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Este artículo se encuentra disponible en la siguiente URL: https://journals.sagepub.com/doi/10.1177/09645284211039523 This is the peer reviewed version of the following article: Montero Navarro, S., Del Rio Medina, S., Martín Botella Rico, J., Isabel Rocha Ortiz, M., & Teresa Pérez Gracia, M. (2022). Analysis and comparison of pain pressure threshold and active cervical range of motion after superficial and deep dry needling techniques of the upper trapezius muscle. Acupuncture in Medicine : journal of the British Medical Acupuncture Society, vol. 40, i. 1 (feb.), pp. 13?23, which has been published in final form at https://doi.org/10.1177/09645284211039523 Este es el post-print del siguiente artículo: Montero Navarro, S., Del Rio Medina, S., Martín Botella Rico, J., Isabel Rocha Ortiz, M., & Teresa Pérez Gracia, M. (2022). Analysis and comparison of pain pressure threshold and active cervical range of motion after superficial and deep dry needling techniques of the upper trapezius muscle. Acupuncture in Medicine : journal of the British Medical Acupuncture Society, vol. 40, n. 1 (feb.), pp. 13?23, que se ha publicado de forma definitiva en https://doi.org/10.1177/09645284211039523 Objectives: To evaluate the changes in pain pressure threshold (PPT) and active cervical range of motion (ACROM) after the application of superficial dry needling (DN) or deep DN in myofascial trigger point (MTrP) 1 of the upper trapezius versus a simulated DN technique in the gastrocnemius muscle (control group). Design: Double-blind, randomized controlled trial with 7-day follow-up. Participants: Asymptomatic volunteers (n = 180; 76 men, 104 women) with a latent MTrP 1 in the upper trapezius were randomly divided into three groups: G1, receiving superficial DN in the upper trapezius; G2, receiving deep DN in the upper trapezius; and G3, control group, receiving simulated DN technique in the gastrocnemius muscle. Main outcome measures: While sitting in a chair, each subject underwent measurements of PPT and ACROM (ipsilateral and contralateral side flexion and rotation, flexion and extension) preintervention, (immediately) postintervention, and at 24 h, 72 h and 7 days. Results: Superficial and deep DN produced an increase in PPT at 7 days with respect to preintervention levels. Furthermore, superficial and deep DN produced a decrease in cervical flexion at 24 h and an increase in ipsilateral rotation until 72 h, increasing to 7 days in the case of deep DN. On the contrary, superficial DN produced an increase in ipsilateral and contralateral side flexion after intervention, unlike deep DN that produced a decrease at 24 h. Furthermore, superficial DN produced an increase in contralateral rotation at 24 h and deep DN decreased extension at 72 h. Conclusion: A single intervention of superficial or deep DN did not produce statistically significant changes in PPT or goniometry measurements.

Obstructive Sleep Apnea (OSA) is one of the most common sleep disorders, and invokes numerous negative health-related outcomes and physiopathological processes. Understanding the mechanisms by which OSA potentiates cardiometabolic risk of patients remains a current challenge. Sleep disruption is highly prevalent among shift workers and shift work (SW) is an important modulator of circadian rhythms, with health consequences intimately related to cardiometabolic health. Since the circadian timing system (CTS) interacts with the normal functioning of the ANS, CTS impact on OSA patients should be closely assessed. This review raises the question of whether SW-induced circadian misalignment potentiates the cardiometabolic risk of OSA patients, providing a novel perspective on the role of autonomic modulation as a key downstream mechanism linking cardiometabolic risk with both OSA and CTS misalignment.

Doxorubicin (DOX) is a chemotherapeutic agent that improves the survival and quality of life of patients with solid tumours. However, these improvements are counterbalanced by various dose-dependent side effects including cardiac dysfunction, which may occur in a subset of patients leading to treatment discontinuation. In addition, despite overall insufficiently studied, available data clearly show that women are more susceptible to drugs toxicity due to sex differences in drug metabolism or sensitivity. Regarding doxorubicin, apart its acute toxicity, women are also more vulnerable to late cardiotoxicity. Currently, there are no robust clinical imaging techniques or biomarkers available to detect DOX-cardiotoxicity before functional decline and, despite treatment personalization, subclinical signs of toxicity are not yet well identified. Thus, in the present work, we sought to characterize the toxic effects of a sub-therapeutic dose of doxorubicin upon cardiovascular and autonomic function. For that, adult healthy female wistar rats (n=14), aged >3 months, were intraperitoneally treated with doxorubicin (2 mg/kg) at weekly intervals for up to 4 weeks. A control (Ctrl, n=7) group received saline solution 0,9% NaCl as a vehicle. Rats underwent an echocardiographic evaluation at 4 weeks. Blood pressure, heart rate and respiratory frequency were assessed in an acute experiment. Cardiovascular variability studies in the time-frequency domain (LF, HF and LF/HF calculation) and cardiorespiratory reflexes assessment were performed. T-Student test for paired observations was applied (level significance p DOX-treated animals showed a severe bradypnea and hypotension, significant decrease in ejection fraction and fractional shortening, sympatho-inhibition and reduced baroreceptor reflex gain and chemoreflex sensitivity. Our functional results might be due to cellular respiratory dysfunction and vascular adaptations induced by doxorubicin via TNF alpha actions at central nervous system (CNS) and peripheral level. In fact, peripheral TNF alpha release elicits NO production, which through vasodilation will induce hypotension and baroreceptor reflex adjustments. Reinforcing these actions, and despite doxorubicin low ability to pass BBB, TNF alpha acting at CNS induces neuronal apoptosis and impairment of mitochondrial function which might also contribute to affect autonomic and respiratory function, expressed by a decreased chemoreflex sensitivity and sympathetic tone. In conclusion, sub-therapeutic doses of doxorubicin are able to produce per se the impairment of autonomic and cardiac functions. Thus, a tight monitoring of these functions in patients treated with therapeutic doses of doxorubicin is highly recommended. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fundação para a Ciência e a Tecnologia

Supine hypertension commonly occurs in patients with neurogenic orthostatic hypotension due to autonomic failure. Supine hypertension promotes nocturnal sodium excretion and orthostatic hypotension, thus, interfering with quality of life. Perusal of the literature on essential hypertension and smaller scale investigations in autonomic failure patients also suggest that supine hypertension may predispose to cardiovascular and renal disease. These reasons provide a rationale for treating supine hypertension. Yet, treatment of supine hypertension, be it through nonpharmacological or pharmacological approaches, may exacerbate orthostatic hypotension when patients get up during the night. Fall-related complications may occur. More research is needed to define the magnitude of the deleterious effects of supine hypertension on cardiovascular, cerebrovascular, and renal morbidity and mortality. Integration of more precise cardiovascular risk assessment, efficacy, and safety data, and the prognosis of the underlying condition causing autonomic failure is required for individualized management recommendations.

Cuidado paliativo e um cuidado em saude representando por um conjunto de acoes designadas a uma equipe multiprofissional junto a um paciente que possui alguma patologia incuravel com o objetivo de controle de sintomas e, consequentemente, a melhoria da qualidade de vida do paciente, de forma continua. Nesse sentido, foi objetivo deste estudo avaliar o conhecimento dos estudantes internos de medicina de diferentes faculdades brasileiras acerca da dor em cuidados paliativos. Trata-se de um estudo descritivo com abordagem quantitativa. A amostra do estudo abrangeu 180 alunos de faculdades de medicina brasileiras que estavam cursando os quatro ultimos periodos da faculdade. A estes alunos, aplicou-se um questionario online utilizando a ferramenta Google Forms. O periodo de coleta foi entre os meses de agosto a outubro do ano de 2020. Os dados obtidos foram compilados no programa Microsoft Excel e no Programa Statistical Package for the Social Sciences (SPSS - versao 21.0), com realizacao de dupla digitacao e, posteriormente, conferidos eletronicamente. A analise dos dados, por sua vez, foi efetivada ora por meio da estatistica descritiva. Ao final, percebeu-se que Diante do clara a necessidade de incentivar a academia medica no ensino do manejo terapeutico da dor, tanto durante a faculdade quanto durante a residencia, haja vista sua importância e prevalencia, sendo assim necessario haver um enfoque maior na formacao academica sobre o assunto.

