The impact of PIPs on mortality and readmissions in older adults: a retrospective cohort study.

PURPOSE: Our aim was to determine the impact of potentially inappropriate prescriptions (PIP), according to "Screening Tool of Older Persons' Prescriptions" criteria version 2 (STOPP-2), on mortality and hospital admissions. METHODS: Monocentric retrospective cohort study. Patients over 65 years of age and who were consecutively discharged from internal medicine at a Spanish university hospital in 2016 were included. The mortality and hospital admissions of the cohort of patients were analysed using their electronic health records within two years from the time of discharge. Analysis was done based on the type and number of STOPP-2 criteria as well as taking into account the total number of medications. The subdistribution hazard ratios (SHR) were estimated through a competing proportional hazards model. RESULTS: A total of 270 patients with a median age of 82 years (interquartile range/IQR 76-86 years), and 152 (56.3%) women were studied. It was found out that 28.3% of patients with PIP died compared to 17.2% of patients without it. Digoxin (B1 STOPP-2 criterion) with a subdistribution hazard ratio (SHR) 2.40 (95% CI 0.63-9.18), selective serotonin re-uptake inhibitors/SSRIs (D4) with a SHR 1.76 (95% CI 0.52-5.96) and neuroleptic drugs (K2) with a SHR 2.01 (95% CI 0.82-4.95) non-significantly increased the risk of death. Dementia (SHR 5.45; 95% CI 2.76-10.78) was then the only statistically significant risk factor for death. Sixty percent of patients with a PIP had shown at least one hospital admission compared to 51% of patients without it. The number of drugs at discharge (SHR 1.03; 95% CI 1.01-1.05) and having 1-2 STOPP-2 criteria (SHR 1.17; 95% CI 1.02-1.35) significantly increased the risk of hospital admission. CONCLUSION: The number of drugs at discharge and having any STOPP criteria significantly increased the risk of hospital admission in this cohort. PIP, only according to some specific STOPP-2 criteria involving digoxin, neuroleptics and SSRIs, might associate with a statistically non-significantly higher risk on mortality.

DNA methylation levels and telomere length in human teeth: usefulness for age estimation.

In the last decade, increasing knowledge of epigenetics has led to the development of DNA methylation-based models to predict age, which have shown high predictive accuracy. However, despite the value of teeth as forensic samples, few studies have focused on this source of DNA. This study used bisulfite pyrosequencing to measure the methylation levels of specific CpG sites located in the ELOVL2, ASPA, and PDE4C genes, with the aim of selecting the most age-informative genes and determining their associations with age, in 65 tooth samples from individuals 15 to 85 years old. As a second aim, methylation data and measurements of relative telomere length in the same set of samples were used to develop preliminary age prediction models to evaluate the accuracy of both biomarkers together and separately in estimating age from teeth for forensic purposes. In our sample, several CpG sites from ELOVL2 and PDE4C genes, as well as telomere length, were significantly associated with chronological age. We developed age prediction quantile regression models based on DNA methylation levels, with and without telomere length as an additional variable, and adjusted for type of tooth and sex. Our results suggest that telomere length may have limited usefulness as a supplementary marker for DNA methylation-based age estimation in tooth samples, given that it contributed little improvement in the prediction errors of the models. In addition, even at older ages, DNA methylation appeared to be more informative in predicting age than telomere length when both biomarkers were evaluated separately.

Systemic inflammatory impact of periodontitis on cognitive impairment.

OBJECTIVES: The role in dementia of systemic inflammation derived from periodontal disease is not fully elucidated. The objective of our study was to examine the impact of inflammation on the relationship between periodontitis and cognitive impairment. METHODS: We have designed a case (n = 171) and control (n = 131) study to determine the periodontal health status, grade of cognitive impairment/dementia and systemic inflammation level, the last being measured by analysis of 29 inflammatory biomarkers using multiplex techniques. RESULTS: At the time of sampling, 11 of the 29 inflammatory biomarkers were associated with cognitive impairment in patients with more severe periodontitis. However, the inflammatory response to severe periodontitis was more reduced (lower biomarker concentrations) in cases (with cognitive impairment or dementia) than in (cognitively healthy) controls, an unexpected finding. CONCLUSIONS: Based on these results, we cannot confirm that systemic inflammation derived from periodontal disease plays a relevant role in the aetiology of cognitive impairment.

