acetyltransferase and acetylcholinesterase. Astrocyte glial fibrillary acidic protein immunoreactivity also showed a normal increase. There was a normal influx of macrophages and granulocytes into the injured facial nerve. Synaptic stripping, neuronal survival, and speed of axonal regeneration were also not affected. The current results show a strong, selective effect of MCSF on the early activation of microglia and, indirectly, on lymphocyte recruitment. This early phase of microglial activation appears not to be involved in the process of repair following peripheral nerve injury. However, it is important in the initiation of inflammatory changes in the brain and in the interaction with the immune system.

Forage plant breeding has been largely based on phenotypic selection following sexual recombination of natural genetic variation found between and within ecotypes. Advances in plant genetic manipulation over the last 15 years have provided convincing evidence that these powerful technologies can complement and enhance plant breeding programs. Significant progress in the establishment of the methodologies required for the molecular breeding of forage plants has been made. Examples of current products and approaches for the application of these methodologies to forage grass and legume improvement are outlined. Large-scale genomic analysis of many organisms is under way with human, arabidopsis and rice genome sequences almost completed. Forage plant breeding is just now entering the genome era. The plethora of new technologies and tools now available for high-throughput gene discovery and genome-wide gene expression analysis have opened up opportunities for innovative applications in the identification, functional characterisation and use of genes of value in forage production systems and beyond. Examples of these opportunities, such as ‘molecular phenotyping’, ‘symbio-genomics’ and ‘xeno-genomics’ are introduced.

Viruses such as alfalfa mosaic alfamovirus (AMV), white clover mosaic potex virus (WCMV) and clover yellow vein potyvirus (CYVV), which are members of the three largest groups of plant viruses, have been found to have significant adverse effects on forage legumes. Each of these viruses individually infects a large number of plant species, has a worldwide distribution, and causes significant losses, especially in pasture and grain legumes.

Introduction EMR of large colorectal polyps has been reported to be a safe and effective technique in UK. Although the success of large polyp EMR has been reported within regional bowel cancer screening centres, there is a paucity of data comparing outcomes between screening and non-screening centres. Methods A total of 61 screening and 60 non-screening EMR of polyps 2cm or greater were performed from January 2008 to December 2011. Data was collected from 3 hospitals for screening EMR and 1 district hospital for non-screening EMR. Results The table below summarises the findings at initial EMR for both groups. Surveillance data was available for 37 patients in the non-screening group compared to all 61 patients in the screening group up-to 3 months post EMR. Number of recurrences were 6 (10%) with mean polyp size of 25mm in the screening group compared to 10 (27%) in the non screening group with mean polyp size of 50mm. All recurrences in both groups were resected and complete. Histology confirmed low grade dysplasia (LGD) in 80%, while 2 patients had evidence of high grade dysplasia (HGD) in the non-screening group. All showed LGD in the screening group. At 12 months surveillance post EMR, 43 screening patients had follow-up data with 8 recurrences detected compared to 14 in the non screening group with 4 recurrences. Conclusion Endoscopic mucosal resection of polyps in screening group appears to be safer with low complication rates and low recurrence rate up to 12 months post EMR compared to the non-screening groups. This may be due to a multitude of factors such as patient age, co-morbidites and the characteristics of polyps. Clinical features of patients undergoing EMR were similar in both groups. There was a trend to higher recurrence and complication rate in the non screening group. The follow up post EMR was less consistent in the non screening group possibly due to less stringent protocols for follow up. This may have affected the surveillance and recurrence rates. Disclosure of Interest None Declared. References Lim TR, Mahesh V, Singh S, et al. Endoscopic mucosal resection of colorectal polyps in typical UK hospitals. World J Gastroenterol .2010; 16(42): 5324–8. Boix J, Lorenzo-Zuniga V, Moreno de Vega V, et al. Endoscopic removal of large sessile colorectal adenomas: is it safe and effective? Dig Dis Sci 2007; 52 : 840–844 Salama M, Ormonde D, Quach T, et al. Outcomes of endoscopic resection of large colorectal neoplasms: an Australian experience. J Gastroenterol Hepatol 2010; 25 : 84–89