International audience; This position paper analyses the threats from the current situation of the clinical investigation to the expectations of the new European regulations focusing on high risk medical devices (HRMDs). We present also some opportunities to improve the feasibility and quality of clinical investigation. In summary, investigation protocols of medical devices, advised and authorized by the competent authorities, are few and heterogenous. There is a lack of quality in the existing studies, a lack of methodological knowledge and consequently high expectations for assistance from those involved in the design of clinical study protocols on HRMD. Guidance that is specific to the different type of devices is missing. Adaptive designs, pragmatic trial, usability methods, computer modeling and real world data are gaining more and more traction for assessing the safety and performance of high risk medical devices from a regulatory view-point.

8 March (8M), now known as International Women’s Day, is a day for feminist claims where demonstrations are organized in over 150 countries, with the participation of millions of women all around the world. These demonstrations can be viewed as collective rituals and thus focus attention on the processes that facilitate different psychosocial effects. This work aims to explore the mechanisms (i.e., behavioral and attentional synchrony, perceived emotional synchrony, and positive and transcendent emotions) involved in participation in the demonstrations of 8 March 2020, collective and ritualized feminist actions, and their correlates associated with personal well-being (i.e., affective well-being and beliefs of personal growth) and collective well-being (i.e., social integration variables: situated identity, solidarity and fusion), collective efficacy and collective growth, and behavioral intention to support the fight for women’s rights. To this end, a cross-cultural study was conducted with the participation of 2,854 people (age 18–79; M = 30.55; SD = 11.66) from countries in Latin America (Mexico, Chile, Argentina, Brazil, Peru, Colombia, and Ecuador) and Europe (Spain and Portugal), with a retrospective correlational cross-sectional design and a convenience sample. Participants were divided between demonstration participants (n = 1,271; 94.0% female) and non-demonstrators or followers who monitored participants through the media and social networks (n = 1,583; 75.87% female). Compared with non-demonstrators and with males, female and non-binary gender respondents had greater scores in mechanisms and criterion variables. Further random-effects model meta-analyses revealed that the perceived emotional synchrony was consistently associated with more proximal mechanisms, as well as with criterion variables. Finally, sequential moderation analyses showed that proposed mechanisms successfully mediated the effects of participation on every criterion variable. These results indicate that participation in 8M marches and demonstrations can be analyzed through the literature on collective rituals. As such, collective participation implies positive outcomes both individually and collectively, which are further reinforced through key psychological mechanisms, in line with a Durkheimian approach to collective rituals.

The cerebrovascular effects of a failing heart-pump are largely unknown. Chronic heart failure (HF) might cause pre-conditioning effect on cerebral hemodynamics but not study so far in acute stroke. We aimed to investigate if HF induces effects in dynamic cerebral autoregulation (CA), within 6 h of symptom-onset through chronic stage of ischemic stroke. We enrolled 50 patients with acute ischemic stroke. Groups with (N = 8) and without HF and 20 heathy controls were compared. Arterial blood pressure (Finometer) and cerebral blood flow velocity (transcranial Doppler) were monitored within 6 and at 24 h from symptom-onset and at 3 months. We assessed dynamic CA by transfer function analysis and cardiac disease markers. HF associated with higher phase (better dynamic CA) at ischemic hemisphere within 6 (p = 0.042) and at 24 h (p = 0.006) but this effect was not evident at 3 months (p > 0.05). Gain and coherence trends were similar between groups. We found a positive correlation between phase and admission troponin I levels (Spearman’s r = 0.348, p = 0.044). Our findings advances on the knowledge of how brain and heart interact in acute ischemic stroke by showing a sustained dynamic cerebral autoregulation response in HF patients mainly with severe aortic valve disease. Understanding the physiological mechanisms that govern this complex interplay can be useful to find novel therapeutic targets which can improve outcome in ischemic stroke.

© 2020 Springer Nature Switzerland AG. Part of Springer Nature., Long-term lead (Pb) exposure alters the normal development of the nervous system and physiology. It affects multiple organ systems, causing hypertension, cardiorespiratory dysfunction, being a well-known neurotoxin, inducing changes in neurogenesis, neurodegeneration, and glial cells. However, studies of the developmental effects of lead and its outcomes throughout life are lacking. Determine morphofunctional, behavioral, and cognitive developmental effects of long-term lead exposure at three different ages. Wistar rats were exposed to a Pb-acetate solution from fetal period until adulthood and compared to a non-exposed control group. General behavior and cognitive skills were evaluated by behavioral tests and physiological data and cardiorespiratory reflexes measured. Neurodegeneration, neuroinflammation, and synaptic activity were assessed by immunohistochemistry. Lead exposure caused long-lasting anxiety-like behavior and strong long-term memory impairment without changes in locomotor and exploratory activity. Hypertension was observed at all time points, concomitant with baroreflex impairment and increased chemoreflex sensitivity. Persistent neuroinflammation, transient synaptic overexcitation without neurodegeneration was observed. Long-term Pb exposure, since fetal period, causes long-lasting anxiety-like behavior, concomitant with hypertension, without general motor skills impairment. Synaptic overexcitation, reactive astrogliosis, and microgliosis could underlie behavioral and long-term memory changes, which might have been caused during developmental phases and consolidated during adulthood. Also, alterations observed in the cardiorespiratory reflexes can explain persistent hypertension. This longitudinal study identifies and characterizes lead toxicity nature and magnitude, important to devise and test potential interventions to attenuate the long-term harmful effects of lead on the nervous and cardiovascular systems., Vera Geraldes received the post-doctoral fellowship given by the Fundação para a Ciência e Tecnologia (FCT) (Ref: SFRH/BPD/119315/2016).

Following the success of and the high demand for recombinant protein-based therapeutics during the last 25 years, the pharmaceutical industry has invested significantly in the development of novel treatments based on biologics. Mammalian cells are the major production systems for these complex biopharmaceuticals, with Chinese hamster ovary (CHO) cell lines as the most important players. Over the years, various engineering strategies and modeling approaches have been used to improve microbial production platforms, such as bacteria and yeasts, as well as to create pre-optimized chassis host strains. However, the complexity of mammalian cells curtailed the optimization of these host cells by metabolic engineering. Most of the improvements of titer and productivity were achieved by media optimization and large-scale screening of producer clones. The advances made in recent years now open the door to again consider the potential application of systems biology approaches and metabolic engineering also to CHO. The availability of a reference genome sequence, genome-scale metabolic models and the growing number of various “omics” datasets can help overcome the complexity of CHO cells and support design strategies to boost their production performance. Modular design approaches applied to engineer industrially relevant cell lines have evolved to reduce the time and effort needed for the generation of new producer cells and to allow the achievement of desired product titers and quality. Nevertheless, important steps to enable the design of a chassis platform similar to those in use in the microbial world are still missing. In this review, we highlight the importance of mammalian cellular platforms for the production of biopharmaceuticals and compare them to microbial platforms, with an emphasis on describing novel approaches and discussing still open questions that need to be resolved to reach the objective of designing enhanced modular chassis CHO cell lines., This work has been supported the Federal Ministry for Digital and Economic Affairs (bmwd), the Federal Ministry for Transport, Innovation and Technology (bmvit), the Styrian Business Promotion Agency SFG, the Standortagentur Tirol, Government of Lower Austria and ZIT - Technology Agency of the City of Vienna through the COMET-Funding Program managed by the Austrian Research Promotion Agency FFG. A.H. has been supported by the Portuguese NORTE-08-5369-FSE-000053 operation. Additional funding came from the PhD program BioToP (Biomolecular Technology of Proteins) of the Austrian Science Fund (FWF Project W1224) and MIT-Portugal PhD program (Bioengineering Systems). The funding agencies had no influence on the conduct of this research. Open Access Funding by the University of Vienna., info:eu-repo/semantics/publishedVersion

[EN] This work presents a set of laboratory experiments that can be carried out by students who are taking digital design courses in engineering programs like Electronics, Communications Systems and Mechatronics. The purpose of these labs is to help students develop their skills and confidence designing arithmetic hardware blocks through solving of specific problems. In this aspect, this paper shows a method to be followed in the laboratory to design arithmetic blocks and implement them in microcontrollers and FPGAs. More specifically, the block design of a number's multiplicative inverse (1/root x), its square root (root x) and the square root of its inverse (1/root x) are presented. To complete these exercises, knowledges on Newton-Raphson algorithm, difference equations and digital design are required. Students of our institution completed the lab practices, and after analyzing the results from student surveys and classroom observations, we found out that completing these tasks significantly contributed to the students' training in the hardware design field., Este trabajo fue financiado por el Consejo Nacional de Ciencia y Tecnología (CONACYT) de México, mediante el proyecto de Ciencia Básica número 241272

