Salubrious Effect Research Articles

Gene therapy encoding cell cycle factors to treat chronic ischemic heart failure in rats.

Gene therapies to induce cardiomyocyte (CM) cell cycle re-entry have shown a potential to treat subacute ischaemic heart failure (IHF) but have not been tested in the more relevant setting of chronic IHF. Our group recently showed that polycistronic non-integrating lentivirus encoding Cdk1/CyclinB1 and Cdk4/CyclinD1 (TNNT2-4Fpolycistronic-NIL) is effective in inducing CM cell cycle re-entry and ameliorating subacute IHF models and preventing the subsequent IHF-induced congestions in the liver, kidneys, and lungs in rats and pigs. Here, we aim to test the long-term efficacy of TNNT2-4Fpolycistronic-NIL in a rat model of chronic IHF, a setting that differs pathophysiologically from subacute IHF and has greater clinical relevance. Rats were subjected to a 2-h coronary occlusion followed by reperfusion; 4 weeks later, rats were injected intramyocardially with either TNNT2-4Fpolycistronic-NIL or LacZ-NIL. Four months post-viral injection, TNNT2-4Fpolycistronic-NIL-treated rats showed a significant reduction in scar size and a significant improvement in left ventricular (LV) systolic cardiac function but not in the LV dilatation associated with chronic IHF. A mitosis reporter system developed in our lab showed significant induction of CM mitotic activity in TNNT2-4Fpolycistronic-NIL-treated rats. This study demonstrates, for the first time, that TNNT2-4Fpolycistronic-NIL gene therapy induces CM cell cycle re-entry in chronic IHF and improves LV function, and that this salubrious effect is sustained for at least 4 months. Given the high prevalence of chronic IHF, these results have significant clinical implications for developing a novel treatment for this deadly disease.

Yogic Spirituality and Positive Psychology vis-à-vis the Mental Health of Adolescents During COVID-19.

COVID-19 ushered in a period of uncertainty and insecurity. It has affected the mental well-being of all, but certain groups are more vulnerable, including adolescents. Adolescence is a period of transition from childhood to adulthood in which the mental domain is still developing. The pandemic has had an adverse effect on the mental well-being of adolescents. Their normal routines are severely affected by the pandemic and related restrictions. There is a need for a coping mechanism or resources to empower this group of people. Spirituality has salubrious effect on all dimensions of health. The concept of spirituality is closely related to yoga and positive psychology. The article describes the similarities between yoga and positive psychology. It further posits that spirituality is closely related to yoga and positive psychology. The article also argues that both yoga and positive psychology could be useful in improving the mental dimension of health in adolescents in the COVID-19 era. A thorough study of the literature helped the authors to conclude that yoga and positive psychology definitely enhance mental well-being. The tenets of yoga and positive psychology can be incorporated into the daily regimen of children and adolescents to increase their resilience and mental strength. Further studies with robust study designs could ascertain the benefits of such measures.

Knowledge, practice and technique of facemask usage among healthcare workers in a tertiary hospital in Ado-Ekiti, Nigeria

IntroductionInfection prevention and control remains very key to safety in healthcare settings and community. The use of personal protective equipment is now more relevant especially with the advent of COVID-19 pandemic. This study aimed to assess the knowledge, attitude, practice and technique of wearing facemask among healthcare workers at Ekiti State University Teaching Hospital, Ado-Ekiti, Nigeria MethodsA descriptive cross-sectional questionnaire-based study explored knowledge, attitude and reported practice on the use of facemask. Also, a checklist was used to directly observe how participants put on and remove facemasks. ResultsOf the 450 respondents, 316 (70.2%) had good knowledge score. Only 255 (56.7%) had good attitude and barely half of the respondents 229 (50.9%) had good practice. However, the majority of those who were observed had good technique of wearing facemask 387 (86.4%). Also, 188 (41.8%) of the healthcare workers believed that face shield alone offers adequate protection against transmission of COVID-19. ConclusionsOur finding suggests that knowledge does not translate to good practice. Furthermore, the fact that two out of every five healthcare workers held erroneous belief about face shield, and another one-third had poor knowledge points to the need for training and retraining of healthcare workers with the aim of reinforcing the need for consistent and correct use of facemasks. This should have a salubrious effect on the community knowledge of COVID-19 prevention as healthcare workers are believed to be the most common sources of health information to the lay public

Changes in Self-Perceptions of Aging Among Black and White Older Adults: The Role of Volunteering.

