Activin a protects midbrain neurons in the 6-hydroxydopamine mouse model of Parkinson's disease

© 2015 Stayte et al. Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by a significant loss of dopaminergic neurons within the substantia nigra pars compacta (SNpc) and a subsequent loss of dopamine (DA) within the striatum. Despite advances in the development of pharmacological therapies that are effective at alleviating the symptoms of PD, the search for therapeutic treatments that halt or slow the underlying nigral degeneration remains a particular challenge. Activin A, a member of the transforming growth factor β superfamily, has been shown to play a role in the neuroprotection of midbrain neurons against 6-hydroxydopamine (6-OHDA) in vitro, suggesting that activin A may offer similar neuroprotective effects in in vivo models of PD. Using robust stereological methods, we found that intrastriatal injections of 6-OHDA results in a significant loss of both TH positive and NeuN positive populations in the SNpc at 1, 2, and 3 weeks post-lesioning in drug naive mice. Exogenous application of activin A for 7 days, beginning the day prior to 6-OHDA administration, resulted in a significant survival of both dopaminergic and total neuron numbers in the SNpc against 6-OHDA-induced toxicity. However, we found no corresponding protection of striatal DA or dopamine transporter (DAT) expression levels in animals receiving activin A compared to vehicle controls. These results provide the first evidence that activin A exerts potent neuroprotection in a mouse model of PD, however this neuroprotection may be localized to the midbrain

A Mutation in Amino Acid Permease AAP6 Reduces the Amino Acid Content of the Arabidopsis Sieve Elements but Leaves Aphid Herbivores Unaffected.

The aim of this study was to investigate the role of the amino acid permease gene AAP6 in regulating phloem amino acid composition and then to determine the effects of this altered diet on aphid performance. A genotype of Arabidopsis thaliana (L.) was produced in which the function of the amino acid permease gene AAP6 (At5g49630) was abolished. Plants homozygous for the insertionally inactivated AAP6 gene had a significantly larger mean rosette width than the wild type and a greater number of cauline leaves. Seeds from the aap6 mutant were also significantly larger than those from the wild-type plants. Sieve element (SE) sap was collected by aphid stylectomy and the amino acids derivatized, separated, and quantified using Capillary Electrophoresis with Laser Induced Fluorescence (CE-LIF). In spite of the large variation across samples, the total amino acid concentration of SE sap of the aap6 mutant plants was significantly lower than that of the wild-type plants. The concentrations of lysine, phenylalanine, leucine, and aspartic acid were all significantly lower in concentration in the aap6 mutant plants compared with wild-type plants. This is the first direct demonstration of a physiological role for an amino acid transporter in regulating SE composition in vivo. The amino acid availability in sieve element sap is thought to be the major limiting factor for aphid growth and reproduction. Despite the changes in their diet, the aphid Myzus persicae(Sulzer) displayed only small changes in feeding behaviour on mutant plants when measured using the Electronic Penetration Graph (EPG) technique. Salivation by the aphid into the SE (E1 phase) was increased on mutant plants but there was no significant effect on other feeding EPG behaviours, or in the rate of honeydew production. Consistent with the small effect on aphid feeding behaviour, there was only a small effect of reduced sieve element amino acid concentration on aphid reproduction. The data are discussed in relation to the regulation of phloem composition and the role of phloem amino acids in regulating aphid performance

Surgery for Colorectal Cancer - Trends, Developments, and Future Perspectives

Background: Although colorectal surgery is long established as the mainstay treatment for colon cancer, certain topics regarding technical fine-tuning to increase postsurgical recurrence-free survival have remained a matter of debate throughout the past years. These include complete mesocolic excision (CME), treatment strategies for metastatic disease, significance of hyperthermic intraperitoneal chemotherapy (HIPEC), and surgical techniques for the treatment of colorectal cancer recurrence. In addition, new surgical techniques have been introduced in oncologic colorectal surgery, and their potential to provide sufficiently radical resection has yet to be proven. Methods: A structured review of the literature was performed to identify the current state of the art with regard to the mentioned key issues in colorectal surgery. Results: This article provides a comprehensive review of the current literature addressing the above-mentioned current challenges in colorectal surgery. The focus lies on the impact of CME and, in relation to this, on lymph node dissection, as well as on treatment of metastatic disease including peritoneal spread, and finally on the treatment of recurrent disease. Conclusion: Uniformly, the current literature reveals that surgery aiming at complete malignancy elimination within multimodal treatment approaches represents the fundamental quantum leap for the achievement of long-term tumor-free survival. (C) 2016 S. Karger GmbH, Freibur

Targeting the cannabinoid receptor CB2 in a mouse model of l-dopa induced dyskinesia.