Background Actinobacillus succinogenes is a promising bacterial catalyst for the bioproduction of succinic acid from low-cost raw materials. In this work, a genome-scale metabolic model was reconstructed and used to assess the metabolic capabilities of this microorganism under producing conditions. Results The model, iBP722, was reconstructed based on the functional reannotation of the complete genome sequence of A. succinogenes 130Z and manual inspection of metabolic pathways, covering 1072 enzymatic reactions associated with 722 metabolic genes that involve 713 metabolites. The highly curated model was effective in capturing the growth of A. succinogenes on various carbon sources, as well as the SA production under various growth conditions with fair agreement between experimental and predicted data. Calculated flux distributions under different conditions show that a number of metabolic pathways are affected by the activity of some metabolic enzymes at key nodes in metabolism, including the transport mechanism of carbon sources and the ability to fix carbon dioxide. Conclusions The established genome-scale metabolic model can be used for model-driven strain design and medium alteration to improve succinic acid yields., Financially supported by BRIGIT (KBBE-2012-6-311935, FP7 project Contract nr 311935) and by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684), in addition to the BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte., info:eu-repo/semantics/publishedVersion

We would like to thank the European Union Framework Program 7 ‘BacHBerry’ (www.bachberry.eu), Project No. FP7- 613793 for financial support, the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit, COMPETE 2020 (POCI-01- 0145-FEDER-006684) and BioTecNorte operation (NORTE-01-0145- FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte.

© 2017 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L.U. All rights reserved, Knowledge of the physiology underlying the autonomic nervous system is pivotal for understanding autonomic dysfunction in clinical practice. Autonomic dysfunction may result from primary modifications of the autonomic nervous system or be secondary to a wide range of diseases that cause severe morbidity and mortality. Together with a detailed history and physical examination, laboratory assessment of autonomic function is essential for the analysis of various clinical conditions and the establishment of effective, personalized and precise therapeutic schemes. This review summarizes the main aspects of autonomic medicine that constitute the background of cardiovascular autonomic dysfunction., O conhecimento subjacente à fisiologia do sistema nervoso autónomo é fundamental para se entender a disfunção autonómica na prática clinica. A disfunção autonómica pode resultar primariamente de modificações do sistema ou, secundariamente, a uma série de patologias conducentes a morbilidade ou mortalidade. Juntamente com a colheita detalhada da história clínica e do exame objetivo, a avaliac¸ão autonómica laboratorial torna-se essencial na análise de algumas condições clínicas e no estabelecimento de esquemas terapêuticos mais eficazes, refinados e personalizados. Assim, nesta revisão sumarizam-se os aspetos mais relevantes da fisiologia autonómica subjacente a disfunção autonómica cardiovascular.

Background Hemorrhagic transformation and cerebral edema are feared complications of acute ischemic stroke but mechanisms are poorly understood and reliable early markers are lacking. Early assessment of cerebrovascular hemodynamics may advance our knowledge in both areas. We examined the relationship between dynamic cerebral autoregulation (CA) in the early hours post ischemia, and the risk of developing hemorrhagic transformation and cerebral edema at 24 h post stroke Methods We prospectively enrolled 46 patients from our center with acute ischemic stroke in the middle cerebral artery territory. Cerebrovascular resistance index was calculated. Dynamic CA was assessed by transfer function analysis (coherence, phase and gain) of the spontaneous blood flow velocity and blood pressure oscillations. Infarct volume, hemorrhagic transformation, cerebral edema, and white matter changes were collected from computed tomography performed at presentation and 24 h. Results At admission, phase was lower (worse CA) in patients with hemorrhagic transformation [6.6 ± 30 versus 45 ± 38°; adjusted odds ratio 0.95 (95% confidence internal 0.94–0.98), p = 0.023] and with cerebral edema [6.6 ± 30 versus 45 ± 38°, adjusted odds ratio 0.96 (0.92–0.999), p = 0.044]. Progression to edema was associated with lower cerebrovascular resistance (1.4 ± 0.2 versus 2.3 ± 1.5 mm Hg/cm/s, p = 0.033) and increased cerebral blood flow velocity (51 ± 25 versus 42 ± 17 cm/s, p = 0.033) at presentation. All hemodynamic differences resolved at 3 months Conclusions Less effective CA in the early hour post ischemic stroke is associated with increased risk of hemorrhagic transformation and cerebral edema, possibly reflecting breakthrough hyperperfusion and microvascular injury. Early assessment of dynamic CA could be useful in identifying individuals at risk for these complications.

Portugal presents the highest incidence of stage 5 chronic kidney disease in Europe. It is speculated that a high consumption of non-steroidal anti-inflammatory drugs (NSAIDS) may contribute to this high incidence. Our aim was to characterize the prescription of non-steroidal anti-inflammatory drugs to patients with diabetes mellitus in Portugal.We analyzed the national prescription database in triennium 2015 - 2017. In patients with diabetes mellitus, we evaluated the prescription of non-steroidal anti-inflammatory drugs according to age, gender and region of the patient and specialty of the prescribing physician. We evaluated the prescription of non-steroidal anti-inflammatory drugs in all patients with diabetes mellitus, in patients with presumed renal impairment, and in those with concomitant prescription of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists.We analyzed 23 320 620 prescriptions, corresponding to 610 157 adults, including 104 306 patients with diabetes mellitus. The most prescribed non-steroidal anti-inflammatory drugs were ibuprofen (20.1%), metamizole (14.7%), and diclofenac (11.4%). The prescription of non-steroidal anti-inflammatory drugs was higher in females, in patients aged 51 - 70 years and in the Alentejo region. Non-steroidal anti-inflammatory drugs were prescribed to 70.6% of patients with diabetes mellitus, from which 10.6% were prescribed ≥ 10 packages during the three years. Among patients with diabetes mellitus on angiotensin converting enzyme inhibitors/angiotensin receptor antagonists and with presumed reduction in kidney function, 69.3% were prescribed non-steroidal anti-inflammatory drugs and 11.5% were prescribed ≥ 10 packages during the three years.The level of prescribing of non-steroidal anti-inflammatory drugs to patients with diabetes mellitus is high. The concern of reducing non-steroidal anti-inflammatory drugs prescription to patients already on angiotensin converting enzyme inhibitors/angiotensin receptor antagonists and/or decreased renal function does not seem to exist.In Portugal, the level of prescribing of non-steroidal anti-inflammatory drugs to patients with diabetes mellitus should be reduced, particularly in the subgroups identified with higher prescription and with higher risk of progression to stage 5 chronic kidney disease.Introdução: Portugal apresenta a incidência mais elevada de doença renal crónica estádio 5 na Europa. Especula-se que o elevado consumo de anti-inflamatórios não esteroides possa contribuir para esta incidência. O objetivo do presente estudo foi caracterizar a prescrição de anti-inflamatórios não esteroides a doentes com diabetes mellitus em Portugal. Material e Métodos: Na Base de Dados Nacional de Prescrições do Ministério da Saúde, triénio 2015 - 2017, analisámos a prescrição de anti-inflamatórios não esteroides em doentes com diabetes mellitus, de acordo com a idade, género e região do doente e a especialidade do médico prescritor. Avaliámos a prescrição de anti-inflamatórios não esteroides no total de doentes com diabetes mellitus, em doentes com diminuição presumida da função renal e naqueles com prescrição concomitante de inibidores da enzima de conversão da angiotensina ou antagonistas dos recetores da angiotensina. Resultados: Analisámos 23 320 620 prescrições, correspondendo a 610 157 adultos, dos quais 104 306 doentes com diabetes mellitus. Os anti-inflamatórios não esteroides mais prescritos foram ibuprofeno (20,1%), metamizol (14,7%) e diclofenac (11,4%). A prescrição foi mais frequente nas mulheres, nos doentes com 51 - 70 anos e no Alentejo. Foram prescritos anti-inflamatórios não esteroides a 70,6% dos doentes com diabetes mellitus, dos quais 10,6% receberam prescrições de ≥ 10 embalagens durante os três anos. Dos doentes com diabetes mellitus medicados com inibidores da enzima de conversão da angiotensina ou antagonistas dos receptores da angiotensina e com diminuição presumida da taxa de filtração glomerular, 69,3% receberam prescrição de anti-inflamatórios não esteroides e 11,5% receberam ≥ 10 embalagens durante os três anos. Discussão: A prescrição de anti-inflamatórios não esteroides na diabetes mellitus é elevada. Não parece existir uma preocupação na menor utilização de anti-inflamatórios não esteroides em doentes simultaneamente medicados com inibidores da enzima de conversão da angiotensina ou antagonistas dos recetores da angiotensina e/ou com diminuição da função renal. Conclusão: A prescrição de anti-inflamatórios não esteroides em Portugal a doentes com diabetes mellitus deverá ser reduzida, particularmente nos subgrupos identificados com prescrição mais elevada e com maior risco de progressão para doença renal crónica estádio 5.

