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Why do informal, plurilateral summit institutions such as the Group of Eight (G8) major market democracies succeed in advancing costly public health priorities such as maternal, newborn, and child health (MNCH), even when the formal, multilateral United Nations (UN) system fails to meet such goals, when G8 governments afflicted by recession, deficit, and debt seek to cut expenditures, and when the private sector is largely uninvolved, despite the growing popularity of public-private partnerships to meet global health and related nutrition, food, and agriculture needs? Guided by the concert-equality model of G8 governance, this case study of the G8's 2010 Muskoka Initiative on MNCH traces the process through which that initiative was planned within Canada, internationally prepared through negotiations with Canada's G8 partners, produced at Muskoka by the leaders in June, multiplied in its results by the UN summit in September, and reinforced by the new accountability mechanism put in place. It finds that the Muskoka summit succeeded in mobilizing major money and momentum for MNCH. This was due to the initiative and influence of children-focused nongovernmental organizations (NGOs), working with committed individuals and agencies within the host Canadian government, as well as supportive public opinion and the help of those in the UN responsible for realizing its Millennium Development Goals. Also relevant were the democratic like-mindedness of G8 leaders and their African partners, the deference of G8 members to the host's priority, and the need of the G8 to demonstrate its relevance through a division of labor between it and the new Group of Twenty summit. This study shows that G8 summits can succeed in advancing key global health issues without a global shock on the same subject to galvanize agreement and action. It suggests that, when committed, focused NGOs and government officials will lead and the private sector will follow, but that there will be a lag in the implementation needed to obtain the intended results. The need to improve the accompanying accountability mechanisms to improve implementation, thus, remains., (© 2014 New York Academy of Sciences.)

The synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles as potent p38α mitogen-activated protein kinase inhibitors is described. The trisubstituted imidazole series was found to be more potent than the tetrasubstituted imidazole series. Many of these compounds show low-nanomolar activities in the isolated p38α MAP kinase inhibition assay. The structure-activity relationships between these two series are different and not comparable., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The p38 mitogen-activated protein (MAP) kinase alpha plays a central role in the regulation of cellular responses such as differentiation, proliferation, apoptosis, and inflammation. Inhibition of p38 results in decreased synthesis of pro-inflammatory cytokines. To date, diverse p38alpha inhibitors are in phase II clinical trials for numerous cytokine-dependent diseases. 2-Sulfanylimidazole derivatives offer advantages over the prototype inhibitor SB 203580, including fewer cytochrome P450 interactions and better kinetic properties. The aim of this study was to develop novel 1,2,4,5-tetrasubstituted pyridinylimidazoles with acyl residues at the imidazole N1 position that can interact with the kinase's hydrophobic region II (HR II) or sugar pocket (SP) to improve both selectivity and activity. The substitution pattern was optimized by variation of the acyl moiety at the N1 position of the N-aminoimidazole core. Acylation of the amino function was used for optimization and led to potent p38alpha MAPK inhibitors.

Background and Aims: Since the 1980s the group of people surviving with the aid of artificial respiration has expanded. So far, however, no information centre for such persons exists in Germany. Likewise, peer counselling is not a widely accepted method of allocating responsibility to afflicted persons. The task of an information centre would be to provide peer counselors who would advise people on artificial respiration., Patients and Methods: Interviews with subjects and their relatives regarding the various aspects of artificial respiration., Conclusion: The foundation of such a counselling centre is recommended on account of the present need for a national information exchange and contact centre.

Although there is evidence of partial sympathetic reinnervation late after transplantation, little is known about the relative frequency of sympathetic and, in particular, parasympathetic reinnervation. We examined the heart rate response to various maneuvers (standing up, handgrip exercise, phase 2 of Valsalva maneuver for sympathetic function, carotid sinus massage, phase 4 of Valsalva maneuver, and atropine for parasympathetic function) in 65 patients 3 to 110 months after transplantation and in 16 healthy volunteers and defined reinnervation as either one normal (>50% of control group) and at least one partial (>33% of control group) heart rate response or partial responses in all three tests of the respective part of the autonomic nervous system. Thirty-five (54%) patients had sympathetic reinnervation, but only 16 (25%) had parasympathetic reinnervation (p < 0.001); earliest reinnervation was found 11 months after transplantation, and all but one patient with parasympathetic reinnervation also had sympathetic reinnervation. Signs of sympathetic but not parasympathetic reinnervation were common late (>5 years) after transplantation (74% vs 30%).