Cultural effects on neurodevelopmental testing in children from six European countries: an analysis of NUTRIMENTHE Global Database.

Cultural background is an important variable influencing neuropsychological performance. Multinational projects usually involve gathering data from participants from different countries and/or different cultures. Little is known about the influence of culture on neuropsychological testing results in children and especially in European children. The objectives of this study were to compare neuropsychological performance of children from six European countries (Belgium, Germany, Italy, The Netherlands, Poland and Spain) using a comprehensive neuropsychological battery and to apply a statistical procedure to reduce the influence of country/cultural differences in neuropsychological performance. As expected, the results demonstrated differences in neuropsychological performance among children of the six countries involved. Cultural differences remained after adjusting for other confounders related to neuropsychological execution, such as sex, type of delivery, maternal age, gestational age and maternal educational level. Differences between countries disappeared and influence of culture was considerably reduced when standardised scores by country and sex were used. These results highlight the need for developing specific procedures to compare neuropsychological performance among children from different cultures to be used in multicentre studies.

Light-dark influence on enkephalinase activity in hypothalamus and pituitary.

OBJECTIVES: Enkephalins functions are partly modulated by enkephalinases especially membrane-bound alanyl aminopeptidase (EC-3.4.11.2) considered as the major enkephalin-degrading enzyme in brain. The analysis of its activity in standard and non-standard light/dark conditions may help the understanding of the regulatory mechanisms of enkephalins. METHODS: Enkephalinase activity was determined fluorometrically, using an arylamide derivative as substrate, in hypothalamus and pituitary of adult male rats, in a standard 12:12 h light/dark cycle; samples were collected at 10:00 h, 13:00 h and 16:00 h of the light period (light on from 7:00 to 19:00 h) and at 22:00 h, 01:00 h and 04:00 h of the dark one (light off from 19:00 h to 07:00 h). For comparison, the enzymatic activity was also measured in the same locations at the same time-points but under constant light conditions. RESULTS: In standard light/dark conditions, the results demonstrated an opposite daily rhythm in hypothalamus and pituitary. While the highest levels of AlaAP or enkephalinase activities were measured in hypothalamus during the dark period, they were the highest in the pituitary during the light one. In contrast, the lowest levels of activity were observed in the light period in the hypothalamus whereas they were in the dark one in the pituitary. A similar pattern was observed under constant light. The differences were however higher in hypothalamus and lower, but still significant, in pituitary. CONCLUSION: These results may reflect the behaviour of the endogenous substrates of enkephalinase and consequently be involved in their functions. This observation may affect the chronotherapeutic strategies.

Effectiveness of Psychological and Educational Interventions to Prevent Depression in Primary Care: A Systematic Review and Meta-Analysis.

PURPOSE: Although evidence exists for the efficacy of psychosocial interventions to prevent the onset of depression, little is known about its prevention in primary care. We aimed to evaluate the effectiveness of psychological and educational interventions to prevent depression in primary care. METHODS: We conducted a systematic review and meta-analysis of relevant randomized controlled trials (RCTs) examining the effect of psychological and educational interventions to prevent depression in nondepressed primary care attendees. We searched MEDLINE, PsycINFO, Web of Science, OpenGrey Repository, Cochrane Central Register of Controlled Trials, and other sources up to May 2016. At least 2 reviewers independently evaluated the eligibility criteria, extracted data, and assessed the risk of bias. We calculated standardized mean differences (SMD) using random-effects models. RESULTS: We selected 14 studies (7,365 patients) that met the inclusion criteria, 13 of which were valid to perform a meta-analysis. Most of the interventions had a cognitive-behavioral orientation, and in only 4 RCTs were the intervention clinicians primary care staff. The pooled SMD was -0.163 (95%CI, -0.256 to -0.070; P = .001). The risk of bias and the heterogeneity (I2 = 20.6%) were low, and there was no evidence of publication bias. Meta-regression detected no association between SMD and follow-up times or SMD and risk of bias. Subgroup analysis suggested greater effectiveness when the RCTs used care as usual as the comparator compared with those using placebo. CONCLUSIONS: Psychological and educational interventions to prevent depression had a modest though statistically significant preventive effect in primary care. Further RCTs using placebo or active comparators are needed.