Practices of using active methodologies as facilitating tools in the teaching-learning process in higher education are increasing, especially in bioengineering courses. The university is a good model for facilitating the implementation of innovative processes due to its role and proximity to science, teaching and research. To embrace this challenge, the university is reaching a broader interaction with the community, from the area of scientific education that includes the awakening of children to science and research. Thus, this article reports on the pilot experience of the Laboratory of Cardiovascular Autonomic Function of the Cardiovascular Center of the University of Lisbon, in the approach of different academic and scientific knowledge together with society as a means to stimulate the pleasure of science and research in children.

In recent years microorganisms have been engineered towards synthesizing interesting plant polyphenols such as flavonoids and stilbenes from glucose. Currently, low endogenous supply of malonylCoA, indispensable for plant polyphenol synthesis, impedes high product titers. Usually, limited malonylCoA availability during plant polyphenol production is avoided by supplementing fatty acid synthesisinhibiting antibiotics such as cerulenin, which are known to increase the intracellular malonylCoA pool as a side effect. Motivated by the goal of microbial polyphenol synthesis being independent of such expensive additives, we used rational metabolic engineering approaches to modulate regulation of fatty acid synthesis and flux into the citric acid cycle in Corynebacterium glutamicum strains capable of flavonoid and stilbene synthesis. Initial experiments showed that sole overexpression of genes coding for the native malonylCoAforming acetylCoA carboxylase is not sufficient for increasing polyphenol production in C. glutamicum. Hence, the intracellular acetylCoA availability was also increased by reducing the flux into the citric acid cycle through reduction of citrate synthase activity. In defined cultivation medium, the constructed C. glutamicum strains accumulated 24 mg/L (0.088 mM) naringenin or 112 mg/L (0.49 mM) resveratrol from glucose without supplementation of phenylpropanoid precursor molecules or any inhibitors of fatty acid synthesis., We would like to thank the European Union Framework Program 7 ''BacHBerry'' (www.bachberry.eu), Project No. FP7‐ 613793 for financial support and also the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/ BIO/04469 unit, COMPETE 2020 (POCI‐01–0145‐FEDER‐006684) and BiotecNorte operation (NORTE‐01–0145‐FEDER‐000004) funded by the European Regional Development Fund under the scope of Norte2020 ‐ Programa Operacional Regional do Norte. Furthermore, we would like to thank Dr. Tino Polen for providing the plasmids to replace the gltA promoter by dapA promoter variants., info:eu-repo/semantics/publishedVersion

© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated., Background: Depressive symptoms are common in individuals suffering from severe somatic conditions. There is a lack of interventions and evidence-based interventions aiming to reduce depressive symptoms in patients with severe somatic conditions. The aim of the NEVERMIND project is to address these issues and provide evidence by testing the NEVERMIND system, designed to reduce and prevent depressive symptoms in comparison to treatment as usual. Methods: The NEVERMIND study is a parallel-groups, pragmatic randomised controlled trial to assess the effectiveness of the NEVERMIND system in reducing depressive symptoms among individuals with severe somatic conditions. The NEVERMIND system comprises a smart shirt and a user interface, in the form of a mobile application. The system is a real-time decision support system, aiming to predict the severity and onset of depressive symptoms by modelling the well-being condition of patients based on physiological data, body movement, and the recurrence of social interactions. The study includes 330 patients who have a diagnosis of myocardial infarction, breast cancer, prostate cancer, kidney failure, or lower limb amputation. Participants are randomised in blocks of ten to either the NEVERMIND intervention or treatment as usual as the control group. Clinical interviews and structured questionnaires are administered at baseline, at 12 weeks, and 24 weeks to assess whether the NEVERMIND system is superior to treatment as usual. The endpoint of primary interest is Beck Depression Inventory II (BDI-II) at 12 weeks defined as (i) the severity of depressive symptoms as measured by the BDI-II. Secondary outcomes include prevention of the onset of depressive symptoms, changes in quality of life, perceived stigma, and self-efficacy. Discussion: There is a lack of evidence-based interventions aiming to reduce and prevent depressive symptoms in patients with severe somatic conditions. If the NEVERMIND system is effective, it will provide healthcare systems with a novel and innovative method to attend to depressive symptoms in patients with severe somatic conditions., The NEVERMIND project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 689691. The funding body had no role in the design of the study and collection as well as in writing the manuscript. Open access funding provided by Karolinska Institute.

Background Chronic kidney disease increases stroke incidence and severity but the mechanisms behind this cerebro-renal interaction are mostly unexplored. Since both vascular beds share similar features, microvascular dysfunction could be the possible missing link. Therefore, we examined the relationship between renal function and cerebral autoregulation in the early hours post ischemia and its impact on outcome. Methods We enrolled 46 ischemic strokes (middle cerebral artery). Dynamic cerebral autoregulation was assessed by transfer function (coherence, phase and gain) of spontaneous blood pressure oscillations to blood flow velocity within 6 h from symptom-onset. Estimated glomerular filtration rate (eGFR) was calculated. Hemorrhagic transformation (HT) and white matter lesions (WML) were collected from computed tomography performed at presentation and 24 h. Outcome was evaluated with modified Rankin Scale at 3 months. Results High gain (less effective autoregulation) was correlated with lower eGFR irrespective of infarct side (p

©Springer Science+Business Media, LLC, part of Springer Nature 2018, Hypertension is a prevalent and major health problem, involving a complex integration of different organ systems, including the central nervous system (CNS). The CNS and the hypothalamus in particular are intricately involved in the pathogenesis of hypertension. In fact, evidence supports altered hypothalamic neuronal activity as a major factor contributing to increased sympathetic drive and increased blood pressure. Several mechanisms have been proposed to contribute to hypothalamic-driven sympathetic activity, including altered ion channel function. Ion channels are critical regulators of neuronal excitability and synaptic function in the brain and, thus, important for blood pressure homeostasis regulation. These include sodium channels, voltage-gated calcium channels, and potassium channels being some of them already identified in hypothalamic neurons. This brief review summarizes the hypothalamic ion channels that may be involved in hypertension, highlighting recent findings that suggest that hypothalamic ion channel modulation can affect the central control of blood pressure and, therefore, suggesting future development of interventional strategies designed to treat hypertension., Dr. Rocha reports a grant from Portuguese Foundation for Science and Technology [2010–2013–FCT/PTDC/SAUOSM/109081/2008].

Purpose: Patients suffering from cardiovascular autonomic failure often develop neurogenic supine hypertension (nSH), i.e., high blood pressure (BP) in the supine position, which falls in the upright position owing to impaired autonomic regulation. A committee was formed to reach consensus among experts on the definition and diagnosis of nSH in the context of cardiovascular autonomic failure. Methods: As a first and preparatory step, a systematic search of PubMed-indexed literature on nSH up to January 2017 was performed. Available evidence derived from this search was discussed in a consensus expert round table meeting in Innsbruck on February 16, 2017. Statements originating from this meeting were further discussed by representatives of the American Autonomic Society and the European Federation of Autonomic Societies and are summarized in the document presented here. The final version received the endorsement of the European Academy of Neurology and the European Society of Hypertension. Results: In patients with neurogenic orthostatic hypotension, nSH is defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, measured after at least 5 min of rest in the supine position. Three severity degrees are recommended: mild, moderate and severe. nSH may also be present during nocturnal sleep, with reduced-dipping, non-dipping or rising nocturnal BP profiles with respect to mean daytime BP values. Home BP monitoring and 24-h-ambulatory BP monitoring provide relevant information for a customized clinical management. Conclusions: The establishment of expert-based criteria to define nSH should standardize diagnosis and allow a better understanding of its epidemiology, prognosis and, ultimately, treatment.

