Evolving views on the first two ligands of the angiotensin II type 2 receptor. From putative antagonists to potential agonists?

The renin-angiotensin system is one of the most complex regulatory systems that controls multiple organ functions. One of its key components, angiotensin II (Ang II), stimulates two G-protein coupled class A receptors: the Ang II type 1 (AT1) receptor and the Ang II type 2 (AT2) receptor. While stimulation of the AT1 receptor causes G-protein-dependent signaling and arrestin recruitment, the AT2 receptor seems to have a constitutively active-like conformation and appears to act via G-protein-dependent and -independent pathways. Overstimulation of the AT1 receptor may lead to unwanted effects like inflammation and fibrosis. In contrast, stimulation of the AT2 receptor leads to opposite effects thus restoring the balance. However, the role of the AT2 receptor has become controversial due to beneficial effects of putative AT2 receptor antagonists. The two first synthetic AT2 receptor-selective ligands, peptide CGP42112 and small molecule PD123319, were initially both considered antagonists. CGP42112 was subsequently considered a partial agonist and it was recently demonstrated to be a full agonist. Based on the search-term PD123319 in Pubmed, 1652 studies have investigated putative AT2 receptor antagonist PD123319. Here, we put forward literature that shows beneficial effects of PD123319 alone, even at doses too low for antagonist efficacy. These beneficial effects appear compatible with agonist-like activity via the AT2 receptor. Taken together, a more consistent image of a therapeutic role of stimulated AT2 receptor emerges which may clarify current controversies.</p

Evolving views on the first two ligands of the angiotensin II type 2 receptor. From putative antagonists to potential agonists?

The renin-angiotensin system is one of the most complex regulatory systems that controls multiple organ functions. One of its key components, angiotensin II (Ang II), stimulates two G-protein coupled class A receptors: the Ang II type 1 (AT1) receptor and the Ang II type 2 (AT2) receptor. While stimulation of the AT1 receptor causes G-protein-dependent signaling and arrestin recruitment, the AT2 receptor seems to have a constitutively active-like conformation and appears to act via G-protein-dependent and -independent pathways. Overstimulation of the AT1 receptor may lead to unwanted effects like inflammation and fibrosis. In contrast, stimulation of the AT2 receptor leads to opposite effects thus restoring the balance. However, the role of the AT2 receptor has become controversial due to beneficial effects of putative AT2 receptor antagonists. The two first synthetic AT2 receptor-selective ligands, peptide CGP42112 and small molecule PD123319, were initially both considered antagonists. CGP42112 was subsequently considered a partial agonist and it was recently demonstrated to be a full agonist. Based on the search-term PD123319 in Pubmed, 1652 studies have investigated putative AT2 receptor antagonist PD123319. Here, we put forward literature that shows beneficial effects of PD123319 alone, even at doses too low for antagonist efficacy. These beneficial effects appear compatible with agonist-like activity via the AT2 receptor. Taken together, a more consistent image of a therapeutic role of stimulated AT2 receptor emerges which may clarify current controversies.</p

Evolving views on the first two ligands of the angiotensin II type 2 receptor. From putative antagonists to potential agonists?

The renin-angiotensin system is one of the most complex regulatory systems that controls multiple organ functions. One of its key components, angiotensin II (Ang II), stimulates two G-protein coupled class A receptors: the Ang II type 1 (AT1) receptor and the Ang II type 2 (AT2) receptor. While stimulation of the AT1 receptor causes G-protein-dependent signaling and arrestin recruitment, the AT2 receptor seems to have a constitutively active-like conformation and appears to act via G-protein-dependent and -independent pathways. Overstimulation of the AT1 receptor may lead to unwanted effects like inflammation and fibrosis. In contrast, stimulation of the AT2 receptor leads to opposite effects thus restoring the balance. However, the role of the AT2 receptor has become controversial due to beneficial effects of putative AT2 receptor antagonists. The two first synthetic AT2 receptor-selective ligands, peptide CGP42112 and small molecule PD123319, were initially both considered antagonists. CGP42112 was subsequently considered a partial agonist and it was recently demonstrated to be a full agonist. Based on the search-term PD123319 in Pubmed, 1652 studies have investigated putative AT2 receptor antagonist PD123319. Here, we put forward literature that shows beneficial effects of PD123319 alone, even at doses too low for antagonist efficacy. These beneficial effects appear compatible with agonist-like activity via the AT2 receptor. Taken together, a more consistent image of a therapeutic role of stimulated AT2 receptor emerges which may clarify current controversies.</p