Background: Therapy with nitroglycerin is widely used in the treatment of angina pectoris, but development of tolerance is a major problem. Nitrovasodilators other than nitroglycerin may be less prone to induce vascular tolerance. This investigation was designed to test whether the alternative nitric oxide donor linsidomine maintains its vasodilator effects in the presence of nitroglycerin tolerance., Methods: We tested the vascular effects of nitroglycerin and linsidomine (SIN-1) in forearm resistance arteries (venous occlusion plethysmography) and hand veins (venous compliance technique) using a randomized, double-blind placebo-controlled regimen in 33 healthy subjects (age range, 22 to 38 years; mean age, 26 years) before and after 7 days of assignment to either 1 week of nitroglycerin administration (0.83 mg/hr) for induction of tolerance or placebo administration., Results: Vascular responses of both vascular beds to nitroglycerin (in veins: mean difference, 42.3%; confidence interval [CI], 3% to 81.7%; p < 0.05; in arteries: mean difference, 65.0%; CI, 38.9% to 91.1%; p < 0.01) but not to linsidomine (in veins: mean difference, -13.8%; CI, -53.5 to 25.8%; not significant; in arteries: -19.7%; CI, -33.7% to -5.6%; not significant) were attenuated in the nitroglycerin patch group, whereas the placebo group showed no differences to either nitroglycerin (in arteries: mean difference, -7.5%; CI, -44.6% to 29.6%; in veins: -10.6%; CI, -58.2% to 36.9%) or linsidomine (in arteries: 4.5%; CI, -12.8% to 21.7%; in veins: -13.1%; CI, -4.5% to 29.8%)., Conclusion: These results suggest that short-term administration of sydnonimines can overcome the loss of vascular relaxation associated with long-term nitroglycerin therapy.

Background: Atropine is widely used as a parasympatholytic agent during diagnostic and therapeutic procedures. We observed an unexpected paradoxical response to atropine after cardiac transplantation., Methods: In a study investigating the occurrence of autonomic reinnervation after cardiac transplantation, atropine, at 0.015 mg/kg body weight, was given intravenously to 23 patients (mean age, 56+/-8 years) 98 days to 6.4 years after transplantation., Results: Two patients experienced a witnessed syncope 40 and 150 min after administration of atropine. Second-degree atrioventricular (AV) block was documented in the first patient immediately afterward, and third-degree AV block was seen on 24-hr electrocardiogram monitoring in the second patient. A third patient developed documented AV block 15 min after atropine but experienced no sequelae because of a previously implanted pacemaker., Conclusions: Although the underlying mechanism is not clear, these findings suggest that atropine may paradoxically cause high-degree AV block in patients after transplantation. Accordingly, it should be used with caution and appropriate monitoring in these patients.

Cardiac reinnervation late after heart transplantation has been reported in individual patients. As a measure for reinnervation, circadian changes in arterial blood pressure and heart rate have been used but not yet systemically evaluated in cardiac transplant recipients. Ambulatory blood pressure and heart rate monitoring was performed in 62 patients for 24 hr early (<6 months, mean 26 days, range 5-90 days, n=30) and late (> or = 6 months, mean 12 months, range 7-78 months, n=32) after heart transplantation. A loss of physiological nocturnal decline in blood pressure and heart rate was noted early after transplantation, whereas late after operation an improvement in circadian changes of blood pressure and heart rate was observed. The patients late after heart transplantation had a significant higher diastolic blood pressure. A pathological circadian blood pressure and heart rate pattern was observed in patients early after heart transplantation, which was improved late after operation. This could be explained by partial reinnervation of the heart. Diastolic hypertension late after transplantation may be due to cyclosporine treatment and/or neuroendocrine hyperactivity.

A loss of the circadian rhythm pattern of blood pressure (BP) and heart rate, as well as the development of hypertension have been found after heart transplantation (Htx). To study whether a return of this rhythm occurs in the long-term after Htx, we used 24-h ambulatory monitoring to study 62 patients 5 days to 6.5 years after Htx. Patients were divided into two groups (Group 1: less than 6 months after Htx (n = 30), Group 2: 6 months or more after Htx (n = 32)). Group 2 had a higher BP and heart rate, as well as a significantly higher difference between systolic day and systolic night BP than group 1. There was also a significantly higher difference in heart rate between day and night values in group 2. The return of the circadian rhythm pattern in the longer term after heart transplantation may result from partial reinnervation of the heart, although other neurohumoral factors or concomitant medication may play a role.

Transcutaneous oxygen pressure (tcPO2) on the dorsum of the foot and Doppler ankle/arm pressure ratio (AAR) were measured in nine patients with peripheral arterial occlusive disease (PAOD)-stage IIb-III during treadmill exercise before and after (two days and one month) atherectomy. These parameters were compared with nine normal controls and nine PAOD I-IIa patients without atherectomy. All patients with atherectomy showed an increase in their pain free walking distance, and, both two days and one month after the intervention, a significant (p less than 0.05) increase in their exercise/rest tcPO2 ratio (pre-atherectomy: 25% (12-81), two days after: 78% (49-92), one month after: 85% (81-92). AAR displays a significant increase only between pre- and two days after atherectomy, without further significant improvement after one month. We conclude that tcPO2 measurement is an adequate measurement for follow-up studies in patients with PAOD after invasive therapeutic interventions. Furthermore, these data suggest that, while the maximum improvement for the macrocirculation (AAR) occurs shortly after atherectomy, improvement of the microcirculation (tcPO2) is delayed for a prolonged period after revascularization of major arteries, possibly due to reperfusion injury.

Transcutaneous oxygen and carbon dioxide tensions were measured during treadmill exercise in 30 patients with stages I and II arterial occlusive disease and 28 normal controls. Measuring sites were the dorsum of the foot and the frontal thorax. The calculated oxygen index at maximum exercise/rest (foot/thorax) differentiated with 100% sensitivity and specifity between the two groups. The oxygen index was the only parameter with a significant positive correlation with the pain-free walking distance, whereas, eg, oscillography and Doppler analysis did not correlate. Carbon dioxide tensions showed significant differences only in the recovery time between patients and normal controls.