Given the health consequences of self-perceptions of aging (SPA), understanding how SPA change among Black and White older adults may shed light on racial disparities in late-life health. The current study is the first to assess whether Black older adults exhibit less favorable patterns of change in SPA than White older adults. We also tested whether the salubrious effect of volunteering on SPA would be particularly salient among Black older adults. A pooled sample of adults aged 50+ (N=10,183; Black: n=1,672, White: n=8,511) from the Health and Retirement Study rated positive and negative SPA once every 4years across 3 waves (2008/2010, 2012/2014, and 2016/2018). We assessed participants' reports on volunteering status in each wave. Growth curve models revealed that positive SPA decreased over time whereas negative SPA increased. Black older adults reported more positive and less negative SPA at baseline and flatter time-related changes than their White counterparts. We found that volunteering was significantly associated with more positive and less negative SPA across waves, but this effect was only evident in White older adults. Findings revealed vulnerabilities in White older adults as they experience and perceive age-related changes but also identified volunteering as a way to uniquely protect them. More research is needed to refine our understanding of racial disparities in the United States and help tailor interventions intended to maximize benefits to older adults from diverse backgrounds.

Institutional Herding: Causality and Persistence

We investigate the causality in herding between foreign portfolio investors (FPIs) and domestic mutual funds (MFs) in the Indian stock market. The estimated herding levels are considerably higher than those observed in other international markets, and herding is prevalent in small stocks. We find that institutional investors follow contrarian-trading strategies, unlike what was documented in most other markets. Analysis of the aggregate herding measure shows a bi-directional causality between FPIs and MFs. Further analysis using directional herding measures indicate no evidence of causality between institutional herds on the sell-side. But we find causality on the buy-side and it is running in both directions between FPIs and MFs, implying a feedback of information. Given the tendency of institutions for herding in small stocks, adopting contrarian-trading strategies, the observed sell-side causality is perhaps having a salubrious effect. As institutional investors are contrarians, their trading activity will lead to price corrections in small stocks aligning with the fundamentals, thereby contributing to market efficiency. JEL Classification: C23, C58, G23, G15, G40

Proteomic and molecular evidences of Il1rl2, Ric8a, Krt18 and Hsp90b1 modulation during experimental hepatic fibrosis and pomegranate supplementation

The inspection of variations in the proteomic aspects conspire the biomarker discovery in diagnostics of peculiar diseases. Recent developments in high-throughput proteomic techniques have provided leverage in the discovery of biomarkers during the etiology of various diseases. We identified potential biomarkers by utilizing proteomics, bioinformatics and gene expression studies. Meticulous assessment of collagen and hydroxyproline levels along with the glycogen and protein carbonyl levels exhibited deterioration in the N' - Nitrosodiethylamine (NDEA) administered rat livers and subsequent salubrious effect of pomegranate juice. The immunohistochemical inspection of iNOS and nitrite estimation indicated the peccant fibrotic alterations. 2D proteome profiling and MALDI-TOF MS/MS furthered the significant biomarkers to be analyzed for the gene ontology by PANTHER, cluster analysis by DAVID and network simulation by STRING 10.0. Several genes found relevant after MALDI analysis were evaluated by real-time PCR (RTPCR). Our data revealed CYP2b15, HSP70, TRFE, HPT, Il1rl2, Ric8a, Krt18, Hsp90b1 and iNOS as novel biomarkers for the mechanism of pomegranate against liver fibrosis. It can be inferred that NDEA-induced liver fibrosis actuates various biological pathways by the identified biomarkers and pomegranate juice modifies them.

