Interplay between Cocaine, Drug Removal, and Methylphenidate Reversal on Phospholipid Alterations in Drosophila Brain Determined by Imaging Mass Spectrometry

Cocaine dependence displays a broad impairment in cognitive performance including attention, learning, and memory. To obtain a better understanding of the action of cocaine in the nervous system, and the relation between phospholipids and memory, we have investigated whether phospholipids recover in the brain following cocaine removal using the fly model, Drosophila melanogaster. In addition, the effects of methylphenidate, a substitute medication for cocaine dependence, on fly brain lipids after cocaine abuse are also determined to see if it can rescue the lipid changes caused by cocaine. Time of flight secondary ion mass spectrometry with a (CO2)6000+ gas cluster ion beam was used to detect intact phospholipids. We show that cocaine has persistent effects, both increasing and decreasing the levels of specific phosphatidylethanolamines and phosphatidylinositols. These changes remain after cocaine withdrawal and are not rescued by methylphenidate. Cocaine is again shown to generally increase the levels of phosphatidylcholines in the fly brain; however, after drug withdrawal, the abundance of these lipids returns to the original level and methylphenidate treatment of the flies following cocaine exposure enhances the reversal of the lipid level reducing them below the original control. The study provides insight into the molecular effects of cocaine and methylphenidate on brain lipids. We suggest that phosphatidylcholines could be a potential target for the treatment of cocaine abuse as well as be a significant hallmark of cognition and memory loss with cocaine

The prognostic value of the hypoxia markers CA IX and GLUT 1 and the cytokines VEGF and IL 6 in head and neck squamous cell carcinoma treated by radiotherapy ± chemotherapy

BACKGROUND: Several parameters of the tumor microenvironment, such as hypoxia, inflammation and angiogenesis, play a critical role in tumor aggressiveness and treatment response. A major question remains if these markers can be used to stratify patients to certain treatment protocols. The purpose of this study was to investigate the inter-relationship and the prognostic significance of several biological and clinicopathological parameters in patients with head and neck squamous cell carcinoma (HNSCC) treated by radiotherapy ± chemotherapy. METHODS: We used two subgroups of a retrospective series for which CT-determined tumoral perfusion correlated with local control. In the first subgroup (n = 67), immunohistochemistry for carbonic anhydrase IX (CA IX) and glucose transporter-1 (GLUT-1) was performed on the pretreatment tumor biopsy. In the second subgroup (n = 34), enzyme linked immunosorbent assay (ELISA) was used to determine pretreatment levels of the cytokines vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) in serum. Correlation was investigated between tumoral perfusion and each of these biological markers, as well as between the markers mutually. The prognostic value of these microenvironmental parameters was also evaluated. RESULTS: For CA IX and GLUT-1, the combined assessment of patients with both markers expressed above the median showed an independent correlation with local control (p = 0.02) and disease-free survival (p = 0.04) with a trend for regional control (p = 0.06). In the second subgroup, IL-6 pretreatment serum level above the median was the only independent predictor of local control (p = 0.009), disease-free survival (p = 0.02) and overall survival (p = 0.005). CONCLUSION: To our knowledge, we are the first to report a link in HNSCC between IL-6 pretreatment serum levels and radioresistance in vivo. This link is supported by the strong prognostic association of pretreatment IL-6 with local control, known to be the most important parameter to judge radiotherapy responses. Furthermore, the combined assessment of CA IX and GLUT-1 correlated independently with prognosis. This is a valuable indication that a combined approach is important in the investigation of prognostic markers

"Getting the water-carrier to light the lamps": Discrepant role perceptions of traditional, complementary, and alternative medical practitioners in government health facilities in India.

