Respiratory Subsets in Patients with Moderate to Severe Acute Respiratory Distress Syndrome for Early Prediction of Death.

Introduction: In patients with acute respiratory distress syndrome (ARDS), the PaO2/FiO2 ratio at the time of ARDS diagnosis is weakly associated with mortality. We hypothesized that setting a PaO2/FiO2 threshold in 150 mm Hg at 24 h from moderate/severe ARDS diagnosis would improve predictions of death in the intensive care unit (ICU). Methods: We conducted an ancillary study in 1303 patients with moderate to severe ARDS managed with lung-protective ventilation enrolled consecutively in four prospective multicenter cohorts in a network of ICUs. The first three cohorts were pooled (n = 1000) as a testing cohort; the fourth cohort (n = 303) served as a confirmatory cohort. Based on the thresholds for PaO2/FiO2 (150 mm Hg) and positive end-expiratory pressure (PEEP) (10 cm H2O), the patients were classified into four possible subsets at baseline and at 24 h using a standardized PEEP-FiO2 approach: (I) PaO2/FiO2 ≥ 150 at PEEP < 10, (II) PaO2/FiO2 ≥ 150 at PEEP ≥ 10, (III) PaO2/FiO2 < 150 at PEEP < 10, and (IV) PaO2/FiO2 < 150 at PEEP ≥ 10. Primary outcome was death in the ICU. Results: ICU mortalities were similar in the testing and confirmatory cohorts (375/1000, 37.5% vs. 112/303, 37.0%, respectively). At baseline, most patients from the testing cohort (n = 792/1000, 79.2%) had a PaO2/FiO2 < 150, with similar mortality among the four subsets (p = 0.23). When assessed at 24 h, ICU mortality increased with an advance in the subset: 17.9%, 22.8%, 40.0%, and 49.3% (p < 0.0001). The findings were replicated in the confirmatory cohort (p < 0.0001). However, independent of the PEEP levels, patients with PaO2/FiO2 < 150 at 24 h followed a distinct 30-day ICU survival compared with patients with PaO2/FiO2 ≥ 150 (hazard ratio 2.8, 95% CI 2.2−3.5, p < 0.0001). Conclusions: Subsets based on PaO2/FiO2 thresholds of 150 mm Hg assessed after 24 h of moderate/severe ARDS diagnosis are clinically relevant for establishing prognosis, and are helpful for selecting adjunctive therapies for hypoxemia and for enrolling patients into therapeutic trials.

Impact of Covid-19 containment on community pharmaceutical spending in Andalusia - Spain.

BACKGROUND: In the field of health, the year 2020 will be remembered for testing (stressing) all health institutions and their forms of management (centralised and decentralised). The everyday activity of primary and hospital care was significantly altered by the introduction of telephone consultations, which reduce the number of visits to health centres or hospitals and are still relevant today in the face of successive waves of the pandemic. OBJECTIVE: To analyse whether population confinement due to the COVID-19 pandemic had an impact on the dispensing of medications in community pharmacies and the associated spending during the period March-July 2020 in Andalusia (Spain). METHODS: A time series analysis applying econometric model analysis techniques to confirm or rule out whether the lockdown caused by the COVID-19 pandemic had an impact on the dispensing of medications by community pharmacies and the associated expenditures. The variables used were the number of medication containers dispensed by community pharmacies (charged to the public funds of the Spanish National Health System) and the expenditure on prescription drugs, both in relation to the population. The analysis was performed within the region of Andalusia, which has 8,464,441 inhabitants. RESULTS: The data obtained from the time series confirmed that there were no significant differences during the studied period between the number of medication containers actually dispensed and the number that would have been expected to be dispensed according to the trend in this variable for the sample period. The expenditure results followed the same pattern. CONCLUSIONS: The health crisis produced by the COVID-19 lockdown had no impact on medication consumption in Andalusia.