Maternal Psychological Resilience During Pregnancy and Newborn Telomere Length: A Prospective Study

In the context of the importance of elucidating the determinants of the initial, newborn setting of telomere length (TL), it is increasingly evident that maternal stress and stress-related processes during pregnancy play a major role. Although psychological resilience may function as a buffer, research in this area has not yet examined its potential role vis-à-vis that of stress. The authors examined the relationship between maternal psychological resilience during pregnancy and newborn TL. In a sample of 656 mother-child dyads from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction cohort, multiple serial assessments were conducted over the course of pregnancy to quantify maternal stress, negative and positive emotional responses to pregnancy events, positive affect, and perceived social support. Principal component analysis identified two latent factors: stress and positivity. A measure of resilience was computed by regressing the positivity factor on the stress factor, in order to quantify positivity after accounting for stress. TL was measured using quantitative polymerase chain reaction in leukocytes extracted from cord blood shortly after birth. Linear regression was used to predict newborn TL from maternal resilience during pregnancy, adjusting for other potential determinants. Maternal stress significantly predicted shorter newborn TL (β=-0.079), and positivity significantly predicted longer TL (β=0.135). Maternal resilience (positivity accounting for stress) was significantly and positively associated with newborn TL (β=0.114, 95% CI=0.035, 0.189), with each standard deviation increase in resilience predicting 12% longer newborn TL. The results indicate that maternal psychological resilience may exert a salubrious effect on offspring telomere biology and highlight the importance of enhancing maternal mental health and well-being during pregnancy.

Words hurt: Political rhetoric, emotions/affect, and psychological well-being among Mexican-origin youth

We examined the effect of political rhetoric on the targets of that rhetoric. Drawing from scholarship on anti-Mexican and anti-immigrant rhetoric found readily in various media and scholarship on emotions, we tested four hypotheses. Hypotheses 1 and 2 predicted that positive and negative political rhetoric would increase and decrease positive and negative emotions, respectively. Hypotheses 3 and 4 then predicted that emotional responses to positive or negative political rhetoric would influence perceived stress, subjective health, and subjective well-being. Data collection occurred between August 2016 and June 2017 at a university in California. A sample of 280 Mexican-origin youth, defined broadly as having at least one ancestor born in Mexico or the participant themselves born in Mexico, participated in an experiment where they were randomly assigned to one of three study conditions: viewing (1) positive or (2) negative political rhetoric about immigrants and Latinos in general, or (3) neutral rhetoric as a control condition before providing qualitative responses to open-ended questions and completing measures of positive and negative affect, perceived stress, subjective health, and subjective well-being. Qualitative responses indicated that negative and positive political rhetoric elicited a range of negative emotions and positive emotions, respectively. Quantitative analysis with independent samples t-tests, ANOVA, and linear regression models found that negative political rhetoric elicited higher negative affect than positive and neutral rhetoric, and positive rhetoric elicited higher positive affect than negative and neutral rhetoric. Negative emotional responses, in turn, were associated with participants’ higher perceived stress, lower subjective health and lower subjective well-being. Conversely, positive emotional responses were associated with lower perceived stress, higher subjective health, and higher subjective well-being. Positive political rhetoric, by eliciting positive emotions, can have a salubrious effect. Altogether, these findings suggest that political rhetoric matters for the targets of that rhetoric.

Heightened early medieval storminess across the Chukchi Sea, AD 400–1100: A proxy of the Late Antique Little Ice Age

Beach ridges and spits along the north-facing coast of the Chukchi Sea record paleo-storm history during the 1st millennium AD, correlative with a widespread global cooling climate episode. Northwest Alaska is a sensitive proxy owing to its absence of tectonism, glacio-isostasy, and a low rate of eustatic sea level rise. Four locales provide a regional transect and detailed chronologies: north-facing Deering and Cape Espenberg and west-facing Kotzebue and southwest facing Point Barrow. A single storm or series of storms during AD 400–600 impacted both north and south areas, while lesser intensity storms occurred across the southern region during the 11th century AD. The first millennium AD storms were as strong as or stronger than those of the 20th century, if paleo-sea level is factored in. Storm-heightened upwelling had a salubrious effect on cultures around the Chukchi Sea, leading to a florescence of whaling and walrusing.