L-dopa induced dyskinesia (LID) is a debilitating side-effect of the primary treatment used in Parkinson's disease (PD), l-dopa. Here we investigate the effect of HU-308, a cannabinoid CB2 receptor agonist, on LIDs. Utilizing a mouse model of PD and LIDs, induced by 6-OHDA and subsequent l-dopa treatment, we show that HU-308 reduced LIDs as effectively as amantadine, the current frontline treatment. Furthermore, treatment with HU-308 plus amantadine resulted in a greater anti-dyskinetic effect than maximally achieved with HU-308 alone, potentially suggesting a synergistic effect of these two treatments. Lastly, we demonstrated that treatment with HU-308 and amantadine either alone, or in combination, decreased striatal neuroinflammation, a mechanism which has been suggested to contribute to LIDs. Taken together, our results suggest pharmacological treatments with CB2 agonists merit further investigation as therapies for LIDs in PD patients. Furthermore, since CB2 receptors are thought to be primarily expressed on, and signal through, glia, our data provide weight to suggestion that neuroinflammation, or more specifically, altered glial function, plays a role in development of LIDs

Dyadic Characteristics and Intimate Partner Violence among Men Who Have Sex with Men

Objective: Although the research community has begun to recognize intimate partner violence (IPV) as an important issue in same-sex relationships, there has been a lack of attention to characteristics of these relationships that may be associated with IPV. In particular, there has been a lack of attention paid to the associations between dyadic characteristics and IPV in same-sex relationships. This paper examined associations between dyadic characteristics, including relationship satisfaction, communal coping and efficacy, and perpetrating and experiencing IPV among a sample of United States men who have sex with men (MSM). Methods: We collected data via an online survey with 528 MSM, who were greater than 18 years of age and reported at least one male sex partner in the last 12 months. The analysis examined dyadic factors associated with reporting of experiencing and perpetrating emotional violence, physical violence, and sexual violence. Results: The prevalence of violence in the sample ranged from nine percent reporting perpetrating sexual violence to 33% of men reporting experiencing emotional violence. MSM who reported greater satisfaction with their relationship or who reported a higher degree of concordance with their partner on lifestyle choices were less likely to report experiencing or perpetrating emotional violence. MSM who perceived a stigma to being in a male same-sex couple were less likely to report experiencing or perpetrating sexual violence. Conclusion: The results presented here demonstrate high levels of IPV among MSM and that dyadic characteristics are associated with the occurrence of IPV. Understanding relationship characteristics associated with increased IPV among same-sex male couples can contribute to the development of more accurate IPV screening tools, and more sensitively and appropriately designed intervention messages. [West J Emerg Med. 2011;12(3):324-332.

Ornithine uptake and the modulation of drug sensitivity in <i>Trypanosoma brucei</i>

Trypanosoma brucei, protozoan parasites that cause human African trypanosomiasis (HAT), depend on ornithine uptake and metabolism by ornithine decarboxylase (ODC) for survival. Indeed, ODC is the target of the WHO “essential medicine” eflornithine, which is antagonistic to another anti-HAT drug, suramin. Thus, ornithine uptake has important consequences in T. brucei, but the transporters have not been identified. We describe these amino acid transporters (AATs). In a heterologous expression system, TbAAT10-1 is selective for ornithine, whereas TbAAT2-4 transports both ornithine and histidine. These AATs are also necessary to maintain intracellular ornithine and polyamine levels in T. brucei, thereby decreasing sensitivity to eflornithine and increasing sensitivity to suramin. Consistent with competition for histidine, high extracellular concentrations of this amino acid phenocopied a TbAAT2-4 genetic defect. Our findings established TbAAT10-1 and TbAAT2-4 as the parasite ornithine transporters, one of which can be modulated by histidine, but both of which affect sensitivity to important anti-HAT drugs.—Macedo, J. P., Currier, R. B., Wirdnam, C., Horn, D., Alsford, S., Rentsch, D. Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei

Concentration of rocuronium in cerebrospinal fluid of patients undergoing cerebral aneurysm clipping†