The Impact of Covid-19 containment on community pharmaceutical spending in Andalusia - Spain

Background: In the field of health, the year 2020 will be remembered for testing (stressing) all health institutions and their forms of management (centralised and decentralised). The everyday activity of primary and hospital care was significantly altered by the introduction of telephone consultations, which reduce the number of visits to health centres or hospitals and are still relevant today in the face of successive waves of the pandemic. Objective: To analyse whether population confinement due to the COVID-19 pandemic had an impact on the dispensing of medications in community pharmacies and the associated spending during the period March-July 2020 in Andalusia (Spain). Methods: A time series analysis applying econometric model analysis techniques to confirm or rule out whether the lockdown caused by the COVID-19 pandemic had an impact on the dispensing of medications by community pharmacies and the associated expenditures. The variables used were the number of medication containers dispensed by community pharmacies (charged to the public funds of the Spanish National Health System) and the expenditure on prescription drugs, both in relation to the population. The analysis was performed within the region of Andalusia, which has 8,464,441 inhabitants. Results: The data obtained from the time series confirmed that there were no significant differences during the studied period between the number of medication containers actually dispensed and the number that would have been expected to be dispensed according to the trend in this variable for the sample period. The expenditure results followed the same pattern. Conclusions: The health crisis produced by the COVID-19 lockdown had no impact on medication consumption in Andalusia (AU)

Neurally adjusted ventilatory assist in acute respiratory failure: a randomized controlled trial.

PURPOSE: We hypothesized that neurally adjusted ventilatory assist (NAVA) compared to conventional lung-protective mechanical ventilation (MV) decreases duration of MV and mortality in patients with acute respiratory failure (ARF). METHODS: We carried out a multicenter, randomized, controlled trial in patients with ARF from several etiologies. Intubated patients ventilated for ≤ 5 days expected to require MV for ≥ 72 h and able to breathe spontaneously were eligible for enrollment. Eligible patients were randomly assigned based on balanced treatment assignments with a computerized randomization allocation sequence to two ventilatory strategies: (1) lung-protective MV (control group), and (2) lung-protective MV with NAVA (NAVA group). Allocation concealment was maintained at all sites during the trial. Primary outcome was the number of ventilator-free days (VFDs) at 28 days. Secondary outcome was all-cause hospital mortality. All analyses were done according to the intention-to-treat principle. RESULTS: Between March 2014 and October 2019, we enrolled 306 patients and randomly assigned 153 patients to the NAVA group and 153 to the control group. Median VFDs were higher in the NAVA than in the control group (22 vs. 18 days; between-group difference 4 days; 95% confidence interval [CI] 0 to 8 days; p = 0.016). At hospital discharge, 39 (25.5%) patients in the NAVA group and 47 (30.7%) patients in the control group had died (between-group difference - 5.2%, 95% CI - 15.2 to 4.8, p = 0.31). Other clinical, physiological or safety outcomes did not differ significantly between the trial groups. CONCLUSION: NAVA decreased duration of MV although it did not improve survival in ventilated patients with ARF.

Ameloplastia positiva en relación céntrica como método auxiliar durante la finalización en el tratamiento de ortodoncia en un paciente bruxista / Positive ameloplasty in centric relationship as an auxiliary method during finalization in the orthodontic treatment in a bruxist patient

A continuación se presenta un caso de un paciente de 12 años de edad, con antecedente de bruxismo, con biotipo mesofacial, tercio inferior dolicofacial, hipertonicidad muscular en maseteros, cierre labial forzado con incompetencia labial de 4 milímetros con dolor en sinoviales anteriores inferiores. Los objetivos de tratamiento consistieron en lograr relajación muscular y promover un posicionamiento condilar ortopédicamente funcional y estable, realizar control vertical para disminuir gap interlabial, alinear líneas medias, mantener clase I molar bilateral, clase I canina bilateral y clase I incisiva, crear overjet y overbite adecuados, con recuperación estética y función del segmento anterior. Debido a eventos adversos durante la etapa de cierre de espacios, la clase molar y canina I no se logró, pero se aseguró mediante ameloplastias positivas la función y estética adecuadas para tener un tratamiento de ortodoncia estable a largo plazo (AU)