Sirtuin 1 Mediates Hydrogen Sulfide-induced Cytoprotection Effects in Neonatal Mouse Cardiomyocytes.

Background:Current knowledge indicates that oxidative damage and the following inflammation is pivotal pathway for myocardial cell death. In recent decades, hydrogen sulfide (H2S) has been identified as a novel endogenous vasodilator and neuromodulator due to its antioxidation capacity. However, whether H2S pretreatment in neonatal mouse cardiomyocytes is a protection effect against oxidative stress remains elusive.Methods:Primary neonatal mouse cardiomyocytes were isolated and cultured, subsequently, pretreated with the H2S donor, sodium hydrosulfide (NaHS). Cell viability, lactate dehydrogenase (LDH) release, and reactive oxygen species (ROS) production are evaluated. The levels of superoxide dismutase (Sod2) and Sirtuin 1 (Sirt1), a deacetylation enzyme, were detected by Western blotting. The statistics was performed using independent-sample t-test.Results:NaHS (100 μmol/L) had no toxicity to primary neonatal mouse cardiomyocytes. Furthermore, NaHS pretreatment significantly improved neonatal mouse cardiomyocytes survival after H2O2-induced cell death, indicated by the decrease in LDH release (40.00 ± 2.65% vs. 65.33 ± 4.33%, P < 0.01) and ROS production (1.90 ± 0.33 vs. 4.56 ± 0.56, P < 0.05), and that the salubrious effect was accompanied by the upregulation of Sod2 expression. In addition, the study showed that NaHS pretreatment improved mitochondrial DNA number in neonatal mouse cardiomyocyte. Furthermore, the result demonstrated NaHS increased the expression of Sirt1 in neonatal mouse cardiomyocyte. Ex 527, an inhibitor of Sirt1, could attenuate these effects of NaHS-induced Sod2 expression and mtDNA number increase, furthermore, abrogate the cytoprotective effects of NaHS for neonatal mouse cardiomyocytes.Conclusion:Sirt1 mediated H2S-induced cytoprotection effects in neonatal mouse cardiomyocytes.

Relaxin Treatment in an Ang-II-Based Transgenic Preeclamptic-Rat Model.

Relaxin is a peptide related to pregnancy that induces nitric oxide-related and gelatinase-related effects, allowing vasodilation and pregnancy-related adjustments permitting parturition to occur. Relaxin controls the hemodynamic and renovascular adaptive changes that occur during pregnancy. Interest has evolved regarding relaxin and a therapeutic principle in preeclampsia and heart failure. Preeclampsia is a pregnancy disorder, featuring hypertension, proteinuria and placental anomalies. We investigated relaxin in an established transgenic rat model of preeclampsia, where the phenotype is induced by angiotensin (Ang)-II production in mid pregnancy. We gave recombinant relaxin to preeclamtic rats at day 9 of gestation. Hypertension and proteinuria was not ameliorated after relaxin administration. Intrauterine growth retardation of the fetus was unaltered by relaxin. Heart-rate responses and relaxin levels documented drug effects. In this Ang-II-based model of preeclampsia, we could not show a salubrious effect on preeclampsia.

A Process View of Opportunity Recognition and Creation for Radical Innovation

One of the fundamental questions addressed in the field of entrepreneurship is how entrepreneurs recognize opportunities for radical innovation (RI) that contributes to new venture creation. Whereas incremental innovation (II) involves minor changes to an existing product or service, RI creates a new user experience by altering the cognitive ecosystem of products and creating new markets. Recent RI products such as PayPal, Snapchat, Dropbox, Magic Leap, and Square have demonstrated the potentially salubrious effect of RI that contributes to new venture creation. However, technological uncertainty, business inexperience, and unknown customer preferences render RI a high- risk proposition, and comparatively little is known about how to engage and manage RI compared with II. Because scholars and practitioners focus more on individual factors that contribute to innovations, they emphasize less the whole-of-process view from the origins of innovation. To analyze innovation processes of opportunity recognition ...