Dental pattern diversity in a military population and its usefulness for assessing the degree of certainty in dental identification.

In forensic dentistry, the analysis of dental diversity forms the basis of probability calculations in dental identification. The present study aimed to contribute to the knowledge of dental diversity in a Spanish military population (considering isolated teeth, sets of different numbers of teeth, and combinations of teeth of forensic interest) and its implications for dental identification. A further aim was to compare the performance of three coding systems (detailed, generic, and binary) to assess dental pattern diversity. Dental diversity of a representative sample of the Spanish military population (3920 individuals aged between 18 and 55 years) was calculated according to a genetic (mitochondrial DNA) model in which diversity was defined as the likelihood that two randomly selected individuals in a sample would exhibit different patterns. By performing all pairwise comparisons of dental patterns in the dataset, the total number of matches was generated, and the diversity of dental patterns was then derived. First and third molars were the teeth that showed the highest levels of diversity, and a high diversity value (>0.99) was obtained with only 5 teeth (16, 36, 38, 46, and 48) when detailed coding was used. In addition, dental diversity in the full dentition and posterior teeth exceeded the threshold of 0.99 in all three coding systems. Although a very high diversity value (≥0.999) was only achieved with detailed coding, it should be noted that the generic coding system requires less time and skill to use, and can also provide high diversity values. Our findings show that further efforts should be made to establish large, periodically updated dental datasets of different populations in order to assess dental pattern diversity (without excluding third molars) based on empirical comparison, and to substantiate the certainty of dental identification.

Exploring the interplay between climate, population immunity and SARS-CoV-2 transmission dynamics in Mediterranean countries.

The relationship between SARS-CoV-2 transmission and environmental factors has been analyzed in numerous studies since the outbreak of the pandemic, resulting in heterogeneous results and conclusions. This may be due to differences in methodology, considered variables, confounding factors, studied periods and/or lack of adequate data. Furthermore, previous works have reported that the lack of population immunity is the fundamental driver in transmission dynamics and can mask the potential impact of environmental variables. In this study, we aimed to investigate the association between climate variables and COVID-19 transmission considering the influence of population immunity. We analyzed two different periods characterized by the absence of vaccination (low population immunity) and a high degree of vaccination (high level of population immunity), respectively. Although this study has some limitations, such us the restriction to a specific climatic zone and the omission of other environmental factors, our results indicate that transmission of SARS-CoV-2 may increase independently of temperature and specific humidity in periods with low levels of population immunity while a negative association is found under conditions with higher levels of population immunity in the analyzed regions.

Propensity score analysis of psychological intimate partner violence and preterm birth.