The following is a case of a 12-year-old patient, with a history of bruxism, with a mesofacial biotype, lower third of the facial area, muscular hypertonicity in the masseters, a forced labial closure with a 4-millimeter labial incompetence with pain in inferior anterior synoviums. Treatment objectives consisted of achieving muscle relaxation and promoting orthopedically functional and stable condylar positioning, perform vertical control to decrease interlabial gap, align midlines, maintain bilateral molar class I, bilateral canine class I and incisive class I, create adequate overjet and overbite, with aesthetic recovery and function of the anterior segment. Due to adverse events during the closing phase of spaces, the molar and canine I class was not achieved, but positive function and aesthetics were ensured by positive ameloplasties in order to have a long-term stable orthodontic treatment (AU)

Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial.

BACKGROUND: There is no proven specific pharmacological treatment for patients with the acute respiratory distress syndrome (ARDS). The efficacy of corticosteroids in ARDS remains controversial. We aimed to assess the effects of dexamethasone in ARDS, which might change pulmonary and systemic inflammation and result in a decrease in duration of mechanical ventilation and mortality. METHODS: We did a multicentre, randomised controlled trial in a network of 17 intensive care units (ICUs) in teaching hospitals across Spain in patients with established moderate-to-severe ARDS (defined by a ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen of 200 mm Hg or less assessed with a positive end-expiratory pressure of 10 cm H2O or more and FiO2 of 0·5 or more at 24 h after ARDS onset). Patients with brain death, terminal-stage disease, or receiving corticosteroids or immunosuppressive drugs were excluded. Eligible patients were randomly assigned based on balanced treatment assignments with a computerised randomisation allocation sequence using blocks of 10 opaque, sealed envelopes to receive immediate treatment with dexamethasone or continued routine intensive care (control group). Patients in the dexamethasone group received an intravenous dose of 20 mg once daily from day 1 to day 5, which was reduced to 10 mg once daily from day 6 to day 10. Patients in both groups were ventilated with lung-protective mechanical ventilation. Allocation concealment was maintained at all sites during the trial. Primary outcome was the number of ventilator-free days at 28 days, defined as the number of days alive and free from mechanical ventilation from day of randomisation to day 28. Secondary outcome was all-cause mortality 60 days after randomisation. All analyses were done according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT01731795. FINDINGS: Between March 28, 2013, and Dec 31, 2018, we enrolled 277 patients and randomly assigned 139 patients to the dexamethasone group and 138 to the control group. The trial was stopped by the data safety monitoring board due to low enrolment rate after enrolling more than 88% (277/314) of the planned sample size. The mean number of ventilator-free days was higher in the dexamethasone group than in the control group (between-group difference 4·8 days [95% CI 2·57 to 7·03]; p<0·0001). At 60 days, 29 (21%) patients in the dexamethasone group and 50 (36%) patients in the control group had died (between-group difference -15·3% [-25·9 to -4·9]; p=0·0047). The proportion of adverse events did not differ significantly between the dexamethasone group and control group. The most common adverse events were hyperglycaemia in the ICU (105 [76%] patients in the dexamethasone group vs 97 [70%] patients in the control group), new infections in the ICU (eg, pneumonia or sepsis; 33 [24%] vs 35 [25%]), and barotrauma (14 [10%] vs 10 [7%]). INTERPRETATION: Early administration of dexamethasone could reduce duration of mechanical ventilation and overall mortality in patients with established moderate-to-severe ARDS. FUNDING: Fundación Mutua Madrileña, Instituto de Salud Carlos III, The European Regional Development's Funds, Asociación Científica Pulmón y Ventilación Mecánica.

[Crisis, Public Spending on Health and Policy]. / Modelos de gestión según el proveedor y sus efectos en la dinámica de los equipos de atención primaria en Cataluña.