What doesn’t kill you makes you stronger: A national study of U.S. military veterans

BackgroundPosttraumatic growth (PTG) is commonly observed among trauma survivors. However, few studies have treated PTG as multi-dimensional and examined how different PTG dimensions may be protective against the negative effects of future trauma. MethodsUsing a nationally representative web-based survey of 1057 U.S. military veterans followed for two years, we examined whether different PTG dimensions had a protective effect on the severity and diagnosis of posttraumatic stress disorder (PTSD) in the face of new traumatic life events. ResultsGreater scores on the Personal Strength domain of the PTG Inventory-Short Form at baseline was associated with reduced severity (β=−.05, p<.05) and incidence (OR=.68, 95% CI=.50–.93) of PTSD at a two-year follow-up. LimitationsResults are associational and causality cannot be inferred so replication is needed. ConclusionsThis study highlights the multi-dimensional nature of PTG and demonstrates a salubrious effect of trauma-related gains in personal strength on incident PTSD.

Dietary Chitosan Supplementation Ameliorates Isoproterenol-Induced Aberrations in Membrane-Bound ATPases and Mineral Status of Rat Myocardium.

Myocardial infarction is one of the major public concerns in both developed and developing countries. Recently, there is growing interest in potential healthcare applications of marine natural products in the field of cardiovascular research. In the present study, we have examined the membrane-stabilizing potential of marine mucopolysaccharide-chitosan in modulating the aberrations of thiol-dependent membrane-bound ATPases activities, mineral status, and cardiac diagnostic markers in isoproterenol-induced myocardial infarction condition in rats. Dietary intake of chitosan significantly (p < 0.05) counteracted the isoproterenol-induced lipid peroxidation and maintained the levels of thiol contents and cardiac biomarkers at concentrations analogous to that of normal controls in the rat myocardium. Chitosan administration also significantly mitigated isoproterenol-induced aberrations in the membrane-bound ATPase activities in the heart tissue and preserved the myocardial mineral status in serum and heart tissue of experimental rats at near normal value. The results of the present study haveindicated that the salubrious effect of dietary chitosan supplementation in attenuating the experimentally induced myocardial infarction condition is probably ascribable to its antioxidant defense and membrane-stabilizing properties.

Longitudinal Associations Between Immigrant Ethnic Density, Neighborhood Processes, and Latino Immigrant Youth Depression.

Depression rates rise in adolescence and the prevalence of depression is higher among Latino adolescents than other race/ethnic groups. Ethnic density among immigrant populations is associated with better health and mental health outcomes among adults, but little is known about its effects among adolescents or its mechanisms. This study examines the pathways by which immigrant density may affect mental health outcomes among Latino youth. Using data from the National Longitudinal Study of Adolescent Health (Add Health), we drew a sample of 2,678 Hispanic youth. Multivariate multilevel logistic regression analyses found that Latino immigrant density predicted lower odds of depression among both male and female immigrant but not non-immigrant Latino adolescents. No mediating effects of neighborhood efficacy, perceived safety or perceived contentment were observed in this study. Results reaffirm the need to further explore the mechanisms through which ethnic density exerts its salubrious effect on immigrant youth mental health.