BACterial Hosts for production of Bioactive phenolics from bERRY fruits (BacHBerry) was a 3-year project funded by the Seventh Framework Programme (FP7) of the European Union that ran between November 2013 and October 2016. The overall aim of the project was to establish a sustainable and economically-feasible strategy for the production of novel high-value phenolic compounds isolated from berry fruits using bacterial platforms. The project aimed at covering all stages of the discovery and pre-commercialization process, including berry collection, screening and characterization of their bioactive components, identification and functional characterization of the corresponding biosynthetic pathways, and construction of Gram-positive bacterial cell factories producing phenolic compounds. Further activities included optimization of polyphenol extraction methods from bacterial cultures, scale-up of production by fermentation up to pilot scale, as well as societal and economic analyses of the processes. This review article summarizes some of the key findings obtained throughout the duration of the project., The authors would like to thank the European Union’s Seventh Framework Programme (BacHBerry, Project No. FP7-613793, and FP7-PEOPLE2013-COFUND, Project No. FP7-609405) for the financial support. AD, RF, MHHN, PG, SGS, and JF would also like to acknowledge the Novo Nordisk Foundation. We express our gratitude to Dr. Martha Cyert (Stanford School of Medicine, EUA), Dr. Hitoshi Shimoi (National Research Institute of Brewing, Japan) and Dr. Yoshio Araki (Graduate School of Biosphere Science, Hiroshima University, Japan) for providing the yeast strain YAA5. We also thank Dr. Ian Macraedie, RMIT University, Australia) for providing the plasmid p416_GPDprGFP-A42., info:eu-repo/semantics/publishedVersion

© 2018 Elsevier B.V. All rights reserved., Background: Exposures to lead (Pb) during developmental phases can alter the normal course of development, with lifelong health consequences. Permanent Pb exposure leads to behavioral changes, cognitive impairment, sympathoexcitation, tachycardia, hypertension and autonomic dysfunction. However, the effects of an intermittent lead exposure are not yet studied. This pattern of exposure has been recently increasing due to migrations, implementation of school exchange programs and/or residential changes. Objective: To determine and compare lead effects on mammal’s behavior and physiology, using a rat model of intermittent and permanent Pb exposures. Methods: Fetuses were intermittently (PbI) or permanently (PbP) exposed to water containing lead acetate (0.2% w/v) throughout life until adulthood (28 weeks of age). A control group (CTL) without any exposure to lead was also used. Anxiety was assessed by elevated plus maze (EPM) and locomotor activity and exploration by open field test (OFT). Blood pressure (BP), electrocardiogram (ECG), heart rate (HR), respiratory frequency (RF), sympathetic and parasympathetic activity and baro- and chemoreceptor reflex profiles were evaluated. Immunohistochemistry protocol for the assessment of neuroinflammation, neuronal loss (NeuN), gliosis and synaptic alterations (Iba-1, GFAP, Syn), were performed at the hippocampus. One-way ANOVA with Tukey’s multiple comparison between means were used (significance p < 0.05) for statistical analysis. Results: The intermittent lead exposure produced a significant increase in diastolic and mean BP values, concomitant with a tendency to sympathetic overactivity (estimated by increased low-frequency power) and without significant changes in systolic BP, HR and RF. A chemoreceptor hypersensitivity and a baroreflex impairment were also observed, however, less pronounced when compared to the permanent exposure. Regarding behavioral changes, both lead exposure profiles showed an anxiety-like behavior without changes in locomotor and exploratory activity. Increase in GFAP and Iba-1 positive cells, without changes in NeuN positive cells were found in both exposed groups. Syn staining suffered a significant decrease in PbI group and a significant increase in PbP group. Conclusion: This study is the first to show that developmental Pb exposure since fetal period can cause lasting impairments in physiological parameters. The intermittent lead exposure causes adverse health effects, i.e, hypertension, increased respiratory frequency and chemoreflex sensitivity, baroreflex impairment, anxiety, decreased synaptic activity, neuroinflammation and reactive gliosis, in some ways similar to a permanent exposure, however some are lower-grade, due to the shorter duration of exposure. This study brings new insights on the environmental factors that influence autonomic and cardiovascular systems during development, which can help in creating public policy strategies to prevent and control the adverse effects of Pb toxicity., Vera Geraldes acknowledges the post-doctoral fellow given by the Fundação para a Ciência e Tecnologia (FCT) (Ref: SFRH/BPD/119315/ 2016).

[EN] The goal of this work is to develop an original and high performance hybrid lab-on-a-chip, coupling actuators and biosensors for the active control and broad range characterization of biofluids samples. These biofluids will be controlled (moved and mixed) actively by Rayleigh-Surface Acoustic Wave (R-SAW) and analysed in real-time by combining Love-SAW (L-SAW) and Surface Plasmon Resonance (SPR) technologies. A microfluidic chamber and specific transducer were designed for this application to interact efficiently with the liquid sample entrapped in the chamber and to detect modifications of its physical properties such as viscosity. AT-cut quartz and LiNbO3 36Y-X substrates were used to generate both Rayleigh and Shear-Horizontal waves and ZnO material as guiding layer. The whole system has proven is full efficiency to interact with the fluid and to detect the signal perturbations with no significant loss compared with the measurements carried out with a probe station., The authors wish to thank the ANR for its financial support through the AWESOM project (ANR-12-BS09-021); the operators Laurent Bouvot, Jean Georges Mussot and Emmanuel Vatoux, for their support and assistance in the fabrication of the cell and the SAW devices; and the engineering students, Olivier Bettoni and Bastien Lafont, for their contribution to the cell design.

[EN] Chagas disease (CD), which mostly affects those living in deprived areas, has become one of Latin America's main public health problems. Effective prevention of the disease requires early diagnosis, initiation of therapy, and regular blood monitoring of the infected individual. However, the majority of the Trypanosoma cruzi infections go undiagnosed because of mild symptoms, limited access to medical attention and to a high variability in the sensitivity and specificity of diagnostic tests. Consequently, more affordable and accessible detection technologies capable of providing early diagnosis and T. cruzi load measurements in settings where CD is most prevalent are needed to enable enhanced intervention strategies. This work analyzes the potential contribution of biosensing technologies, reviewing examples that have been tested and contrasted with traditional methods, both serological and parasitological (i.e., molecular detection by PCR), and discusses some emerging biosensing technologies that have been applied for this public health issue. Even if biosensing technologies still require further research efforts to develop portable systems, we arrive at the conclusion that biosensors could improve the accuracy of CD diagnosis and the follow-up of patients' treatments in terms of the rapidity of results, small sample volume, high integration, ease of use, real-time and low cost detection when compared with current conventional technologies., M.I.R.-G., F.S. and D.B. thank the Agence National de la Recherche (ANR), for its financial support by granting the international AWESOM project. The authors of this work are also grateful to Janine W. Ramsey for her useful comments and suggestions about Figure 2

The present work deals with the development of an integrated microfluidic platform which address several challenges. The sensor array combines a dual Rayleigh wave and Love wave acoustic device with SPR for biomedical diagnosis. Based on simulations and mechanical studies, we optimized the microfluidic cell to limit disturbances to the Love wave. We also studied different combinations of crystal cuts (Quartz-AT, LiNbO3-36YX) and ZnO waveguide thickness to enhance the sensitivity. The results confirm the idea that the whole measurement system must be considered in order to develop an integrated analysis set-up with optimal operation.