OBJECTIVE: The Spanish economic crisis began in 2008 and according to the Ministry of Economy, Industry and Compe- titiveness it concluded in 2014. During the crisis the main macroeconomic indicators had an adverse evolution and the effects have lasted for more than six years to the present. Aim: To assess the influence on public spending (health and pharmaceutical) that the governing policies have had and the time of crisis suffered. METHODS: Public expenditure per inhabitant (health and pharmaceutical) is compared according to the study period (pre, crisis and post), the political ideology of the ruling party (conservative/ progressive) and each autonomous community in reference to GDP per inhabitant in each of they respect the national average (poor, average or rich) according to the quartiles. The sources of the data have been the National Statistics Institute (GDP and inhabitants of each Autonomous Community and study period) and the Ministry of Health, Social Services and Equality (public health and pharmaceutical expenditure). The statistical procedures (SPSS v24) included descriptive and inferential analysis for public healthcare and pharmaceutical expenditure according to the period of study and ideology. There was also a regression fit to know the relative importance of predictor varibles. RESULTS: During the crisis period there were differences in public health expenditure per inhabitant in the different types of Autonomous Communities (poor / medium / rich) and according to political ideology (p <0.05). Public pharmaceutical expenditure was € 327 / inhab (pre-crisis) to € 366 / inhabitant in the final period of the study. There were statistically significant differences in pharmaceutical expenditure according to the different types of CCAA. Likewise, differences were found in per capita pharmaceutical expenditure between the Autonomous Communities run by conservatives and type of Autonomous Communities throughout the study period. CONCLUSIONS: The community pharmaceutical expenditure per capita has decreased by more than 13% since 2006 until 2017, while the hospital pharmaceutical expenditure has increased by more than 84%. Rich regions invest more in the health care costs and the poor more than drugs.

OBJETIVO: La crisis económica española se inició en el año 2008 y según el Ministerio de Economía, Industria y Compe- titividad concluyó en el año 2014. Durante la crisis los principa- les indicadores macro-económicos tuvieron una evolución adversa y los efectos se han prolongado durante más de seis años hasta la actualidad. El objetivo de este trabajo fue valorar la influencia en el gasto público (sanitario y farmacéutico) que han tenido las políticas gobernantes y el tiempo de crisis sufrido. METODOS: Se compara el gasto público por habitante (sanitario y farmacéutico) según el período de estudio (pre, crisis y post), la ideología política del partido gobernante (conservador/ progresista) y cada comunidad autónoma en referencia al PIB por habitante en cada una de ellas respecto de la media nacional (pobres, en la media o ricas) según los cuartiles. Las fuentes de los datos han sido el INE (PIB y habitantes de cada CCAA y periodo de estudio) y del Ministerio de Sanidad, Servicios Sociales e Igualdad (gasto público sanitario y farmacéutico). El examen estadístico (SPSS 24) incluyó análisis descriptivo e inferencial del gasto sanitario y farmacéutico publico según el período de estudio e ideología, también se realizó un ajuste de regresión para conocer la importancia relativa de las variables predictoras. RESULTADOS: Durante el período de crisis hubo diferencias en el gasto sanitario público por habitante en los distintos tipos de CCAA (pobres/medias/ricas) y según ideología política gobernante (p <0,05). El gasto farmacéutico público pasó de 327 €/hab (pre-crisis) a 366 €/hab en el período final del estudio. Hubo diferencias estadísticamente significativas en el gasto farmacéutico según los distintos tipos de CCAA. De igual forma se encontraron diferencias en el gasto farmacéutico por habitante entre las CCAA regentadas por conservadores y tipo de CCAA a lo largo de todo el período de estudio. CONCLUSIONES: El gasto farmacéutico comunitario por habitante ha disminuido en más del 13% desde 2006 hasta 2017, mientras que el gasto farmacéutico hospitalario se ha incrementado en más del 84%. Las CCAA ricas invierten más en gasto sanitario y las pobres más de medicamentos.