The effect of acute endurance exercise on lipoproteins: a comparison of the nuclear magnetic resonance technique with the conventional lipid profile in healthy men

Nuclear magnetic resonance (NMR) of lipoprotein particle size and number may provide greater sensitivity to detecting cardiovascular disease risk compared with the conventional lipid profile in some individuals. The salubrious effect of cardiovascular exercise on blood lipids using the conventional profile is well documented; however, NMR analysis is lacking. The purpose of this study was to examine the effect of a 60-min bout of dynamic exercise on lipoprotein particle size and number as measured by NMR and compare it with the conventional blood lipid profile. Eight active, healthy men (26 ± 5.17 years) ran for 60 min at 70% maximal oxygen uptake on a motor-driven treadmill. Fasting blood samples were drawn at pre-exercise and 5-10 min and 24 h postexercise. The conventional lipid profile showed a significant change in triglycerides (p = 0.019) immediately after exercise with an increase of 22% and a nonsignificant decrease of 13% from baseline after 24 h. The NMR profile showed a significant change in the large high-density lipoprotein particle concentration (p = 0.046) with an increase of 5.8% immediately after exercise, and a decrease of 6.7% at 24 h after exercise. None of the NMR profile changes were significantly different from the baseline value. These data suggest that sensitivity differences between techniques depend on the variable considered; however, they do not warrant concomitant analysis in future studies using this population. Finally, no appreciable favorable or adverse effect was observed in the overall cardiovascular disease risk profile in active, normolipidemic males.

Abstract 9534: Expression of Heme Oxygenase-1 in Cardiac Stem Cells Enhances the Efficacy of Cell Therapy for Attenuating Left Ventricular Dysfunction and Remodeling After Myocardial Infarction

Although transplantation of cardiac stem cells (CSCs) improves LV function and structure after myocardial infarction (MI), this salubrious effect is limited by early massive CSC loss due to apoptosis. Heme oxygenase-1 (HO-1) is known to exert potent antiapoptotic and cytoprotective effects. Thus, we hypothesized that expression of HO-1 in CSCs will enhance their survival and reparative ability. To test this hypothesis, lin - /c-kit + CSCs were isolated and expanded from wild-type (WT), HO-1 transgenic (TG) or knockout (KO) mice. HO-1 protein overexpression in HO-1 TG CSCs (confirmed by FACS and immunoblotting) was mild (3-fold greater than WT CSCs). Mice underwent a 60-minute coronary occlusion followed by reperfusion; 48 h later, they received intramyocardial injection of vehicle or WT, HO-1 TG or HO-1 KO CSCs (10 5 CSCs/heart). Sham mice underwent 1-hour open-chest state with no intervention. At 35 days post-MI, both WT and HO-1 TG CSC transplantation resulted in alleviation of LV dysfunction and remodeling compared with vehicle group; however, the magnitude of the beneficial effects of HO-1 TG CSCs was significantly greater than that of WT CSCs. Compared with WT CSCs, transplantation of HO-1 TG CSCs resulted in a greater improvement in global and regional LV function (assessed by two independent methods - echocardiography and conductance catheter) and a greater increase in viable myocardial tissue in the risk region, suggesting increased formation of new cardiomyocytes (Fig). In contrast, transplantation of HO-1 KO CSCs failed to produce any LV structural or functional benefits. These results indicate, for the first time, that even a mild increase in HO-1 promotes CSC competence and that expression of HO-1 is a powerful strategy to enhance the cardiac reparative actions of CSCs in limiting LV dysfunction and remodeling post-MI. The data provide a potential therapeutic approach for promoting myocardial regeneration via modification of CSCs with cytoprotective genes.

Alpha Particle Radiobiology for Radium-223 (“Alpharadin”): The Fortuitous “Goldilocks” Effect Observed for Hormone-resistant Metastatic Prostate Cancer