Over the last 15 years, several genome-scale metabolic models (GSMMs) were developed for different yeast species, aiding both the elucidation of new biological processes and the shift toward a bio-based economy, through the design of in silico inspired cell factories. Here, an historical perspective of the GSMMs built over time for several yeast species is presented and the main inheritance patterns among the metabolic reconstructions are highlighted. We additionally provide a critical perspective on the overall genome-scale modeling procedure, underlining incomplete model validation and evaluation approaches and the quest for the integration of regulatory and kinetic information into yeast GSMMs. A summary of experimentally validated model-based metabolic engineering applications of yeast species is further emphasized, while the main challenges and future perspectives for the field are finally addressed, This work was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of a Ph.D. grant (PD/BD/52336/2013), of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01–0145FEDER-006684) and also in the context of the EU-funded initiative ERA-NET for Industrial Biotechnology (ERA-IB-2/0003/2013), in addition to the BioTecNorte operation (NORTE-01–0145FEDER-000004) funded by European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte., info:eu-repo/semantics/publishedVersion

Genome-scale metabolic models (GSMMs) have become important assets for rational design of compound overproduction using microbial cell factories. Most computational strain optimization methods (CSOM) using GSMMs, while useful in metabolic engineering, rely on the definition of questionable cell objectives, leading to some bias. Metabolic pathway analysis approaches do not require an objective function. Though their use brings immediate advantages, it has mostly been restricted to small scale models due to computational demands. Additionally, their complex parameterization and lack of intuitive tools pose an important challenge towards making these widely available to the community. Recently, MCSEnumerator has extended the scale of these methods, namely regarding enumeration of minimal cut sets, now able to handle GSMMs. This work proposes a tool implementing this method as a Java library and a plugin within the OptFlux metabolic engineering platform providing a friendly user interface. A standard enumeration problem and pipeline applicable to GSMMs is proposed, making use by the community simpler. To highlight the potential of these approaches, we devised a case study for overproduction of succinate, providing a phenotype analysis of a selected strategy and comparing robustness with a selected solution from a bi-level CSOM., The authors thank the project “DeYeastLibrary—Designer yeast strain library optimized for metabolic engineering applications”, Ref. ERA-IB-2/0003/2013, funded by national funds through “Fundação para a Ciência e Tecnologia / Ministério da Ciência, Tecnologia e Ensino Superior”., info:eu-repo/semantics/publishedVersion

The articles in this special section argue that, by looking at quantification as a technical and political technique of power, we can effectively engage with newly established types of transnational power and better under-stand how numbers can enable reconfigurations and hence reorderings of power relations. The section looks at how numbers, in the form of risk assessments, measuring for results, and governance indicators, have a crucial impact in current transnational politics, which in turn influences resource allocation and recognition, discourses on undesirable individuals, possibilities for political leverage, and potential ownership.

Myocardial infarction (MI) is a high prevalence cardiovascular disease with a tendency to increase. Although MI therapy has increased its effectiveness, the loss of myocardial function in consequence of MI is still responsible for major subsequent complications as rhythm changes and heart failure. In human hearts, MI is characterized by cardiomyocyte death and fibrin deposition, which is later replaced by scar tissue. In opposition, zebrafish heart undergoes minimal scaring and cardiac tissue can undergo full functionally regeneration in 60 to 120 days. Therefore, this animal model has been used in cardiovascular research as a model for studying mechanisms of cardiac regeneration. The hearts of zebrafish is anatomically different from the human heart, though the electrocardiogram (ECG) pattern and the critical conduction pathways are comparable to the human's. The objective of our full project is the implementation of an ECG recording system with 3 orthogonal electrodes in 2 planes, in order to create a 4D recording of the zebrafish cardiac electrical activity. Here we present our preliminary work related to a non-invasive ECG monitoring with two electrodes.

© 2017 Castro, Serrador, Rocha, Sorond and Azevedo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms., Background and purpose: Effective cerebral autoregulation (CA) may protect the vulnerable ischemic penumbra from blood pressure fluctuations and minimize neurological injury. We aimed to measure dynamic CA within 6 h of ischemic stroke (IS) symptoms onset and to evaluate the relationship between CA, stroke volume, and neurological outcome. Methods: We enrolled 30 patients with acute middle cerebral artery IS. Within 6 h of IS, we measured for 10 min arterial blood pressure (Finometer), cerebral blood flow velocity (transcranial Doppler), and end-tidal-CO2. Transfer function analysis (coherence, phase, and gain) assessed dynamic CA, and receiver-operating curves calculated relevant cut-off values. National Institute of Health Stroke Scale was measured at baseline. Computed tomography at 24 h evaluated infarct volume. Modified Rankin Scale (MRS) at 3 months evaluated the outcome. Results: The odds of being independent at 3 months (MRS 0–2) was 14-fold higher when 6 h CA was intact (Phase > 37°) (adjusted OR = 14.0 (IC 95% 1.7–74.0), p = 0.013). Similarly, infarct volume was significantly smaller with intact CA [median (range) 1.1 (0.2–7.0) vs 13.1 (1.3–110.5) ml, p = 0.002]. Conclusion: In this pilot study, early effective CA was associated with better neurological outcome in patients with IS. Dynamic CA may carry significant prognostic implications., This study was part of Ph.D. thesis of PC and received publiC national grant from Fundação para a Ciência e a Tecnologia (FCT), Portugal, PTDC/SAU-ORG/113329/2009. FS is supported by R01 NS085002 (NINDS).

We report a case of a patient with recurrent syncope and paroxysmal atrial fibrillation whose clinical status greatly improved after a period of orthostatic training. The potential efficacy of this non-pharmacological measure in modulating the autonomic tone is discussed below.

Around 15% of children and adolescents experience at least one episode of syncope until adulthood. Excluding cardiac disease, the majority of syncopes are of reflex origin and benign in nature. In this situation, a tilt test is conducted to reproduce symptoms and to evaluate cardiovascular adaptations to orthostatism, but its mechanisms are not yet well defined. Here, we investigated haemodynamics and autonomic activity during tilt in young patients. Patients (n=113) with unexplained syncope were enrolled. Tilt followed a standard protocol without provocative agents. A positive response (fainters) was defined as a sudden development of syncope or presyncope associated with hypotension, bradycardia, or both. Haemodynamic parameters, autonomic activity, and baroreflex sensibility were evaluated. Data were analysed on baseline; immediately after tilting; on tilt adaptation; before fainting or before tilt-down for non-fainters; and on tilt-down. A total of 45 patients experienced syncope after a mean time of 18 minutes. During tilting up, fainters showed lower blood pressure and peripheral resistance values, which decreased progressively with time together with baroreflex sensibility. Sympathetic tone increased massively along time till syncope. No changes in cardiac output and heart rate were observed. Results show a strong effort of the autonomic nervous system to adapt to orthostatic stress through different magnitudes of sympathetic output, which was maximal before syncope without apparent modifications of parasympathetic tone. These changes suggest an imbalance between both branches of the autonomic nervous system, not enabling a time-progressive adaptation and leading the subject to faint.

Oral health is a leading unmet health need among migrant families. This article describes the 1-year, community-based participatory research (CBPR) approach employed to plan and develop a Lider Communitario (lay community health worker)-led educational intervention for Mexican migrant adult caregivers and their families in three underserved, remote communities in North San Diego County, California. Four partner organizations collaborated, reviewed existing oral health curricula, and sought extensive input on educational topics and research design from key informants, migrant caregivers, and Lideres Communitarios. Based on community stakeholder input, partners developed a logic model and drafted educational intervention materials. Key informants ( n = 28), including several members from two community advisory boards, ranked program priorities and intervention subgroup population via online survey. Three focus groups were conducted with Lideres Communitarios ( n = 22) and three with migrant families ( n = 30) regarding the oral health program's design and content. Twelve Lideres Communitarios reviewed draft intervention materials during two focus groups to finalize the curriculum, and their recommended changes were incorporated. Formative research results indicated that community stakeholders preferred to focus on adult caregivers and their families. A 5-week educational intervention with hands on demonstrations and colorful visuals was developed, covering the following topics: bacteria and tooth decay, oral hygiene, nutrition, gum disease, and dental services. The CBPR process engaged multiple community stakeholders in all aspects of planning and developing the educational intervention.