Psychological intimate partner violence (IPV), a global public health problem, affects mothers during pregnancy. We evaluated its relationship with preterm birth. We established a cohort of 779 consecutive mothers receiving antenatal care and giving birth in 15 public hospitals in Spain. Trained midwives collected IPV data using the Index of Spouse Abuse validated in the Spanish language. Preterm was defined as birth before 37 completed weeks of gestation. Gestational age was estimated by early ultrasound. With multivariate logistic regression we estimated the relative association of IPV with preterm birth as adjusted odds ratios (AOR), with 95% confidence intervals (CI). In propensity score analysis, using weighting by inverse probability of exposure to IPV, the whole sample was used for estimating the absolute difference in probability of preterm amongst offspring born to mothers with and without IPV. Socio-demographic and other pregnancy characteristics served as covariates in both analyses. Preterm occurred in 57 (7.3%) pregnancies. Psychological IPV, experienced by 151 (21%) mothers, was associated with preterm birth (11.9% vs 6.5%; AOR = 2.4; 95% CI = 1.1-5.0; p = 0.01). The absolute preterm difference in psychological IPV compared to normal was 0.08 (95% CI = 0.01-0.16; p = 0.04). The probability of preterm birth was 8% higher on average in women with psychological IPV during pregnancy. As our analysis controlled for selection bias, our findings give credence to a causal inference. Screening and management for psychological IPV during pregnancy is an important step in antenatal care to prevent preterm birth.

Asymmetric Interaction of Neuropeptidase Activities between Cortico-Limbic Structures, Plasma and Cardiovascular Function after Unilateral Dopamine Depletions of the Nigrostriatal System.

In emotional processing, dopamine (DA) plays an essential role, and its deterioration involves important consequences. Under physiological conditions, dopamine exhibits brain asymmetry and coexists with various neuropeptides that can coordinate the processing of brain functions. Brain asymmetry can extend into a broader concept of asymmetric neurovisceral integration, including behavior. The study of the activity of neuropeptide regulatory enzymes (neuropeptidases, NPs) is illustrative. We have observed that the left and right brain areas interact intra- and inter-hemispherically, as well as with peripheral tissues or with physiological parameters such as blood pressure or with behaviors such as turning preference. To obtain data that reflect this integrative behavior, we simultaneously analyzed the impact of left or right brain DA depletion on the activity of various NPs in corticolimbic regions of the left and right hemispheres, such as the medial prefrontal cortex, amygdala and hippocampus, as well as on the plasma activity of the same aminopeptidase activities (APs) and on systolic blood pressure (SBP). Intra- and inter-hemispheric interactions as well as the interactions of NPs from the left or right hemispheres were analyzed with the same plasma APs and the SBP obtained from sham and from left or right lesioned rats. The results demonstrate a complex profile depending on the hemisphere considered. They definitively confirm an asymmetric neurovisceral integration and reveal a higher level of inter-hemispheric corticolimbic interactions including with SBP after left dopamine depletion.

Aminopeptidase Activities Interact Asymmetrically between Brain, Plasma and Systolic Blood Pressure in Hypertensive Rats Unilaterally Depleted of Dopamine.

Brain dopamine, in relation to the limbic system, is involved in cognition and emotion. These functions are asymmetrically processed. Hypertension not only alters such functions but also their asymmetric brain pattern as well as their bilateral pattern of neurovisceral integration. The central and peripheral renin-angiotensin systems, particularly the aminopeptidases involved in its enzymatic cascade, play an important role in blood pressure control. In the present study, we report how these aminopeptidases from left and right cortico-limbic locations, plasma and systolic blood pressure interact among them in spontaneously hypertensive rats (SHR) unilaterally depleted of dopamine. The study comprises left and right sham and left and right lesioned (dopamine-depleted) rats as research groups. Results revealed important differences in the bilateral behavior comparing sham left versus sham right, lesioned left versus lesioned right, and sham versus lesioned animals. Results also suggest an important role for the asymmetrical functioning of the amygdala in cardiovascular control and an asymmetrical behavior in the interaction between the medial prefrontal cortex, hippocampus and amygdala with plasma, depending on the left or right depletion of dopamine. Compared with previous results of a similar study in Wistar-Kyoto (WKY) normotensive rats, the asymmetrical behaviors differ significantly between both WKY and SHR strains.

Gender and the professional career of primary care physicians in Andalusia (Spain).