The government of India has, over the past decade, implemented the "integration" of traditional, complementary and alternative medical (TCAM) practitioners, specifically practitioners of Ayurveda, Yoga and Naturopathy, Unani, Siddha, Sowa-rigpa, and Homoeopathy (collectively known by the acronym AYUSH), in government health services. A range of operational and ethical challenges has manifested during this process of large health system reform. We explored the practices and perceptions of health system actors, in relation to AYUSH providers' roles in government health services in three Indian states - Kerala, Meghalaya, and Delhi. Research methods included 196 in-depth interviews with a range of health policy and system actors and beneficiaries, between February and October 2012, and review of national, state, and district-level policy documents relating to AYUSH integration. The thematic 'framework' approach was applied to analyze data from the interviews, and systematic content analysis performed on policy documents. We found that the roles of AYUSH providers are frequently ambiguously stated and variably interpreted, in relation to various aspects of their practice, such as outpatient care, prescribing rights, emergency duties, obstetric services, night duties, and referrals across systems of medicine. Work sharing is variously interpreted by different health system actors as complementing allopathic practice with AYUSH practice, or allopathic practice, by AYUSH providers to supplement the work of allopathic practitioners. Interactions among AYUSH practitioners and their health system colleagues frequently take place in a context of partial information, preconceived notions, power imbalances, and mistrust. In some notable instances, collegial relationships and apt divisions of responsibilities are observed. Widespread normative ambivalence around the roles of AYUSH providers, complicated by the logistical constraints prevalent in poorly resourced systems, has the potential to undermine the therapeutic practices and motivation of AYUSH providers, as well as the overall efficiency and performance of integrated health services

Coordination and transfer

We study the ability of subjects to transfer principles between related coordination games. Subjects play a class of order statistic coordination games closely related to the well-known minimum (or weak-link) and median games (Van Huyck et al. in Am Econ Rev 80:234–248, 1990, Q J Econ 106(3):885–910, 1991). When subjects play a random sequence of games with differing order statistics, play is less sensitive to the order statistic than when a fixed order statistic is used throughout. This is consistent with the prediction of a simple learning model with transfer. If subjects play a series of similar stag hunt games, play converges to the payoff dominant equilibrium when a convention emerges, replicating the main result of Rankin et al. (Games Econ Behav 32:315–337, 2000). When these subjects subsequently play a random sequence of order statistic games, play is shifted towards the payoff dominant equilibrium relative to subjects without previous experience. The data is consistent with subjects absorbing a general principle, play of the payoff dominant equilibrium, and applying it in a new related setting

Bony metastases from breast cancer - a study of foetal antigen 2 as a blood tumour marker

Background : Foetal antigen 2 (FA-2), first isolated in the amniotic fluid, was shown to be the circulating form of the aminopropeptide of the alpha 1 chain of procollagen type I. Serum concentrations of FA-2 appeared to be elevated in a number of disorders of bone metabolism. This paper is the first report of its role as a marker of bone metabolism in metastatic breast cancer. Methods: Serum FA-2 concentrations were measured by radioimmunoassay in 153 women with different stages of breast cancer and in 34 normal controls. Results: Serum FA-2 was significantly elevated in women with bony metastases (p < 0.015). Its levels were not significantly different among women with non-bony metastases, with non-metastatic disease, as well as among normal controls. Conclusions: FA-2 is a promising blood marker of bone metabolism. Further studies to delineate its role in the diagnosis and management of bony metastases from breast cancer are required

Development of an in vitro three dimensional loading-measurement system for long bone fixation under multiple loading conditions: a technical description

The purpose of this investigation was to design and verify the capabilities of an in vitro loading-measurement system that mimics in vivo unconstrained three dimensional (3D) relative motion between long bone ends, applies uniform load components over the entire length of a test specimen, and measures 3D relative motion between test segment ends to directly determine test segment construct stiffness free of errors due to potting-fixture-test machine finite stiffness

Cognitive Load Theory: Advances in Research on Worked Examples, Animations, and Cognitive Load Measurement

The contributions to this special issue document some recent advances of cognitive load theory, and are based on contributions to the Third International Cognitive Load Theory Conference (2009), Heerlen, The Netherlands. The contributions focus on developments in example-based learning, amongst others on the effects of integrating worked examples in cognitive tutoring systems; specify the effects of transience on cognitive load and why segmentation may help counteract these effects in terms of the role of time in working memory load; and discuss the possibilities offered by electroencephalography (EEG) to provide a continuous and objective measure of cognitive load. This article provides a short introduction to the contributions in this issue