New Findings • What is the central question of this study?Will a chronic reduction of neuronal excitability within the paraventricular nucleus of the hypothalamus reduce arterial blood pressure and sympathetic activity in the long term in an animal model of neurogenic hypertension? • What is the main finding and its importance?We show, for the first time, that overexpression of an inwardly rectifying potassium channel in the paraventricular nucleus provided a long-term (>60 days) antihypertensive response in conscious spontaneously hypertensive rats that was associated with a reduction in neurohumorally mediated vasoconstriction, enhanced baroreflex sensitivity and reduced peripheral chemosensitivity; no such response was observed in normotensive rats. Our results support the paraventricular nucleus as a therapeutic target for the chronic control of blood pressure in neurogenic hypertension. Changes in the sympathetic nervous system are responsible for the initiation, development and maintenance of hypertension. An important central sympathoexcitatory region is the paraventricular nucleus (PVN) of the hypothalamus, which may become more active in hypertensive conditions, as shown in acute studies previously. Our objective was to depress PVN neuronal activity chronically by the overexpression of an inwardly rectifying potassium channel (hKir2.1), while evaluating the consequences on blood pressure (BP) and its reflex regulation. In spontaneously hypertensive rats (SHRs) and Wistar rats (WKY) lentiviral vectors (LVV-hKir2.1; LV-TREtight-Kir-cIRES-GFP5 4 × 109 IU and LV-Syn-Eff-G4BS-Syn-Tetoff 6.2 × 109 IU in a ratio 1:4) were stereotaxically microinjected bilaterally into the PVN. Sham-treated SHRs and WKY received bilateral PVN microinjections of LVV-eGFP (LV-Syn-Eff-G4BS-Syn-Tetoff 6.2 × 109 IU and LV-TREtight-GFP 5.7 × 109 IU in a ratio 1:4). Blood pressure was monitored continuously by radio-telemetry and evaluated over 75 days. Baroreflex gain was evaluated using phenylephrine (25 μg ml−1, i.v.), whereas lobeline (25 μg ml−1, i.v.) was used to stimulate peripheral chemoreceptors. In SHRs but not normotensive WKY rats, LVV-hKir2.1 expression in the PVN produced time-dependent and significant decreases in systolic (from 158 ± 3 to 132 ± 6 mmHg; P < 0.05) and diastolic BP (from 135 ± 4 to 113 ± 5 mmHg; P < 0.05). The systolic BP low-frequency band was reduced (from 0.79 ± 0.13 to 0.42 ± 0.09 mmHg2; P < 0.05), suggesting reduced sympathetic vasomotor tone. Baroreflex gain was increased and peripheral chemoreflex depressed after PVN microinjection of LVV-hKir2.1. We conclude that the PVN plays a major role in long-term control of BP and sympathetic nervous system activity in SHRs. This is associated with reductions in both peripheral chemosensitivity and respiratory-induced sympathetic modulation and an improvement in baroreflex sensitivity. Our results support the PVN as a powerful site to control BP in neurogenic hypertension.

Background/Aims: In a previously described model of isolated rabbit eye, we detected myogenic intrinsic vascular tone of unknown origin in the ophthalmic artery. In order to better understand the origin of these low frequency oscillations, we analyzed their spectral characteristics using fast Fourier. Methods: Hybrid New Zealand rabbits of either sex (n = 24) were used; they were divided into 2 groups according to age. The spectral characteristics of the myogenic behaviour of the rabbit external ophthalmic artery were analyzed using the fast Fourier algorithm. Results: The frequency of the oscillations of the myogenic activity seen in the rabbit external ophthalmic artery varied between 0.033 and 0.066 Hz (mean 0.045 ± 0.012 Hz), all in the region of very low frequency (VLF) oscillations (VLF Conclusion: Fast Fourier analysis proved to be an adequate mathematical tool to analyze the myogenic tone oscillations, which were all in the range of VLF in the model we used. These results indicate that myogenic vascular function of ocular blood flow is composed of VLF oscillations, and they provide a new explanation for the origin of VLF in arterial spectra. They also suggest that the ocular local myogenic vascular function observed is more efficient in younger animals.

Given that Newcastle disease (ND) is one of the major threats for the poultry industry, testing of Newcastle disease virus (NDV) has been carried out since 2010 in cases of mortality in wild birds (passive surveillance) in Catalonia. The objective is to provide an early warning system to prevent the infection of poultry. Since 2010, 35 episodes of mortality in wild birds were attributed to NDV infection. Throughout this period there was a progressive expansion of NDV to new areas, with an increase in the episodes of mortality, although it is not clear whether they were the result of the spread of the virus, or of the improvement of the surveillance. Phylogenetic analyses indicate that two distinct sublineages of NDV, 4a and 4b, were circulating in Catalonia. Both sublineages seem to be endemic in the wild bird population, affecting mainly Eurasian-collared doves, with a clear pattern in relation to its spatial distribution (coincident with the distribution of this species), and its temporal distribution (with the majority of cases between September and February). So far, endemicity in wild birds has not resulted in ND outbreaks in poultry. However, there are still many uncertainties about, for example, whether NDV may expand to new areas of Catalonia (with higher poultry density), or about the threat that the apparently more novel sublineage 4a may represent. Hence, efforts should be made so that measures to prevent infection of poultry farms (particularly in high-risk areas and periods) are encouraged, and surveillance is maintained.

Given the huge potential impact of the growing number of complete genome-scale metabolic network reconstructions of organisms, it is necessary to use bioinformatics tools to simplify and accelerate the course of knowledge in this field. One essential component of genome-scale metabolic model is biomass equation, whose maximization is one of the most common objective functions used in Flux Balance Analysis formulations. Some components of biomass, such as amino acids and nucleotides, can be estimated from genome information. In this work it is proposed a Java tool that estimates biomass composition in amino acids and nucleotides, from genome and transcriptomic information, using as input files sequences in FASTA format and files with transcriptomic data in csv format. This application allows to obtain the results rapidly and is also a user-friendly tool since facilitates its use by users with any or little background in informatics., Project DeYeastLibrary - Designer yeast strain library optimized for metabolic engineering applications, Ref. ERA-IB-2/0003/2013, funded by national funds through FCT/MCTES

Introduction: Baroreflex function is an independent marker of prognosis in heart failure (HF). However, little is known about its relation to response to cardiac resynchronization therapy (CRT). The aim of this study is to assess arterial baroreflex function in HF patients who are candidates for CRT. Methods: The study population consisted of 25 patients with indication for CRT, aged 65±10 years, NYHA functional class ≥III in 52%, QRS width 159±15 ms, left ventricular ejection fraction (LVEF) 29±5%, left ventricular end-systolic volume (LVESV) 150±48 ml, B-type natriuretic peptide (BNP) 357±270 pg/ml, and peak oxygen consumption (peak VO2) 18.4±5.0 ml/kg/min. An orthostatic tilt test was performed to assess the baroreflex effectiveness index (BEI) by the sequence method. This group was compared with 15 age-matched healthy individuals. Results: HF patients showed a significantly depressed BEI during tilt (31±12% vs. 49±18%, p=0.001). A lower BEI was associated with higher BNP (p=0.038), lower peak VO2 (p=0.048), and higher LVESV (p=0.031). By applying a cut-off value of 25% for BEI, two clusters of patients were identified: lower risk cluster (BEI >25%) QRS 153 ms, LVESV 129 ml, BNP 146 pg/ml, peak VO2 19.0 ml/kg/min; and higher risk cluster (IEB ≤25%) QRS 167 ms, LVESV 189 ml, BNP 590 pg/ml, peak VO2 16.2 ml/kg/min. Conclusions: Candidates for CRT show depressed arterial baroreflex function. Lower BEI was observed in high-risk HF patients. Baroreflex function correlated closely with other clinical HF parameters. Therefore, BEI may improve risk stratification in HF patients undergoing CRT. Resumo: Introdução: O barorreflexo arterial é comprovadamente um marcador independente de prognóstico na IC. Contudo, pouco se sabe sobre a relação entre a função do barorreflexo e a resposta à TRC. Assim, o objetivo deste estudo é avaliar a função barorreflexa em doentes com IC candidatos a TRC. Métodos: A população deste estudo prospetivo consistiu em 25 doentes com 65±10 anos, classe NYHA ≥III em 52%, QRS 159±15 ms, fração de ejeção do ventrículo esquerdo (FEVE) 29±5%, volume telessistólico do ventrículo esquerdo (VTSVE) 150±48 mL, péptido natriurético tipo-B (BNP) 357±270 pg/ml, consumo máximo de oxigénio (VO2 max) 18,4±5,0 ml/kg/min. Foi implementado um teste de ortostatismo passivo para avaliar o índice de eficácia do barorreflexo (IEB), através do método sequencial. O grupo controlo foi constituído por 15 indivíduos saudáveis emparelhados para a idade. Resultados: Os doentes com IC apresentaram um IEB significativamente reduzido durante o tilt (31±12% versus 49±18%, p=0,001). Um IEB diminuído associou-se a um BNP elevado (p=0,038), a um VO2 diminuído (p=0,048) e a um VTSVE aumentado (p=0,031). Aplicando um cut-off 25% para o IEB, foram identificados dois clusters de doentes: cluster de risco menor risco (IEB>25%) QRS 153 ms, VTSVE 129 mL, BNP 146 pg/mL, VO2 max 19,0 mL/kg/min; cluster de maior risco (IEB≤25%) QRS 167 ms, VTSVE 189 mL, BNP 590 pg/mL, VO2 max 16,2 mL/kg/min. Conclusões: Doentes candidatos a TRC apresentam barorreflexo deprimido. O BEI diminuído foi observado nos doentes de maior risco. O barorreflexo correlacionou-se bem com outros parâmetros de gravidade de IC. Desta forma, o BEI pode contribuir para a estratificação de risco dos doentes com IC submetidos a TRC. Keywords: Heart failure, Cardiac resynchronization therapy, Arterial baroreflex, Palavras-chave: Insuficiência cardíaca, Ressincronização cardíaca, Reflexo barorrecetor arterial