BACKGROUND: Although the proportion of women in medicine is growing, female physicians continue to be disadvantaged in professional activities. The purpose of the study was to determine and compare the professional activities of female and male primary care physicians in Andalusia and to assess the effect of the health center on the performance of these activities. METHODS: Descriptive, cross-sectional, and multicenter study. SETTING: Spain. POPULATION: urban health centers and their physicians. SAMPLE: 88 health centers and 500 physicians. INDEPENDENT VARIABLE: gender. MEASUREMENTS: Control variables: age, postgraduate family medicine specialty (FMS), patient quota, patients/day, hours/day housework from Monday to Friday, idem weekend, people at home with special care, and family situation. DEPENDENT VARIABLES: 24 professional activities in management, teaching, research, and the scientific community. Self-administered questionnaire. Descriptive, bivariate, and multilevel logistic regression analyses. RESPONSE: 73.6%. Female physicians: 50.8%. Age: female physicians, 49.1 ± 4.3 yrs; male physicians, 51.3 ± 4.9 yrs (p < 0.001). Female physicians with FMS: 44.2%, male physicians with FMS: 33.3% (p < 0.001). Female physicians dedicated more hours to housework and more frequently lived alone versus male physicians. There were no differences in healthcare variables. Thirteen of the studied activities were less frequently performed by female physicians, indicating their lesser visibility in the production and diffusion of scientific knowledge. Performance of the majority of professional activities was independent of the health center in which the physician worked. CONCLUSIONS: There are gender inequities in the development of professional activities in urban health centers in Andalusia, even after controlling for family responsibilities, work load, and the effect of the health center, which was important in only a few of the activities under study.

Comparative study of adverse drug reactions among direct-acting oral anticoagulants and vitamin K antagonists using the EudraVigilance database.

Our aim was to compare adverse drug reactions (ADRs) associated with direct-acting oral anticoagulants and vitamin K antagonists from the European EudraVigilance (EV) database. The EV database is the system for the analysis of information on suspected ADRs that are authorised, or being evaluated in clinical trials, in the European Economic Area. Registered ADRs (from the groups "Gastrointestinal disorders", "General disorders and administration site conditions", "Injury, poisoning and procedural complications", "Nervous system (NS) disorders" and "Vascular disorders") for apixaban, rivaroxaban, dabigatran and vitamin K antagonists (VKA) were collected by age group (< 65 years; 65-85 years and > 85 years) and by sex. The proportional reporting ratio (PRR) was used to compare ADRs in relation to the anticoagulants tested. A total of 274,693 ADRs were analysed. For gastrointestinal ADRs, patients treated with rivaroxaban and dabigatran (PRR 2.17 and 2.51, respectively) were at significantly higher risks than those treated with apixaban and VKA (PRR 1.27 and 1.47, respectively), while risks for vascular disorders were increased by all anticoagulants that were tested. Lastly, none of the anticoagulants significantly increased the risk of ADRs within the NS group. Rivaroxaban and dabigatran were associated with a significantly higher risk of gastrointestinal ADR than apixaban or VKA. All anticoagulants increased the risk of vascular pathology while none of them demonstrated significant increased risk of ADR to NS.

Long-Chain Polyunsaturated Fatty Acids, Homocysteine at Birth and Fatty Acid Desaturase Gene Cluster Polymorphisms are Associated with Children's Processing Speed up to Age 9 Years.

