Role of the pituitary adenylate cyclase-activating polypeptide (PACAP) system of the extended amygdala in the behavioral response to stress

Stress is one of the leading predisposing factors for the onset of anxiety and depression. The mechanisms underlying stress vulnerability remain not fully understood and this gap significantly delays the advancement of the biomedical field. Pituitary adenylate cyclase-activating polypeptide (PACAP), a 38-amino acid peptide, has been proposed to regulate the stress response by acting at multiple levels. The central hypothesis of this work was that the PACAP system of the extended amygdala, a basal forebrain structure that includes the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), plays a critical role in the physiological and pathological behavioral response to stress. I found that central (intracerebroventricular) administration of PACAP in rats is able to produce a depressive-like endophenotype, as measured by increased current threshold for intracranial self-stimulation (ICSS), reduced preference for a sweet solution, and reduced time spent interacting with a novel animal in a social interaction test. I then went on investigating the brain structures and mechanisms contributing to PACAP-induced behavioral effects. I found that microinfusion of PACAP, but not VIP, into the CeA and BNST caused a dose-dependent increase in acoustic startle response (ASR), a rapid defensive reflex that is an index of stress. In addition, PACAP(6-38) infusions into either of these structures was instead able to prevent the sensitization of ASR induced by footshock stress, in line with the observation that the acute exposure to footshock stress induced a significant increase in PACAP, but not VIP, levels in both the CeA and the BNST. Finally, I found that the continuous recruitment of the PACAP system of the CeA was essential to the emergence of the negative outcomes of chronic stress. Indeed, chronic social defeat stress significantly increased PACAP levels in the CeA, but not the BNST; furthermore, viral vector-mediated knockdown of the PACAP receptor PAC1R in the CeA significantly attenuated decreased body weight gain, decreased saccharin consumption, and heightened anxiety-like behavior induced by chronic social defeat and also prevented the increase in CeA corticotropin-releasing factor (CRF) levels. The results obtained provide novel insights into the neurobiological mechanisms underlying the psychopathological consequences of stress.2020-06-12T00:00:00

Diabetes-related excess mortality in Mexico: a comparative analysis of National Death Registries between 2017-2019 and 2020

OBJECTIVE: To estimate diabetes-related mortality in Mexico in 2020 compared with 2017-2019 after the onset of the coronavirus disease 2019 (COVID-19) pandemic. RESEARCH DESIGN AND METHODS: This retrospective, state-level study used national death registries of Mexican adults aged ≥20 years for the 2017-2020 period. Diabetes-related death was defined using ICD-10 codes listing diabetes as the primary cause of death, excluding certificates with COVID-19 as the primary cause of death. Spatial and negative binomial regression models were used to characterize the geographic distribution and sociodemographic and epidemiologic correlates of diabetes-related excess mortality, estimated as increases in diabetes-related mortality in 2020 compared with average 2017-2019 rates. RESULTS: We identified 148,437 diabetes-related deaths in 2020 (177 per 100,000 inhabitants) vs. an average of 101,496 deaths in 2017-2019 (125 per 100,000 inhabitants). In-hospital diabetes-related deaths decreased by 17.8% in 2020 versus 2017-2019, whereas out-of-hospital deaths increased by 89.4%. Most deaths were attributable to type 2 diabetes (130 per 100,000 inhabitants). Compared with 2018-2019 data, hyperglycemic hyperosmolar state and diabetic ketoacidosis were the two contributing causes with the highest increase in mortality (128% and 116% increase, respectively). Diabetes-related excess mortality clustered in southern Mexico and was highest in states with higher social lag, rates of COVID-19 hospitalization, and prevalence of HbA1c ≥7.5%. CONCLUSIONS: Diabetes-related deaths increased among Mexican adults by 41.6% in 2020 after the onset of the COVID-19 pandemic, occurred disproportionately outside the hospital, and were largely attributable to type 2 diabetes and hyperglycemic emergencies. Disruptions in diabetes care and strained hospital capacity may have contributed to diabetes-related excess mortality in Mexico during 2020

Association between country preparedness indicators and quality clinical care for cardiovascular disease risk factors in 44 lower- and middle-income countries:A multicountry analysis of survey data