Crisis, gasto público sanitario y política / Crisis, Public Spending on Health and Policy

OBJETIVO: La crisis económica española se inició en el año 2008 y según el Ministerio de Economía, Industria y Competitividad concluyó en el año 2014. Durante la crisis los principales indicadores macroeconómicos tuvieron una evolución adversa y los efectos se han prolongado durante más de seis años hasta la actualidad. El objetivo de este trabajo fue valorar la influencia en el gasto público (sanitario y farmacéutico) que han tenido las políticas gobernantes y el tiempo de crisis sufrido. MÉTODOS: Se compara el gasto público por habitante (sanitario y farmacéutico) según el período de estudio (pre, crisis y post), la ideología política del partido gobernante (conservador/ progresista) y cada comunidad autónoma en referencia al PIB por habitante en cada una de ellas respecto de la media nacional (pobres, en la media o ricas) según los cuartiles. Las fuentes de los datos han sido el INE (PIB y habitantes de cada CCAA y periodo de estudio) y del Ministerio de Sanidad, Servicios Sociales e Igualdad (gasto público sanitario y farmacéutico). El examen estadístico (SPSS 24) incluyó análisis descriptivo e inferencial del gasto sanitario y farmacéutico publico según el período de estudio e ideología, también se realizó un ajuste de regresión para conocer la importancia relativa de las variables predictoras. RESULTADOS: Durante el período de crisis hubo diferencias en el gasto sanitario público por habitante en los distintos tipos de CCAA (pobres/medias/ricas) y según ideología política gobernante (p <0,05). El gasto farmacéutico público pasó de 327 €/hab (pre-crisis) a 366 €/hab en el período final del estudio. Hubo diferencias estadísticamente significativas en el gasto farmacéutico según los distintos tipos de CCAA. De igual forma se encontraron diferencias en el gasto farmacéutico por habitante entre las CCAA regentadas por conservadores y tipo de CCAA a lo largo de todo el período de estudio. CONCLUSIONES: El gasto farmacéutico comunitario por habitante ha disminuido en más del 13% desde 2006 hasta 2017, mientras que el gasto farmacéutico hospitalario se ha incrementado en más del 84%. Las CCAA ricas invierten más en gasto sanitario y las pobres más de medicamentos

OBJECTIVE: The Spanish economic crisis began in 2008 and according to the Ministry of Economy, Industry and Competitiveness it concluded in 2014. During the crisis the main macroeconomic indicators had an adverse evolution and the effects have lasted for more than six years to the present. AIM: To assess the influence on public spending (health and pharmaceutical) that the governing policies have had and the time of crisis suffered. METHODS: Public expenditure per inhabitant (health and pharmaceutical) is compared according to the study period (pre, crisis and post), the political ideology of the ruling party (conservative/ progressive) and each autonomous community in reference to GDP per inhabitant in each of they respect the national average (poor, average or rich) according to the quartiles. The sources of the data have been the National Statistics Institute (GDP and inhabitants of each Autonomous Community and study period) and the Ministry of Health, Social Services and Equality (public health and pharmaceutical expenditure). The statistical procedures (SPSS v24) included descriptive and inferential analysis for public healthcare and pharmaceutical expenditure according to the period of study and ideology. There was also a regression fit to know the relative importance of predictor varibles. RESULTS: During the crisis period there were differences in public health expenditure per inhabitant in the different types of Autonomous Communities (poor / medium / rich) and according to political ideology (p <0.05). Public pharmaceutical expenditure was € 327 / inhab (pre-crisis) to € 366 / inhabitant in the final period of the study. There were statistically significant differences in pharmaceutical expenditure according to the different types of CCAA. Likewise, differences were found in per capita pharmaceutical expenditure between the Autonomous Communities run by conservatives and type of Autonomous Communities throughout the study period. CONCLUSIONS: The community pharmaceutical expenditure per capita has decreased by more than 13% since 2006 until 2017, while the hospital pharmaceutical expenditure has increased by more than 84%. Rich regions invest more in the health care costs and the poor more than drugs

Aminopeptidase activity profile in cultured human osteoblasts.