Purpose/Objectives: The ALSYMPCA Trial of 223 Ra (“Alpharadin”) for men with metastatic castrate-resistant prostate cancer was a Phase III randomized trial comparing 223 Ra plus SOC vs best SOC. This trial was stopped early after 921 patients enrolled at over 100 centers achieved highly significant improvements in primary (overall survival) and all secondary endpoints.These extremely positive results prompted us to review some of the unique aspects of alpha particle radiobiology and ultra-short range molecular targeting capabilities resulting from endosteal surface new bone localization. The anatomic relationships between endosteal surfaces where isotope localization occurs and the positions of metastatic target cells and nearby marrow reserves were especially considered. Materials and Methods: Literature analysis and review of published radium autoradiographs Results: Highly energetic alpha particles such as those released during decay of 223 Ra (T 1/2 = 11.4 days) display unique radiobiologic and dosimetric aspects which may make them ideal for treating bony metastatic disease. The nuclear dose required in vitro for approximately 90% target cell kill by alpha particles is estimated to be less than 1 Gy and electron micrographs of various cell types obtained shortly after exposure confirm bizarre blebbing and condensation of chromosomal material characteristic of apoptosis. These radiobiologic effects may depend heavily on cell culture condition with more nonuniform DNA strand break damage observed in isolated detached cells. The 20-100 micron alpha particle path length (2-10 cells) appears to allow specific target cell populations to be killed within bony stroma without excessive damage to nearby sensitive hematopoietic cells. There may also be advantageous secondary cytokine signals produced as bystander effects. Calculated dosimetry models suggest bone surface to nearby marrow dose ratios of >10:1. 223 Ra treatment in rodent models showed that this family of Ca ++ analogs delivers extremely high doses to stromal elements such as bone-resorbing osteoclasts and this selectivity may aid in decreasing SREs and in pain relief. Conclusions: We highlight the fact that some basic radiobiologic and cell compartment-specific stromal localization principles known to be important in alpha particle radiopharmaceutical therapy may contribute to the very positive clinical outcomes observed while allowing minimal damage accumulation to nontarget cell groups. The highly localized cytotoxicity and fortuitous endosteal uptake patterns oberved (close enough to target cells and destructive osteoclasts for treatment efficacy but far enough away from marrow reserves to limit hemotoxicity) may serve to produce a salubrious Goldilocks effect and thereby aid in the observed treatment success. #3304

Re-Discovering the Role of the Annulment Committee in Shaping International Investment Law Jurisprudence

Much work has been done in the characterization of investment treaty awards as following a legal structure closer to the civil law concepts of jurisprudence constante/ arret de princip as opposed to the common law concepts of stare decisis & precedents. The two major sites where investment law jurisprudence takes shape are under the ICSID and UNCITRAL Rules framework. A distinct feature of the former is the presence of the Annulment Committee. The width of its review powers is considerably narrow as the grounds in which it can annul decisions being very restricted and do not extend to the examination of the merits of the claim. Though the annulment grounds are not modeled in a jurisdiction v. merits framework the effect of its structuring results in a fairly moderate review of an award on jurisdictional issues. The argument made in the paper is that the consequence of this distinction in the standard of review of the Annulment Committee has resulted in a relatively consistent set of awards qua jurisdictional issues which cannot be observed when one studies awards on merits. Thus the central thesis of the paper is that the presence of the Annulment Committee has had a salubrious effect on the development of jurisprudence around issues concerning jurisdiction. Whereas the development of law around substantial issues such as the width and scope of expropriation & FET clauses is still haphazard because the level of review afforded by the annulment Committee is too high to remedy such discrepancies. This trend has been further validated by the latest set of Annulment awards in 2010-2011 and this paper forms part of a series of research papers which would seek to validate the thesis by including these decisions in its study.

Limitations of Targeting Rate-Limiting Step of Renin-Angiotensin-Aldosterone System in Experimental Chronic Allograft Nephropathy