Evolving views on the first two ligands of the angiotensin II type 2 receptor. From putative antagonists to potential agonists?

The renin-angiotensin system is one of the most complex regulatory systems that controls multiple organ functions. One of its key components, angiotensin II (Ang II), stimulates two G-protein coupled class A receptors: the Ang II type 1 (AT1) receptor and the Ang II type 2 (AT2) receptor. While stimulation of the AT1 receptor causes G-protein-dependent signaling and arrestin recruitment, the AT2 receptor seems to have a constitutively active-like conformation and appears to act via G-protein-dependent and -independent pathways. Overstimulation of the AT1 receptor may lead to unwanted effects like inflammation and fibrosis. In contrast, stimulation of the AT2 receptor leads to opposite effects thus restoring the balance. However, the role of the AT2 receptor has become controversial due to beneficial effects of putative AT2 receptor antagonists. The two first synthetic AT2 receptor-selective ligands, peptide CGP42112 and small molecule PD123319, were initially both considered antagonists. CGP42112 was subsequently considered a partial agonist and it was recently demonstrated to be a full agonist. Based on the search-term PD123319 in Pubmed, 1652 studies have investigated putative AT2 receptor antagonist PD123319. Here, we put forward literature that shows beneficial effects of PD123319 alone, even at doses too low for antagonist efficacy. These beneficial effects appear compatible with agonist-like activity via the AT2 receptor. Taken together, a more consistent image of a therapeutic role of stimulated AT2 receptor emerges which may clarify current controversies.</p

Pion-Nucleon Scattering in Kadyshevsky Formalism: I Meson Exchange Sector

In a series of two papers we present the theoretical results of $\pi N$/meson-baryon scattering in the Kadyshevsky formalism. In this paper the results are given for meson exchange diagrams. On the formal side we show, by means of an example, how general couplings, i.e. couplings containing multiple derivatives and/or higher spin fields, should be treated. We do this by introducing and applying the Takahashi-Umezawa and the Gross-Jackiw method. For practical purposes we introduce the $\bar{P}$ method. We also show how the Takashashi-Umezawa method can be derived using the theory of Bogoliubov and collaborators and the Gross-Jackiw method is also used to study the $n$-dependence of the Kadyshevsky integral equation. Last but not least we present the second quantization procedure of the quasi particle in Kadyshevsky formalism.Comment: 29 page