Aminopeptidases (APs) are enzymes involved in a wide variety of biological processes and present in a variety of different cell populations. The authors studied these enzymes in primary cultured human osteoblasts in order to establish an activity profile and thereby contribute to knowledge of bone tissue. The authors used 13 different substrates (N-terminal amino acids) and a fluorimetric assay to examine AP activity associated with the membranes of cultured osteoblasts. The authors demonstrated activity > 10 pmol/min/10(4) cells when glycine, alanine, leucine, arginine, phenylalanine, methionine, and lysine were used as substrates. The activity was markedly lower (<1.6 pmol/min/10(4) cells) when the other N-terminal amino acids were used. Puromycin and bestatin inhibited AP activity, though not completely, when we used AlaNA or LeuNA as substrates. Further studies are warranted to determine the role of these enzymes in bone tissue physiology.

Neuropeptidases.

The control of neuropeptide function is partially accomplished by aminopeptidases (neuropeptidases), which are the most abundant proteolytic enzymes in brain. Their analysis represents an important and quick tool to reflect the functional status of their endogenous substrates. Here, we describe an improved fluorometric method for the determination of neuropeptidase activities based on the fluorescence produced by ß-naphthylamine when released from the artificial substrates aminoacyl-ß-naphthylamides (arylamides) under the hydrolytic action of these enzymes.

Lateralized response of oxytocinase activity in the medial prefrontal cortex of a unilateral rat model of Parkinson's disease.

Individuals in the early stage of Parkinson's disease exhibit cognitive impairments as a result of hemisphere damage. The mesocortical dopamine system, particularly the medial prefrontal cortex (mPFC), is implicated in cognitive functions and is characterized by an asymmetric organization. Oxytocinase activity (OX) is also asymmetrically distributed in the mPFC of normal rats and is involved in cognitive functions. OX was measured in the left and right mPFC of rats with left or right hemi-parkinsonism, induced by intrastriatal injections of 6-hydroxydopamine, and compared with sham controls. These results demonstrated that the striking basal left predominance of OX observed in both the left and the right sham controls was radically disrupted in lesioned animals. The bilateral distribution in lesioned animals was altered differently depending on the injured hemisphere. These results may reflect changes in the enzyme substrates and consequently in the functions in which they are involved. These results may account, in part, for the cognitive abnormalities observed in hemi-parkinsonism.

Stress influences brain enkephalinase, oxytocinase and angiotensinase activities: a new hypothesis.

Brain enkephalin and oxytocin are anxiolytic agents involved in the response mechanism to stress. Degrading enzymes such as enkephalinase and oxytocinase could also be associated with this response. The effect of acute immobilization stress on enkephalinase and oxytocinase activities was determined in the soluble and membrane fractions of the medial prefrontal cortex, hippocampus and amygdala using alanyl- and leucyl-beta-naphthylamide as substrates, the latter in the presence and absence of 20 mM L-methionine. No change in aminopeptidase activities was observed in the prefrontal cortex of stressed rats. In contrast, enkephalinase activity decreased in the soluble fraction of the hippocampus but increased in the membrane fraction. In the amygdala, soluble oxytocinase and membrane enkephalinase activities decreased in stressed animals. These results show that acute immobilization stress affects differentially enkephalinase and oxytocinase activities depending on the fraction and brain region analyzed. A reduction in the activity of soluble enkephalinase in the hippocampus and soluble oxytocinase as well as membrane enkephalinase in the amygdala may suggest higher availability/longer action of enkephalin and oxytocin at these locations. This may explain the relative importance of these enzymatic activities in the anxiolytic properties proposed for enkephalins and oxytocin in the hippocampus and amygdala during stress conditions. This interpretation is not applicable to membrane enkephalinase activity in the hippocampus. However, alanyl-beta-naphthylamide hydrolyzing activity not only measures enkephalinase activity, it also reflects the angiotensinase-induced metabolism of angiotensin III to angiotensin IV. Therefore, our results may also mirror an increase in the formation of Ang IV in hippocampus and a decrease in the amygdala in acute stress. In conclusion, aminopeptidase activities in the hippocampus and amygdala may affect enkephalin, oxytocin and angiotensin III metabolism during acute immobilization stress and therefore be involved in the anxiolytic response.