The renin-angiotensin system is involved in the progression of chronic kidney disease. Evidence exists that the system participates mechanistically beyond blood pressure control. Clinical trials involving angiotensin-converting enzyme inhibitors in patients with type 1 diabetes and similar trials with angiotensin receptor blockers (ARB) in patients with type 2 diabetes support that point of view (1). Plasma renin activity and renin concentration increase when angiotensin (Ang) II formation is inhibited or when Ang II activity is blocked (2). A primary action of Ang II is stimulating aldosterone release. Aldosterone is the critical salt-regulating hormone and itself has important effects in terms of target-organ effects on the cardiovascular system. Because the aspartyl proteinase renin is the rate-limiting step in Ang II production, inhibiting renin directly is the logical step in inhibiting renin-angiotensin system activation and the primary stimulus of aldosterone production. This aim was the dream of pharmacologists for decades; 40 years of hard research was rewarded with the development of aliskiren, the first practicable direct renin inhibitor. Aliskiren lowers circulating Ang II concentrations, aldosterone levels, and reduces plasma renin activity to negligible levels, although the circulating renin protein levels increase. However, because the enzymatic pocket of renin is occupied by aliskiren, this increase is of no consequence. The recently published Aliskiren in the Evaluation of Proteinuria in Diabetes trial in patients with type 2 diabetes supports the conclusion that aliskiren provides a powerful advantage in patients already receiving ARB treatment (3). A similarly salubrious effect would be expected in patients with chronic renal allograft injury. Rusai et al. (4) studied a rat model of chronic kidney allograft nephropathy and found that aliskiren did not achieve the expected result. They found that aliskiren treatment in this model was not superior to the ARB, candesartan. The investigators recorded this result despite similar effects on blood pressure achieved by the two treatments. How can we reconcile this result with the expectations engendered by inhibiting the renin-angiotensin system at its very source? A glance at the expanded renin-angiotensin system may help us further (Fig. 1). We are now aware that Ang II can occupy two receptors, the AT1 receptor and the AT2 receptor. The AT2 receptor has been rather elusive. However, two mouse knockout models and a host of in vitro and in vivo studies have provided incontrovertible evidence of the AT2 receptor's importance (1). Above and beyond this important system, we are now also aware that a second angiotensin-converting enzyme exists which effectively produces hitherto fore unappreciated Ang II metabolites, including Ang 1–7. This congener binds to a receptor coded by the Mas protooncogene (1). Both AT2 receptor signaling and Ang 1–7 signaling are said to have actions that oppose or ameliorate Ang II-mediated effects. A direct renin inhibitor would be expected to reduce not only Ang II signaling through the AT1 receptor but also any actions through the AT2 receptor or any Ang 1–7-related effects.FIGURE 1.: Systemic and local renin-angiotensin-aldosterone systems. Angiotensinogen is cleaved by renin to form Ang I. ACE converts Ang I to Ang II that can be further cleaved to Ang 1–7 by ACE2. Systemic and local activations may differ. Blockade of enzymatic activity of renin by aliskiren reduces the concentrations of the downstream effectors Ang II and Ang (1–7). Low Ang II activity releases feedback inhibition on JGA cells leading to increased release of the renin protein. RAAS, renin-angiotensin-aldosterone system; Ang I, angiotensin I; ACE, angiotensin-converting enzyme; Ang II, angiotensin II; ACE2, angiotensin-converting enzyme 2; Ang 1–7, angiotensin 1–7; VSMC, vascular smooth muscle cell; AT1R, angiotensin II type 1 receptor; JGA, Juxtaglomerular apparatus; MCP-1, macrophage chemoattractant protein-1; AT2R, angiotensin II type 2 receptor.Another confounding possibility is related to species variability. Aliskiren is a human renin inhibitor. The IC50 of aliskiren for humans is 100-fold more active for human than for rat renin. For that reason, rodents were outfitted with human genes to test the compound in earlier studies (5). The authors would have to document that sufficient aliskiren was present in their rat model to adequately block rat renin at all sites in their model. Finally, the (pro)renin receptor (PRR) must be considered (5). This receptor binds renin or prorenin. Prorenin is activated to active renin when bound to the receptor. Aliskiren does not interfere with binding. The PRR is not inhibited by aliskiren and is capable of activating extracellular-related kinase-1/2, when occupied by renin or prorenin. The activity of the PRR in the authors' model is conjecture but should be considered. Finally, the authors could be correct. Perhaps, renin-angiotensin blockade with a direct renin inhibitor posttransplantation provides no specific advantage. Indeed, retrospective human studies involving ARB in transplant patients provided an only modest advantage. Human studies will have to be performed to provide a final answer. ACKNOWLEDGMENT The authors thank F.C. Luft for helpful comments on the manuscript.