Both pre- and early postnatal supplementation with docosahexaenoic acid (DHA), arachidonic acid (AA) and folate have been related to neural development, but their long-term effects on later neural function remain unclear. We evaluated the long-term effects of maternal prenatal supplementation with fish-oil (FO), 5-methyltetrahydrofolate (5-MTHF), placebo or FO + 5-MTHF, as well as the role of fatty acid desaturase (FADS) gene cluster polymorphisms, on their offspring's processing speed at later school age. This study was conducted in NUHEAL children at 7.5 (n = 143) and 9 years of age (n = 127). Processing speed tasks were assessed using Symbol Digit Modalities Test (SDMT), Children Color Trails Test (CCTT) and Stroop Color and Word Test (SCWT). Long-chain polyunsaturated fatty acids, folate and total homocysteine (tHcy) levels were determined at delivery from maternal and cord blood samples. FADS and methylenetetrahydrofolate reductase (MTHFR) 677 C > T genetic polymorphisms were analyzed. Mixed models (linear and logistic) were performed. There were significant differences in processing speed performance among children at different ages (p < 0.001). The type of prenatal supplementation had no effect on processing speed in children up to 9 years. Secondary exploratory analyses indicated that children born to mothers with higher AA/DHA ratio at delivery (p < 0.001) and heterozygotes for FADS1 rs174556 (p < 0.05) showed better performance in processing speed at 9 years. Negative associations between processing speed scores and maternal tHcy levels at delivery were found. Our findings suggest speed processing development in children up to 9 years could be related to maternal factors, including AA/DHA and tHcy levels, and their genetic background, mainly FADS polymorphism. These considerations support that maternal prenatal supplementation should be quantitatively adequate and individualized to obtain better brain development and mental performance in the offspring.

Asymmetrical response of aminopeptidase A and nitric oxide in plasma of normotensive and hypertensive rats with experimental hemiparkinsonism.

Aminopeptidases and dopamine (DA) exhibit asymmetries in the brain that are reflected in the peripheral response to unilateral striatal DA depletions (experimental hemiparkinsonism). This might be due to asymmetries in the autonomic innervation of the peripheral vessels. Nitric oxide (NO) is released through vascular sympathetic activation. A similar pathway could be postulated for aminopeptidases. Angiotensin II, metabolized by aminopeptidase A (AP A), interacts with NO and dopamine in the control of blood pressure. Moreover, plasma AP A activity and NO concentrations are elevated in hypertensive rats in which sympathetic activity is increased. We hypothesize that plasma AP A activity and NO concentrations may reflect a central asymmetry of the sympathetic activity. Therefore, we analyzed the effect of unilateral depletions of brain DA by injecting 6-hydroxydopamine into the left or right striatum and measuring plasma AP A, NO and systolic blood pressure (SBP) in normotensive and hypertensive rats. Changes in plasma AP A and NO in opposite directions may reflect an asymmetry in the function of the nigrostriatal system. Our results also revealed an inverse correlation between AP A and NO, in normotensive rats lesioned or sham operated in the right side and hypertensive rats lesioned in the left one. We concluded that the observed changes in plasma NO and AP A after left or right striatal DA depletions may be due to asymmetries in the peripheral autonomic innervation of the vessels.

[Characteristics of the family of origin and family formed by women and men primary care physicians of Andalusia, Spain]. / Características de la familia de origen y de la familia formada por las médicas y los médicos de familia de Andalucía.

BACKGROUND: The origin and formed family characteristics are related to physician's professional career. The purpose of this study was to know and compare by sex the characteristics of the origin family and formed family of women and men family physician in Andalusia. METHODS: Cross sectional and multicenter study. SETTING: Urban primary health care centres from Andalusian province capitals. PARTICIPANTS: Physician of primary health care centres. INCLUSION CRITERIA: at least one year using computerized medical history with the same quota patients. Multistage random sample, 88 primary health care centres and 500 physicians, 50% of both sexes (alpha=5%, power=90%, precision=15%). Postal auto administrated questionnaire. VARIABLES: sex, age, tutor of resident in family medicine, last father's activity, last mother's activity, number of brothers or sisters, family situation, last couple's activity (if any), to have or not children. RESULTS: 73.6 % responses. In no responses there weren't differences of sex neither tutor of resident in family medicine. Mean age: women physicians 49.5 +/- 4.3 and men physician 51.3 +/- 4.9 (p= or < 0.005). Postgraduate formation in family medicine: 42.2% of women and 33.3% of men (p=0.016). Live alone: 6.1% of women physician and 2.7% men physician (p=0.005). Live alone with children 9.9% of women and 2.2% of men (p=0.005). 16.5% of women and 10.2% of men don t have children (p=0.077). 21.1% of men physician s couples work only at home vs. 0.1% of women physician s couples (p= or < 0.005). 46% of women physician s couples is also physician vs. 22% of men physician s couples (p= or < 0.005). No significant differences registered in parent s activities neither in the number of brother or sisters. CONCLUSION: There are no significant differences in physician s origin family. However important differences in the characteristics of formed family are observed in both sexes.