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.

El papel de los instrumentos internacionales sobre derechos humanos en la salvaguardia de losmismos / The role of the international instruments on the human rights protection. The case of the International Convention on migrant the notection of the rights of all migrant workers

One of the purposes of this document is to place the International Convention about Migrant Workers in the context of the international normative system on human rights. As regards to this topic it reviews the State's responsibilities toward foreigners, and briefly summarizes the content of the Convention. Another purpose of the document is to reflect on the challenges, limitations and difficulties that get in the way of the Convention as it plays a key role in the safeguard of migrant workers rights, and, on the other side, consider the opportunities, advantages and utility of the Convention to grarantee these rights.(AU)

Papel de las aminopeptidasas en el control neuroendocrino de la presión arterial en animales de experimentación / Role of aminopeptidases in the neuroendocrine control of blood pressure in experimental animals

En el control de la presión arterial participan varias enzimas proteolíticas–incluidas en el llamado sistema renina-angiotensina– que producen diversos péptidos activos que son los agentes efectivos del sistema. El estudio de estas enzimas resulta esencial para conocer en profundidad el mecanismo de control de la presión arterial y puede ofrecer la posibilidad de controlar dicho sistema con fármacos. Una glutamato aminopeptidasa transforma la angiotensina II en angiotensina III. Ésta a su vez es transformada en angiotensina IV por la alanina o arginina aminopeptidasa. La angiotensina I, por acción de la aspartato aminopeptidasa, se transforma en angiotensina 2-10, a la que se han atribuido acciones contrapuestas a las hipertensivas de la angiotensina II. La angiotensina III es la forma más activa de las angiotensinas cerebrales y tiene un efecto estimulador tónico de la presión arterial. El estudio de la inhibición de la glutamato aminopeptidasa, por lo tanto, ha permitido el desarrollo de agentes que actúan eficazmente reduciendo la presión arterial. Asimismo, el desarrollo de activadores de la aspartatoaminopeptidasa constituye otro posible objetivo para el diseño de nuevos agentes antihipertensivos. Nuestro grupo de investigación ha observado que las lesiones unilaterales del sistema nigroestriatal en ratas da lugar a modificaciones simultáneas de la presión arterial y de la actividad aminopeptidásica cerebral y plasmática, curiosamente dependiente del lado de la lesión. Esta posible interacción entre presión arterial, actividad aminopeptidásica y asimetría cerebral, que daría lugar a una respuesta neuroendocrina diferenciada sobre el control de la presión arterial, podría ayudarnos a comprender el mecanismo íntimo por el cual el cerebro controla en la circulación la presión arterial (AU)

Control of blood pressure is partially accomplished by several proteolyticenzymes included in the renin-angiotensin system. These enzymes produce several peptides that form the active components of the system. Study of these enzymes is essential for a deep understanding of blood pressure control and could offer the possibility of controlling this system pharmacologically. Glutamyl aminopeptidase converts angiotensin II into angiotensin III, which in turn is converted into angiotensin IV by an alanylor arginyl aminopeptidase. Angiotensin I, through the action of aspartylaminopeptidase, is converted intoangiotensin 2-10, which may counteract the hypertensive actions of angiotensin II. Angiotensin III is the most active form of brain angiotensins and has a tonic stimulatory effect on blood pressure. Analysis of glutamyl-aminopeptidase inhibition has allowed the development of agents that effectively reduce blood pressure. Moreover, the development of as partyl-aminopeptidase activators could be another goal, with a view to designing new antihypertensive agents. Our group has observed that unilateral lesions of the nigrostriatal pathway in rat brain produce simultaneous modifications in blood pressure and aminopeptidase activities, both in brain and plasma, curiously depending on the side of the lesion. This possible interaction among blood pressure, aminopeptidase activities and brain asymmetry, which could produce a differentiated neuroendocrine response on blood pressure control, may help us to understand the deep mechanism by which the brain is able to control blood pressure peripherally (AU)

Role of central and peripheral aminopeptidase activities in the control of blood pressure: a working hypothesis.