Impact of Solitary Involved Lymph Node on Outcome in Localized Cancer of the Esophagus and Esophagogastric Junction

Node-positive esophageal cancer is associated with a dismal prognosis. The impact of a solitary involved node, however, is unclear, and this study examined the implications of a solitary node compared with greater nodal involvement and node-negative disease. The clinical and pathologic details of 604 patients were entered prospectively into a database from1993 and 2005. Four pathologic groups were analyzed: node-negative, one lymph node positive, two or three lymph nodes positive, and greater than three lymph nodes positive. Three hundred and fifteen patients (52%) were node-positive and 289 were node-negative. The median survival was 26 months in the node-negative group. Patients (n = 84) who had one node positive had a median survival of 16 months (p = 0.03 vs node-negative). Eighty-four patients who had two or three nodes positive had a median survival of 11 months compared with a median survival of 8 months in the 146 patients who had greater than three nodes positive (p = 0.01). The survival of patients with one node positive [number of nodes (N) = 1] was also significantly greater than the survival of patients with 2–3 nodes positive (N = 2–3) (p = 0.049) and greater than three nodes positive (p < 0001). The presence of a solitary involved lymph node has a negative impact on survival compared with node-negative disease, but it is associated with significantly improved overall survival compared with all other nodal groups

Anti-plasmodial polyvalent interactions in Artemisia annua L. aqueous extract – possible synergistic and resistance mechanisms

Artemisia annua hot water infusion (tea) has been used in in vitro experiments against P. falciparum malaria parasites to test potency relative to equivalent pure artemisinin. High performance liquid chromatography (HPLC) and mass spectrometric analyses were employed to determine the metabolite profile of tea including the concentrations of artemisinin (47.5±0.8 mg L-1), dihydroartemisinic acid (70.0±0.3 mg L-1), arteannuin B (1.3±0.0 mg L-1), isovitexin (105.0±7.2 mg L-1) and a range of polyphenolic acids. The tea extract, purified compounds from the extract, and the combination of artemisinin with the purified compounds were tested against chloroquine sensitive and chloroquine resistant strains of P. falciparum using the DNA-intercalative SYBR Green I assay. The results of these in vitro tests and of isobologram analyses of combination effects showed mild to strong antagonistic interactions between artemisinin and the compounds (9-epi-artemisinin and artemisitene) extracted from A. annua with significant (IC50 <1 μM) anti-plasmodial activities for the combination range evaluated. Mono-caffeoylquinic acids, tri-caffeoylquinic acid, artemisinic acid and arteannuin B showed additive interaction while rosmarinic acid showed synergistic interaction with artemisinin in the chloroquine sensitive strain at a combination ratio of 1:3 (artemisinin to purified compound). In the chloroquine resistant parasite, using the same ratio, these compounds strongly antagonised artemisinin anti-plasmodial activity with the exception of arteannuin B, which was synergistic. This result would suggest a mechanism targeting parasite resistance defenses for arteannuin B’s potentiation of artemisinin

Acidogenic Potential of “Sugar-Free” Cough Drops

A patient presented with extensive marginal ditching around restorations recently placed during whole-mouth rehabilitation. The patient was not xerostomic and was otherwise normal except for the self-reported excessive use of “sugar-free” cough drops sweetened with sorbitol and Isomalt® (an equimolar mix of glucosyl-mannitol and glucosylsorbitol). This prompted an in vitro investigation to determine whether Streptococcus sobrinus 6715, a cariogenic streptococcus, could grow and produce acid in growth medium containing an aqueous extract of such “sugar-free” cough drops. The results indicate that S. sobrinus 6715 uses Isomalt® and sorbitol extensively, producing terminal culture pH as low as 4.2 when grown on medium with cough drop extract containing these sugars. This pH is sufficient to demineralize dental enamel. Patients should be cautioned against the chronic overuse of “sugar-free” cough drops and other “sugar-free” confections sweetened with a mixture of Isomalt® and sorbitol