This study was designed to investigate the effects of repeated high doses of an LHRH agonist on Swiss porton mouse seminiferous epithelium. Seminiferous epithelium showed more pronounced degenerative effects at the higher dose (1000 micrograms/kg wt/day) of the drug, with arrest of spermatogenesis at all stages of differentiation; effects on spermatogenesis become more evident after pachytene spermatocyte stage. The decrease in the testis-specific enzyme LDH-X is accounted for by the decrease in the number of cells of gametogenic origin. Although complete azoospermia was not observed, acute inhibition of motility of spermatozoa may account for severely decreased fertility rates after mating. However, reduced fertility rates due to decreased libido as a consequence of diminished testosterone levels cannot be discounted.

Introduction Endoscopic mucosal resection (EMR) of colorectal polyps has been reported to be a safe and effective technique within the UK. Most series have however included smaller polyps (1 cms or less) and there is paucity of data on EMRs limited to large polyps. We report the outcomes on a series with large polyps (>2 cms) from a bowel cancer screening centre in the UK. Methods A total of 5190 polypectomies were performed within the region from January 2008 to December 2011 on the Bowel Screening Programme. Data were collected from three hospitals on all large polyp EMR greater than 2 cm in size. Data were analysed using the SPSS V.20. Results A total of 61 patients with polyps 2cm or greater were identified. The mean age was 69 years, 75% (n=46) of which were male. The mean size of the polyps resected was 35 mm (range 20–60 mm). The majority of the polyps were sessile (n=40) and located in the left colon (n=43). Tattooing was performed in 46% (n=28) and Argon-beam photocoagulation (APC) therapy was applied in 41% of cases (n=25). In 97%, the resections were complete (n=59). Histopathology results were obtainable in 57 patients of whom 12% (n=7/57) showed high grade dysplasia and 5% (n=3/57) were confirmed as adenocarcinoma. The overall major complication rate was 3% (n=2). Both complications were bleeding post-EMR. Surveillance data were available for 43 patients up-to 12 months post EMR. Six recurrences (10%) were seen at the EMR site at 3 months, five of these in left colon. On reviewing their initial EMR, the polyps had a median size of 25±6 mm; 50% (n=3/6) had APC therapy and 5/6 the excision was endoscopically complete on initial EMR. Histology confirmed low grade dysplasia (LGD) in all cases. Recurrence was endoscopically treated successfully in all cases. Recurrence rate was not influenced by the size or site of the polyp or APC therapy. Sessile polyp EMR were more likely to show recurrence (n=5/6). At 12 months, eight patients had recurrence. Six of these patients had endoscopically complete excision on initial EMR. On reviewing their initial EMR, the polyps had a median size of 35±5 mm; 50% had APC therapy. Recurrence was treated successfully in all cases. Conclusion Endoscopic mucosal resection for large colorectal polyps is safe with relatively low complication rates compared to laproscopic surgery. Recurrence rate is low at 3 months but can still occur upto 12 months in lesions felt to be completely excised. Competing interests None declared.

To determine the (reversible) antifertility effect in the male rat of sulfasalazine, a common therapy for inflammatory bowel disease.Sulfasalazine (120, 250 and 500 mg/kg) was administered for 60 days by oral gavage to sexually mature male rats.Both motility of sperm and fertility of animals was significantly altered at the highest dose (500 mg/kg). Morphological abnormalities included alteration in the normal profile of the spermatozoa and presence of lesions on the sperm head.Results suggest that sulfasalazine brings about its antifertility effects by altering sperm motility and number of spermatozoa in addition to increased surface abnormalities, which render the spermatozoa infertile.