Although there is a large body of knowledge on protein synthesis, the available data on protein catabolism, although quite substantial, are still inadequate. This is due to the marked differences in the activity of proteolytic enzymes, compounded by different substrate specificities and multiple environmental factors. Understanding enzyme behavior under physiological and pathological conditions requires the identification of specific proteolytic activities, such as aminopeptidases, as able to degrade certain peptidergic hormones or neuropeptides. Another requirement is the isolation, purification and characterization of the enzymes involved. In addition, systematic studies are needed to determine each enzyme's subcellular location, tissue distribution, and the influence of environmental factors such as diurnal rhythm, age, gender, diet, cholesterol, or steroids. Central and peripheral aminopeptidases may play a role in the control of blood pressure by coordinating the effect of the different peptides of the renin-angiotensin system cascade, acting through the AT(1), AT(2), and AT(4) receptors. Our review of the available data suggests the hypothesis that cholesterol or steroids, particularly testosterone, significantly influence aminopeptidase activities, their substrate availability and consequently their functions. These observations may have relevant clinical implications for a better understanding of the pathophysiology of cardiovascular diseases, and thus for their treatment with aminopeptidase inhibitors.

Role of aminopeptidases in the neuroendocrine control of blood pressure in experimental animals.

Control of blood pressure is partially accomplished by several proteolytic enzymes included in the renin-angiotensin system. These enzymes produce several peptides that form the active components of the system. Study of these enzymes is essential for a deep understanding of blood pressure control and could offer the possibility of controlling this system pharmacologically. Glutamylaminopeptidase converts angiotensin II into angiotensin III, which in turn is converted into angiotensin IV by an alanyl or arginyl aminopeptidase. Angiotensin I, through the action of aspartyl aminopeptidase, is converted into angiotensin 2-10, which may counteract the hypertensive actions of angiotensin II. Angiotensin III is the most active form of brain angiotensins and has a tonic stimulatory effect on blood pressure. Analysis of glutamyl-aminopeptidase inhibition has allowed the development of agents that effectively reduce blood pressure. Moreover, the development of aspartyl-aminopeptidase activators could be another goal, with a view to designing new antihypertensive agents. Our group has observed that unilateral lesions of the nigrostriatal pathway in rat brain produce simultaneous modifications in blood pressure and aminopeptidase activities, both in brain and plasma, curiously depending on the side of the lesion. This possible interaction among blood pressure, aminopeptidase activities and brain asymmetry, which could produce a differentiated neuroendocrine response on blood pressure control, may help us to understand the deep mechanism by which the brain is able to control blood pressure peripherally.

Brain aminopeptidases and hypertension.

The brain aminopeptidases that participate in the enzymatic cascade of the renin-angiotensin system play a major role in blood pressure (BP) control, and their study offers new perspectives for the understanding of central BP control and the treatment of hypertension. In this system, angiotensin II is converted to angiotensin III (Ang III) by glutamyl aminopeptidase (GluAP) and Ang III is further metabolised to angiotensin IV by alanyl aminopeptidase or arginine-aminopeptidase. It is now clear that Ang III is the key active form of the central angiotensins, exerting tonic stimulatory control over BP. Therefore, the development of GluAP inhibitors as potential antihypertensive agents offers new perspectives for therapy. Brain aspartyl aminopeptidase, which converts angiotensin I to angiotensin 2-10, is also a possible target for antihypertensive therapy because of its potential role in BP control. Finally, since changes in BP levels, that paralleled changes in brain and plasma aminopeptidase activities, were observed after unilateral lesions of the nigrostriatal system, brain asymmetry, aminopeptidase activities and BP control appear to be related, resulting their interplay in an asymmetrical neuroendocrine response that differentially affect BP control. The study of this interaction may contribute to our understanding of how the brain controls BP.