Functional and neurometabolic asymmetry in SHR and WKY rats following vasoactive treatments.

A lateralized distribution of neuropeptidase activities in the frontal cortex of normotensive and hypertensive rats has been described depending on the use of some vasoactive drugs and linked to certain mood disorders. Asymmetrical neuroperipheral connections involving neuropeptidases from the left or right hemisphere and aminopeptidases from the heart or plasma have been suggested to play a role in this asymmetry. We hypothesize that such asymmetries could be extended to the connection between the brain and physiologic parameters and metabolic factors from plasma and urine. To assess this hypothesis, we analyzed the possible correlation between neuropeptidases from the left and right frontal cortex with peripheral parameters in normotensive (Wistar Kyoto [WKY]) rats and hypertensive rats (spontaneously hypertensive rats [SHR]) untreated or treated with vasoactive drugs such as captopril, propranolol and L-nitro-arginine methyl ester. Neuropeptidase activities from the frontal cortex were analyzed fluorometrically using arylamide derivatives as substrates. Physiological parameters and metabolic factors from plasma and urine were determined using routine laboratory techniques. Vasoactive drug treatments differentially modified the asymmetrical neuroperipheral pattern by changing the predominance of the correlations between peripheral parameters and central neuropeptidase activities of the left and right frontal cortex. The response pattern also differed between SHR and WKY rats. These results support an asymmetric integrative function of the organism and suggest the possibility of a different neurometabolic response coupled to particular mood disorders, depending on the selected vasoactive drug.

Thyroid Disorders Change the Pattern of Response of Angiotensinase Activities in the Hypothalamus-Pituitary-Adrenal Axis of Male Rats.

Thyroid disorders affect the hypothalamic-pituitary-adrenal axis with important consequences on the cardiovascular function in which the renin-angiotensin system plays a major role. Hypo and hyperthyroidism influence the classic main components of the renin-angiotensin system. However, the behavior of other elements of the renin-angiotensin system such as Ang III, Ang 2-10, Ang IV, or AT4, regulated by angiotensinase enzymes such as alanyl- (AlaAP), cystinyl- (CysAP), glutamyl- (GluAP), or aspartyl-aminopeptidase (AspAP), has not yet been described. In order to obtain a comprehensive view on the response of the renin-angiotensin system in the hypothalamic-pituitary-adrenal axis of animals with thyroid disorders, these enzyme activities were simultaneously analyzed fluorometrically, using arylamide derivatives as substrates in hypothalamus, anterior and posterior pituitary, adrenals and plasma of euthyroid, hypothyroid, and hyperthyroid rats, and their intra- and inter-tissue correlations were evaluated. The response is depending on the type of enzyme studied, its location and the thyroid status. Anterior pituitary, adrenals and plasma were mainly affected by the thyroid disorders. In the anterior pituitary, GluAP and AspAP increased in hypothyroid rats. In adrenals, AlaAP and CysAP decreased in hypothyroid whereas GluAP and AspAP decreased in hyperthyroid rats. In plasma, while AlaAP increased in hypo- and hyperthyroid rats, CysAP and GluAP decreased only in hyperthyroid. In comparison with euthyroid, intra-tissue correlations decreased in hypothyroid but inter-tissue correlations decreased mainly in hyperthyroid rats. Thyroid disorders also produced a disruption in the pattern of inter-tissue correlations observed in euthyroid. These results suggest that thyroid hormone levels hit components of the renin-angiotensin system and may influence the paracrine and endocrine cross talk between cells.