Forty-three children with displaced transcervical femoral fractures were reviewed at a mean follow-up of 7.2 years and results were assessed using Ratliff's criteria. Of 22 patients treated by internal fixation alone, 10 had good, 6 had fair and 6 had poor results. The results in 21 children treated by internal fixation along with primary transverse intertrochanteric undisplaced osteotomy were: 14 good, 5 fair and 2 poor, but none improved to a statistically significant level (P = 0.139). However, the osteotomy improved the fracture union significantly and no delayed union or non-union was noted in this group (P = 0.05). There were no complications related to the osteotomy itself.

Male rats administered sulphapyridine (60, 120 and 250 mg/kg) for 60 days demonstrated no change in body weight and testicular weight. However, there was a decrease in the weight of the epididymis. Motility and sperm reserves were reduced and were evident from fewer implantation sites and number of pregnancies. Furthermore, sulphapyridine did not show any effect on the histoarchitecture of the testis or epididymis. Serum levels of testosterone in the treated rats were comparable to their respective controls. Morphological abnormalities as revealed by scanning electron microscopic studies clearly demonstrated the detrimental effects of the drug.

Male rabbits and rats were administered gossypol (20 mg/kg/day) for 12 and 7 weeks respectively. Gossypol was estimated in different organs by the aniline method of Smith. Rat and rabbit spleen accumulated the highest level of gossypol. The lowest amount of gossypol was accumulated in the rabbit brain; the level of gossypol in rat brain was below the detectable limit of our method. Although rabbits were administered gossypol for 12 weeks, the accumulation of gossypol in rabbit testis was much lower than that of the rat testis. Our data suggest that non-sensitivity of rabbit to the antifertility effect of gossypol may be due to poor accumulation of gossypol in the testis. Negligible amount of gossypol in the brain rules out the possibility of involvement of hypothalamus-pituitary axis in the mechanism of action of gossypol on the testis.

Male hamsters and rats were administered gossypol 10 mg/kg/day for 45 and 56 days respectively. Twenty four hours before the last dose, animals were administered 65Zn (specific activity 0.258 uci/mg) subcutaneously. A marked decrease in 65Zn incorporation was observed in testis, epididymis, seminal vesicles and prostate following drug administration. A significant increase in 65Zn uptake was however observed in vas deferens in both rat and hamster following drug administration. Our results suggest that whatever the mechanism of gossypol action on testis-epididymis complex may be, the marked decrease in 65Zn uptake by testis--epididymis complex following gossypol treatment may be related to the antispermatogenic effect of gossypol.

Sexually mature male albino rats were divided into four groups of 5 animals each. Animals of group I served as control, whereas animals of group II received gossypol (20 mg/kg body weight/day) for 45 days. Animals of groups III and IV were maintained on protein deficient diet. Animals of group IV received 20 mg/kg gossypol in addition to the protein deficient diet. Animals of group III and IV received protein deficient diet for 45 days before initiating gossypol treatment. The total period of maintaining the animals on protein deficient diet was 90 days. In another experiment, the same experimental protocol was followed except that the animals were maintained on low potassium diet instead of protein deficient diet. A significant decrease in body weight of animals was observed following protein deficient and gossypol (group IV) treatment. Testis weight decreased significantly in the animals of group III (protein deficient) and group IV (protein deficient + gossypol). Similar observations were made in the animals maintained on low potassium diet. In both the experiments, sperm motility was reduced significantly. Histologically, in the testis of animals of group IV (protein deficient + gossypol) almost all the tubules were disorganised and vacuolated and total arrest of spermatogenesis could be observed in majority of the tubules.

Domestic fowls (Gallus domesticus) were administered gossypol (10 mg/kg body weight/day) by oral intubation for 15 weeks. Drug treatment did not have any effect on body growth rate. The drug treatment, however, caused a marked decrease in the weights of testis and epididymis. Predominant changes in the histoarchitecture of testis (desquamation of germinal epithelium and inhibition of spermatogenesis) were observed following gossypol treatment. Epididymal tubules in gossypol treated animals were devoid of spermatozoa. Gossypol treatment had no effect on hematological parameters (total erythrocyte count, total leucocyte count, hematocrit and hemoglobin) studied in the present investigations.