ROLE OF ENDOTHELIUM-DERIVED PROSTAGLANDINS IN HYPOXIA-ELICITED ARTERIOLAR DILATION IN RAT SKELETAL-MUSCLE

The aims of the present study were to determine the response of rat cremaster muscle first-order arterioles to hypoxia and the role of endothelium-derived prostaglandins in the response. Isolated arterioles were cannulated, pressurized to 65 mm Hg, and studied in a no-flow condition in a bath containing Krebs' bicarbonate solution, pH 7.4, equilibrated with 21% O2-5% CO2-74% N2 (PO2, 150 mm Hg) or 95% N2-5% CO2 (Po2, 15 mm Hg [hypoxia]). Responses to hypoxia and vasoactive substances were studied before and after removal of the endothelium or blockade of prostaglandin synthesis by the administration of indomethacin (10(-5) M). Addition to the suffusion solution of arachidonic acid (10(-7) and 10(-6) M), prostaglandin E2 (10(-9) and 10(-8) M), acetylcholine (10(-8) and 10(-6) M), or sodium nitroprusside 10(-8) M) evoked significanT arteriolar dilation. When the bath Po2 was reduced from 150 to 15 mm Hg, arteriolar diameters increased by 58.8+/-9.3-mu-m (61%). Removal of the endothelium completely inhibited responses to hypoxia, acetylcholine, and arachidonic acid, whereas responses to sodium nitroprusside and prostaglandin E2 remained unaltered. In arterioles with an intact endothelium, indomethacin completely inhibited the responses to hypoxia and arachidonic acid, whereas responses to acetylcholine and sodium nitroprusside were unaltered. These findings support the conclusion that endothelium-derived prostaglandins mediate the arteriolar dilation to hypoxia in rat skeletal muscle arterioles

Magnetic irreversibility and Verwey transition in nano-crystalline bacterial magnetite

The magnetic properties of biologically-produced magnetite nanocrystals biomineralized by four different magnetotactic bacteria were compared to those of synthetic magnetite nanocrystals and large, high quality single crystals. The magnetic feature at the Verwey temperature, $T_{V}$, was clearly seen in all nanocrystals, although its sharpness depended on the shape of individual nanoparticles and whether or not the particles were arranged in magnetosome chains. The transition was broader in the individual superparamagnetic nanoparticles for which $T_{B}<T_{V}$, where $T_{B}$ is the superparamagnetic blocking temperature. For the nanocrystals organized in chains, the effective blocking temperature $T_{B}>T_{V}$ and the Verwey transition is sharply defined. No correlation between the particle size and $T_{V}$ was found. Furthermore, measurements of $M(H,T,time)$ suggest that magnetosome chains behave as long magnetic dipoles where the local magnetic field is directed along the chain and this result confirms that time-logarithmic magnetic relaxation is due to the collective (dipolar) nature of the barrier for magnetic moment reorientation

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors

Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11

Agonism Reloaded: Potentia, Renewal and Radical Democracy

This article focuses on the agonistic account of renewal and discusses its place within the broader horizon of radical democracy. It suggests that while the emphasis which agonistic theorists place on difference and popular struggles (particularly social movement politics) ensures some common ground with other theories of radical democracy, their account of renewal also displays some marked differences. The article explores these differences and discusses whether agonism is sufficient to address the limits of the current neoliberal order

Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: The CLARINET open-label extension study

In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 %) nonfunctioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n=101) or placebo (n=103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n=41; placebo, n=47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection

'A habitual disposition to the good': on reason, virtue and realism

Amidst the crisis of instrumental reason, a number of contemporary political philosophers including Jürgen Habermas have sought to rescue the project of a reasonable humanism from the twin threats of religious fundamentalism and secular naturalism. In his recent work, Habermas defends a post-metaphysical politics that aims to protect rationality against encroachment while also accommodating religious faith within the public sphere. This paper contends that Habermas’ post-metaphysical project fails to provide a robust alternative either to the double challenge of secular naturalism and religious fundamentalism or to the ruthless instrumentalism that underpins capitalism. By contrast with Habermas and also with the ‘new realism’ of contemporary political philosophers such as Raymond Geuss or Bernard Williams, realism in the tradition of Plato and Aristotle can defend reason against instrumental rationality and blind belief by integrating it with habit, feeling and even faith. Such metaphysical–political realism can help develop a politics of virtue that goes beyond communitarian thinking by emphasising plural modes of association (not merely ‘community’), substantive ties of sympathy and the importance of pursuing goodness and mutual flourishing

Physical activity and risk of colon adenoma: A meta-analysis

BACKGROUND: Little evidence is available on the relation of physical activity with colon adenomas, a colon cancer precursor. METHODS: We conducted a systematic literature review and meta-analysis of published studies (in English) through April 2010, examining physical activity or exercise and risk or prevalence of colon adenoma or polyp. Random effects models were used to estimate relative risks (RRs) and corresponding confidence intervals (CIs). A total of 20 studies were identified that examined the association and provided RRs and corresponding 95% CIs. RESULTS: A significant inverse association between physical activity and colon adenomas was found with an overall RR of 0.84 (CI: 0.77–0.92). The association was similar in men (RR=0.81, CI: 0.67–0.98) and women (RR=0.87, CI: 0.74–1.02). The association appeared slightly stronger in large/advanced polyps (RR=0.70, CI: 0.56–0.88). CONCLUSION: This study confirms previous reports of a significant inverse association of physical activity and colon adenoma, and suggests that physical activity can have an important role in colon cancer prevention

Lifeworld Inc. : and what to do about it

Can we detect changes in the way that the world turns up as they turn up? This paper makes such an attempt. The first part of the paper argues that a wide-ranging change is occurring in the ontological preconditions of Euro-American cultures, based in reworking what and how an event is produced. Driven by the security – entertainment complex, the aim is to mass produce phenomenological encounter: Lifeworld Inc as I call it. Swimming in a sea of data, such an aim requires the construction of just enough authenticity over and over again. In the second part of the paper, I go on to argue that this new world requires a different kind of social science, one that is experimental in its orientation—just as Lifeworld Inc is—but with a mission to provoke awareness in untoward ways in order to produce new means of association. Only thus, or so I argue, can social science add to the world we are now beginning to live in

Evaluating Active U: an Internet-mediated physical activity program.

Background: Engaging in regular physical activity can be challenging, particularly during the winter months. To promote physical activity at the University of Michigan during the winter months, an eight-week Internet-mediated program (Active U) was developed providing participants with an online physical activity log, goal setting, motivational emails, and optional team participation and competition. Methods: This study is a program evaluation of Active U. Approximately 47,000 faculty, staff, and graduate students were invited to participate in the online Active U intervention in the winter of 2007. Participants were assigned a physical activity goal and were asked to record each physical activity episode into the activity log for eight weeks. Statistics for program reach, effectiveness, adoption, and implementation were calculated using the Re-Aim framework. Multilevel regression analyses were used to assess the decline in rates of data entry and goal attainment during the program, to assess the likelihood of joining a team by demographic characteristics, to test the association between various predictors and the number of weeks an individual met his or her goal, and to analyze server load. Results: Overall, 7,483 individuals registered with the Active U website (≈16% of eligible), and 79% participated in the program by logging valid data at least once. Staff members, older participants, and those with a BMI < 25 were more likely to meet their weekly physical activity goals, and average rate of meeting goals was higher among participants who joined a competitive team compared to those who participated individually (IRR = 1.28, P < .001). Conclusion: Internet-mediated physical activity interventions that focus on physical activity logging and goal setting while incorporating team competition may help a significant percentage of the target population maintain their physical activity during the winter months