Background. This study assessed the concentration of rocuronium in the cerebrospinal fluid (CSF) of patients undergoing cerebral aneurysm clipping, and investigated whether the mode of administration (single bolus vs continuous infusion) influenced the CSF concentration. Methods. Twenty patients with subarachnoid haemorrhage were randomly allocated to receive a bolus dose (bolus group), or a bolus followed by a continuous infusion of rocuronium (infusion group) (n=10 for each group). Arterial blood and ventricular CSF were sampled 2 h after the rocuronium bolus. Samples were analysed by liquid chromatography electrospray ionization‐tandem mass spectrometry. Results. Rocuronium could be detected in all the CSF samples. The mean (range) CSF concentration was 2.2 (0.9-4.6) ng ml-1 in the bolus group and 12.4 (2.4-34.6) ng ml-1 in the infusion group; P<0.01. Conclusions. This study demonstrated that rocuronium, normally not considered to cross the blood-brain barrier, is regularly found in the CSF of patients undergoing cerebral clipping; continuous infusion of the drug led to higher plasma and CSF concentrations than after a single bolus dose. Br J Anaesth 2004; 92: 419-2

Dyadic Characteristics and Intimate Partner Violence among Men Who Have Sex with Men.

OBJECTIVE: Although the research community has begun to recognize intimate partner violence (IPV) as an important issue in same-sex relationships, there has been a lack of attention to characteristics of these relationships that may be associated with IPV. In particular, there has been a lack of attention paid to the associations between dyadic characteristics and IPV in same-sex relationships. This paper examined associations between dyadic characteristics, including relationship satisfaction, communal coping and efficacy, and perpetrating and experiencing IPV among a sample of United States men who have sex with men (MSM). METHODS: We collected data via an online survey with 528 MSM, who were greater than 18 years of age and reported at least one male sex partner in the last 12 months. The analysis examined dyadic factors associated with reporting of experiencing and perpetrating emotional violence, physical violence, and sexual violence. RESULTS: The prevalence of violence in the sample ranged from nine percent reporting perpetrating sexual violence to 33% of men reporting experiencing emotional violence. MSM who reported greater satisfaction with their relationship or who reported a higher degree of concordance with their partner on lifestyle choices were less likely to report experiencing or perpetrating emotional violence. MSM who perceived a stigma to being in a male same-sex couple were less likely to report experiencing or perpetrating sexual violence. CONCLUSION: The results presented here demonstrate high levels of IPV among MSM and that dyadic characteristics are associated with the occurrence of IPV. Understanding relationship characteristics associated with increased IPV among same-sex male couples can contribute to the development of more accurate IPV screening tools, and more sensitively and appropriately designed intervention messages

Activin A inhibits MPTP and LPS-induced increases in inflammatory cell populations and loss of dopamine neurons in the mouse midbrain in Vivo

© 2017 Stayte et al. Parkinson's disease is a chronic neurodegenerative disease characterized by a significant loss of dopaminergic neurons within the substantia nigra pars compacta region and a subsequent loss of dopamine within the striatum. A promising avenue of research has been the administration of growth factors to promote the survival of remaining midbrain neurons, although the mechanism by which they provide neuroprotection is not understood. Activin A, a member of the transforming growth factor β superfamily, has been shown to be a potent anti-inflammatory following acute brain injury and has been demonstrated to play a role in the neuroprotection of midbrain neurons against MPP+-induced degeneration in vitro. We hypothesized that activin A may offer similar anti-inflammatory and neuroprotective effects in in vivo mouse models of Parkinson's disease. We found that activin A significantly attenuated the inflammatory response induced by both MPTP and intranigral administration of lipopolysaccharide in C57BL/6 mice. We found that administration of activin A promoted survival of dopaminergic and total neuron populations in the pars compacta region both 8 days and 8 weeks after MPTP-induced degeneration. Surprisingly, no corresponding protection of striatal dopamine levels was found. Furthermore, activin A failed to protect against loss of striatal dopamine transporter expression in the striatum, suggesting the neuroprotective action of activin A may be localized to the substantia nigra. Together, these results provide the first evidence that activin A exerts potent neuroprotection and anti-inflammatory effects in the MPTP and lipopolysaccharide mouse models of Parkinson's disease

The Structure of Polyfulvenes

Cationic polymerisation of 6,6-disubstituted pentafulvenes yields highly unsaturated, reactive macromolecules of high mo- . lecular weight. The mechanistic pathways leading to the polymers are discussed, and the structure XIV of the polymers has been elucidated by a combination of spectroscopic methods as well as by comparison with model compounds. In contrast to reports in the literature, the main process in thermal oligomerisation of simple pentafulvenes at 20 °c is a Diels-Alder reaction giving products of type XXI. Anionic polymerisation of pentafulvenes is initiated by traces of sodium cyclopentadienide or phenylsodium respectively. The reaction products consist of a mixture of oligomers of the series (fulvene)n. This surprising result can be explained by structure elucidation of the fulvene dimers, which gives formula XX. The mechanistic aspects of the reaction are discussed