Effects of augmented exercise therapy time after stroke: a meta-analysis

&lt;p&gt;&lt;b&gt;Background and Purpose:&lt;/b&gt; To present a systematic review of studies that addresses the effects of intensity of augmented exercise therapy time (AETT) on activities of daily living (ADL), walking, and dexterity in patients with stroke.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Summary of Review:&lt;/b&gt; A database of articles published from 1966 to November 2003 was compiled from MEDLINE, CINAHL, Cochrane Central Register of Controlled Trials, PEDro, DARE, and PiCarta using combinations of the following key words: stroke, cerebrovascular disorders, physical therapy, physiotherapy, occupational therapy, exercise therapy, rehabilitation, intensity, dose–response relationship, effectiveness, and randomized controlled trial. References presented in relevant publications were examined as well as abstracts in proceedings. Studies that satisfied the following selection criteria were included: (1) patients had a diagnosis of stroke; (2) effects of intensity of exercise training were investigated; and (3) design of the study was a randomized controlled trial (RCT). For each outcome measure, the estimated effect size (ES) and the summary effect size (SES) expressed in standard deviation units (SDU) were calculated for ADL, walking speed, and dexterity using fixed and random effect models. Correlation coefficients were calculated between observed individual effect sizes on ADL of each study, additional time spent on exercise training, and methodological quality. Cumulative meta-analyses (random effects model) adjusted for the difference in treatment intensity in each study was used for the trials evaluating the effects of AETT provided. Twenty of the 31 candidate studies, involving 2686 stroke patients, were included in the synthesis. The methodological quality ranged from 2 to 10 out of the maximum score of 14 points. The meta-analysis resulted in a small but statistically significant SES with regard to ADL measured at the end of the intervention phase. Further analysis showed a significant homogeneous SES for 17 studies that investigated effects of increased exercise intensity within the first 6 months after stroke. No significant SES was observed for the 3 studies conducted in the chronic phase. Cumulative meta-analysis strongly suggests that at least a 16-hour difference in treatment time between experimental and control groups provided in the first 6 months after stroke is needed to obtain significant differences in ADL. A significant SES supporting a higher intensity was also observed for instrumental ADL and walking speed, whereas no significant SES was found for dexterity.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusion:&lt;/b&gt; The results of the present research synthesis support the hypothesis that augmented exercise therapy has a small but favorable effect on ADL, particularly if therapy input is augmented at least 16 hours within the first 6 months after stroke. This meta-analysis also suggests that clinically relevant treatment effects may be achieved on instrumental ADL and gait speed.&lt;/p&gt

Depression, suicidal ideation, and associated factors: a cross-sectional study in rural Haiti

BACKGROUND: Since the 2010 earthquake in Haiti, there has been increased international attention to mental health needs throughout the country. The present study represents one of the first epidemiologic studies of depression symptomatology, suicidal ideation, and associated factors in Haiti’s Central Plateau. METHODS: We conducted a cross-sectional, zone-stratified household survey of 408 adults in Haiti’s Central Plateau. Depression symptomatology was assessed with a culturally-adapted Kreyòl version of the Beck Depression Inventory (BDI). Multivariable linear and logistic regression models were built using backward elimination, with the outcomes being continuous BDI scores and endorsing suicidal ideation, respectively. RESULTS: The mean BDI score was 20.4 (95% confidence interval [CI]: 19.3-21.5), and 6.13% (N = 25) of participants endorsed current suicidal ideation. Factors associated with BDI scores were: continuous age (adjusted beta [aβ]: 0.14, CI: 0.06-0.22), female gender (aβ: 2.1, CI: 0.18-4.0), suicidal ideation (aβ: 11.1, CI: 7.3-14.9), death in family (aβ: 2.7, CI: 0.57-4.9), and prior life-threatening illness (aβ: 2.6, CI: 0.77-4.5). Education was a risk factor for depression among women but not among men, and employment was a risk factor for both genders. Factors associated with endorsing suicidal ideation were: BDI score (ten point change) (adjusted odds ratio [aOR]: 2.5, CI: 1.7-3.6), lack of care if sick (aOR: 5.5, CI: 1.1-28.6), alcohol use (aOR: 3.3, CI: 1.3-8.2), and ever having been to a Vodou priest (aOR: 3.2, CI: 1.1-9.5). CONCLUSIONS: A large proportion of Haiti’s Central Plateau may be experiencing high levels of depression symptomatology and/or current suicidal ideation. Screening could be conducted in biomedical, religious, and Vodou healing contexts. For prevention, poverty reduction and improved healthcare access are key elements. For treatment, general psychiatric services, psychosocial services for the medically ill and their families, and substance abuse interventions should be explored. Paradoxical associations related to education and employment require further exploration