BackgroundCardiovascular diseases are leading causes of death, globally, and health systems that deliver quality clinical care are needed to manage an increasing number of people with risk factors for these diseases. Indicators of preparedness of countries to manage cardiovascular disease risk factors (CVDRFs) are regularly collected by ministries of health and global health agencies. We aimed to assess whether these indicators are associated with patient receipt of quality clinical care.Methods and findingsWe did a secondary analysis of cross-sectional, nationally representative, individual-patient data from 187,552 people with hypertension (mean age 48.1 years, 53.5% female) living in 43 low- and middle-income countries (LMICs) and 40,795 people with diabetes (mean age 52.2 years, 57.7% female) living in 28 LMICs on progress through cascades of care (condition diagnosed, treated, or controlled) for diabetes or hypertension, to indicate outcomes of provision of quality clinical care. Data were extracted from national-level World Health Organization (WHO) Stepwise Approach to Surveillance (STEPS), or other similar household surveys, conducted between July 2005 and November 2016. We used mixed-effects logistic regression to estimate associations between each quality clinical care outcome and indicators of country development (gross domestic product [GDP] per capita or Human Development Index [HDI]); national capacity for the prevention and control of noncommunicable diseases ('NCD readiness indicators' from surveys done by WHO); health system finance (domestic government expenditure on health [as percentage of GDP], private, and out-of-pocket expenditure on health [both as percentage of current]); and health service readiness (number of physicians, nurses, or hospital beds per 1,000 people) and performance (neonatal mortality rate). All models were adjusted for individual-level predictors including age, sex, and education. In an exploratory analysis, we tested whether national-level data on facility preparedness for diabetes were positively associated with outcomes. Associations were inconsistent between indicators and quality clinical care outcomes. For hypertension, GDP and HDI were both positively associated with each outcome. Of the 33 relationships tested between NCD readiness indicators and outcomes, only two showed a significant positive association: presence of guidelines with being diagnosed (odds ratio [OR], 1.86 [95% CI 1.08-3.21], p = 0.03) and availability of funding with being controlled (OR, 2.26 [95% CI 1.09-4.69], p = 0.03). Hospital beds (OR, 1.14 [95% CI 1.02-1.27], p = 0.02), nurses/midwives (OR, 1.24 [95% CI 1.06-1.44], p = 0.006), and physicians (OR, 1.21 [95% CI 1.11-1.32], p ConclusionIn this study, we observed that indicators of country preparedness to deal with CVDRFs are poor proxies for quality clinical care received by patients for hypertension and diabetes. The major implication is that assessments of countries' preparedness to manage CVDRFs should not rely on proxies; rather, it should involve direct assessment of quality clinical care

Multiple cardiovascular risk factor care in 55 low- and middle-income countries:A cross-sectional analysis of nationally-representative, individual-level data from 280,783 adults

The prevalence of multiple age-related cardiovascular disease (CVD) risk factors is high among individuals living in low- and middle-income countries. We described receipt of healthcare services for and management of hypertension and diabetes among individuals living with these conditions using individual-level data from 55 nationally representative population-based surveys (2009–2019) with measured blood pressure (BP) and diabetes biomarker. We restricted our analysis to non-pregnant individuals aged 40–69 years and defined three mutually exclusive groups (i.e., hypertension only, diabetes only, and both hypertension-diabetes) to compare individuals living with concurrent hypertension and diabetes to individuals with each condition separately. We included 90,086 individuals who lived with hypertension only, 11,975 with diabetes only, and 16,228 with hypertension-diabetes. We estimated the percentage of individuals who were aware of their diagnosis, used pharmacological therapy, or achieved appropriate hypertension and diabetes management. A greater percentage of individuals with hypertension-diabetes were fully diagnosed (64.1% [95% CI: 61.8–66.4]) than those with hypertension only (47.4% [45.3–49.6]) or diabetes only (46.7% [44.1–49.2]). Among the hypertension-diabetes group, pharmacological treatment was higher for individual conditions (38.3% [95% CI: 34.8–41.8] using antihypertensive and 42.3% [95% CI: 39.4–45.2] using glucose-lowering medications) than for both conditions jointly (24.6% [95% CI: 22.1–27.2]).The percentage of individuals achieving appropriate management was highest in the hypertension group (17.6% [16.4–18.8]), followed by diabetes (13.3% [10.7–15.8]) and hypertension-diabetes (6.6% [5.4–7.8]) groups. Although health systems in LMICs are reaching a larger share of individuals living with both hypertension and diabetes than those living with just one of these conditions, only seven percent achieved both BP and blood glucose treatment targets. Implementation of cost-effective population-level interventions that shift clinical care paradigm from disease-specific to comprehensive CVD care are urgently needed for all three groups, especially for those with multiple CVD risk factors

Enzymatic Reaction Mechanisms, pp ranca

ABSTRACT: The mechanism of the argininosuccinate lyase reaction has been probed by the measurement of the effects of isotopic substitution a t the reaction centers. A primary deuterium isotope effect of 1.0 on both Vand V / K is obtained with (2S,3R)-argininosuccinate-3-d, while a primary 15N isotope effect on V / K of 0.9964 f 0.0003 is observed. The 15N isotope effect on the equilibrium constant is 1.018 f 0.001. The proton that is abstracted from C-3 of argininosuccinate is unable to exchange with the solvent from the enzyme-intermediate complex but is rapidly exchanged with solvent from the enzyme-fumaratearginine complex. A deuterium solvent isotope effect of 2.0 is observed on the V,,, of the forward reaction. These and other data have been interpreted to suggest that argininosuccinate lyase catalyzes the cleavage of argininosuccinate via a carbanion intermediate. The proton abstraction step is not rate limiting, but the inverse 15N primary isotope effect and the solvent deuterium isotope effect suggest that protonation of the guanidino group and carbon-nitrogen bond cleavage of argininosuccinate are kinetically significant. Argininsuccinate lyase catalyzes the cleavage of argininosuccinate to arginine and fumarate. The enzyme is found in the liver where it functions in the biosynthesis of urea. The enzyme from bovine liver has been shown by Lusty and Ratner (1972) to be a tetramer of four identical subunits. No external cofactor is involved, and the enzyme apparently does not require metal ions for catalytic activity. The details of the catalytic events leading to the chemical transformation of argininosuccinate to fumarate and arginine are largely unknown. Ratner and co-workers have shown that the reaction involves the trans elimination of arginine and the pro-R hydrogen at C-3 of argininosuccinate (Hoberman et al., 1965). The kinetic mechanism of the reaction is random In this paper we report on our efforts to determine the magnitude and the timing of the bond-breaking steps in the conversion of argininosuccinate to arginine and fumarate. Th

Multiple cardiovascular risk factor care in 55 low- and middle-income countries: A cross-sectional analysis of nationally-representative, individual-level data from 280,783 adults

The prevalence of multiple age-related cardiovascular disease (CVD) risk factors is high among individuals living in low- and middle-income countries. We described receipt of healthcare services for and management of hypertension and diabetes among individuals living with these conditions using individual-level data from 55 nationally representative population-based surveys (2009–2019) with measured blood pressure (BP) and diabetes biomarker. We restricted our analysis to non-pregnant individuals aged 40–69 years and defined three mutually exclusive groups (i.e., hypertension only, diabetes only, and both hypertension-diabetes) to compare individuals living with concurrent hypertension and diabetes to individuals with each condition separately. We included 90,086 individuals who lived with hypertension only, 11,975 with diabetes only, and 16,228 with hypertension-diabetes. We estimated the percentage of individuals who were aware of their diagnosis, used pharmacological therapy, or achieved appropriate hypertension and diabetes management. A greater percentage of individuals with hypertension-diabetes were fully diagnosed (64.1% [95% CI: 61.8–66.4]) than those with hypertension only (47.4% [45.3–49.6]) or diabetes only (46.7% [44.1–49.2]). Among the hypertension-diabetes group, pharmacological treatment was higher for individual conditions (38.3% [95% CI: 34.8–41.8] using antihypertensive and 42.3% [95% CI: 39.4–45.2] using glucose-lowering medications) than for both conditions jointly (24.6% [95% CI: 22.1–27.2]).The percentage of individuals achieving appropriate management was highest in the hypertension group (17.6% [16.4–18.8]), followed by diabetes (13.3% [10.7–15.8]) and hypertension-diabetes (6.6% [5.4–7.8]) groups. Although health systems in LMICs are reaching a larger share of individuals living with both hypertension and diabetes than those living with just one of these conditions, only seven percent achieved both BP and blood glucose treatment targets. Implementation of cost-effective population-level interventions that shift clinical care paradigm from disease-specific to comprehensive CVD care are urgently needed for all three groups, especially for those with multiple CVD risk factors

Efficient Peacekeeping for a New World Order

With the convergence of preferences for democracy and free markets in so many nations, the UN has a momentous opportunity to provide the infrastructure needed to attain international peace. Given that peace is a public good, its provision by the international community currently suffers from the problems associated with these commodities, in particular that of “collective action." Namely, peacekeeping will entail “free-riding," by member states of the international system. This leads to the underprovision of peacekeeping/peace-enforcing efforts. This article presents a market- based proposal to remedy this problem. The proposed changes to peacekeeping operations aim to discourage wealthier nations from vetoing missions of genuine humanitarian concern for fear of casualties to their troops. Second, it also more justly compensates low-income nations participating in operations. Thirdly, it corrects for the current tendency to use more weapons and less personnel, and finally and most importantly, it would reflect the preferences of the international community for different peacekeeping operations in a transparent manner.

Pricing with Monitoring Costs

This paper presents empirical evidence which at first glance appears to show that firms are not pricing to maximize profits. We then present a model to explain how this behavior is in fact optimal when we account for additional constraints faced by firms in certain product markets.info:eu-repo/semantics/publishe

Argininosuccinate synthetase: steady state kinetics

Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Bibliography: leaf 38.Not availabl

Capsaicinoids in various pepper cultivars

Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Bibliography: leaves 45-47.Not availabl