Under the realm of in silico Metabolic Engineering, pathway analysis approaches to strain optimization have shown a large potential as tools capable of providing an unbiased view over metabolic models. Most of these methods were difficult or impossible to use due to their heavy computational needs, since they are based in the calculation of elementary modes/minimal cut sets in large networks. However, a recent method (MCSEnumerator) has enabled the application of these approaches to genome-scale metabolic models. This work proposes a new software tool where this method is implemented in a novel Java library, that provides support for a plugin for the OptFlux metabolic engineering platform. Together, these tools implement the routines necessary for the calculation of minimal cut sets and their use to provide strain optimization methods. The aim is to provide an open-source software tool that includes an intuitive graphical user interface, thus facilitating its use by the community., Project “DeYeastLibrary - Designer yeast strain library optimized for metabolic engineering applications”, Ref. ERA-IB-2/0003/2013, funded by national funds through FCT/MCTES

Dynamic models of metabolism have been developed for a variety of systems and can be applied in metabolic engineering design and to understand the time-varying characteristics of the systems when exposed to different stimuli. Hereby we analyse and compare the most used and complete kinetic models available for the central carbon metabolism of E. coli. Stoichiometric and kinetic comparisons showed several differences, discrepancies and incoherence especially regarding the kinetic mechanisms assumed, parameters and units. Time course and steady-state simulations and also comparison with an experimental dataset put in evidence major differences regarding responses to the same stimulus. The results presented raise important questions regarding the need of using standard methodologies in dynamic model construction as well as in using experimental data for model validation., The authors thank the project “Dynamics”, Ref. ERA-IB2/0002/2014, funded by national funds through FCT/MCTES. This study was also supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684).

© 2016 Elsevier B.V. All rights reserved., Background: Chronic overexpression of an inwardly rectifying potassium channel (hKir2.1) in the paraventricular nucleus of the hypothalamus (PVN) and in the rostral ventrolateral medulla (RVLM) to suppress neuronal excitability, resulted in a long term decrease of blood pressure and sympathetic output in spontaneously hypertensive rats (SHR). Objective: Evaluate gene expression in end-organs of SHR after a chronic overexpression of hKir2.1 channels in either the PVN or RVLM. Methods: mRNA levels of 16 genes known to be involved with blood pressure regulation were evaluated using RT-PCR in tissues from the heart, common carotid artery and kidney of SHR submitted to chronic depression of PVN and RVLM excitability using a lentiviral vector (LVhKir2.1). Results: In SHR hearts in which either the PVN or RVLM were injected with LVhKir2.1, there was a downregulation of angiotensin II receptor 1b (AT1), ATPase, Ca(2+)-transporter, troponin T2 and tropomyosin2 (only in RVLM) relative to the sham group. In the kidney of SHR with LVhKir2.1 injections in PVN and RVLM, angiotensinogen, angiotensin II receptor2 (AT2) and endothelin1 were all upregulated compared to sham. In the carotid artery, endothelin2, endothelin receptor A and B were up-regulated following LVhKir2.1 in to either the PVN or RVLM relative to sham. Conclusion: Chronic overexpression of hKir2.1 channels in PVN and RVLM, promoted a BP decrease with up-regulation of angiotensinogen and AT2 genes expression in the kidney and down-regulation of AT1 in the heart of SHR. Thus, we demonstrate the potential efficacy of central manipulation to protect against end-organ damage in essential hypertension., This work was supported by Fundação para a Ciência e Tecnologia (PTDC/SAU-OSM/109081/2008) and Sorin Portugal grants to Isabel Rocha; British Heart Foundation (RG/12/6/29670) and National Institutes of Health (RO1 NS069220). The authors want to acknowledge the technical contributions of Raquel Laires and technical advices of Mafalda Carvalho.

Motivation: The description of a metabolic network in terms of elementary (flux) modes (EMs) provides an important framework for metabolic pathway analysis. However, their application to large networks has been hampered by the combinatorial explosion in the number of modes. In this work, we develop a method for generating random samples of EMs without computing the whole set. Results: Our algorithm is an adaptation of the canonical basis approach, where we add an additional filtering step which, at each iteration, selects a random subset of the new combinations of modes. In order to obtain an unbiased sample, all candidates are assigned the same probability of getting selected. This approach avoids the exponential growth of the number of modes during computation, thus generating a random sample of the complete set of EMs within reasonable time. We generated samples of different sizes for a metabolic network of Escherichia coli, and observed that they preserve several properties of the full EM set. It is also shown that EM sampling can be used for rational strain design. A well distributed sample, that is representative of the complete set of EMs, should be suitable to most EM-based methods for analysis and optimization of metabolic networks. Availability: Source code for a cross-platform implementation in Python is freely available at http://code.google.com/p/emsampler. Contact: dmachado@deb.uminho.pt Supplementary information: Supplementary data are available at Bioinformatics online.

Neurocardiogenic syncope (NCS) is a common clinical entity resulting from an excessive reflex autonomic response, particularly during orthostatism. Treatment options are controversial and of limited effectiveness. Tilt training (TT) is a promising option to treat these patients. However, its mechanism of action and clinical impact remain unclear. Objective: To characterize hemodynamic and autonomic responses during a TT program in patients with NCS refractory to conventional measures. Methods: We studied 28 patients (50% male, mean age 41 ± 14 years) without structural heart disease, with NCS documented by tilt testing. The TT program included nine tilt sessions (three times a week, 30 min) (60° – 6 sessions, 70° – 3 sessions), under ECG and blood pressure monitoring combined with home orthostatic self-training and 10° head-up during sleep. Systolic volume, cardiac output, total peripheral resistance, baroreflex sensitivity and heart-rate variability were computed. Patients were reassessed at 1 month and every 6 months for a maximum of 36 months (24 ± 12 months). Results: Over the course of the TT program there was a significant increase in total peripheral resistance (1485 ± 225 vs. 1591 ± 187 dyn s cm−5, p

Introduction: Atrial fibrillation (AF) is a complex disease with multiple mechanisms, including the interaction with the autonomic nervous system (ANS), electrophysiological properties of the atria and pulmonary veins (PVs), and vulnerability for AF. We assessed the effects of acute vagal (vagus_stim) and sympathetic stimulation (symp_stim) on atrial conduction, atrial and PV refractoriness and inducibility of AF in an in vivo rabbit model with preserved autonomic innervation. Methods: An open-epicardial approach was used in 17 anesthetized and artificially ventilated New Zealand white rabbits. The ECG was recorded with bipolar subcutaneous electrodes placed in the four limbs. Electrograms were obtained with four monopolar electrodes placed epicardially along the atria, and an electrode adapted to the proximal PVs. The cervical vagus nerve and thoracic sympathetic trunk were stimulated with bipolar electrodes. Epicardial activation was recorded in sinus rhythm, and effective refractory periods (ERPs) and conduction times from the high-lateral right atrium (RA) to the high-lateral left atrium (LA) and PVs were quantified at baseline and during vagus_stim, symp_stim, or combined vagal and sympathetic stimulation (dual_stim). Burst pacing (50 Hz, 10 s), alone or combined with vagus_stim, symp_stim or dual_stim, was performed in the right (RAA) and left atrial appendage (LAA) and PVs to test for AF inducibility. Results: At baseline, ERPs were higher in the LAA and there was a delay in the conduction time from RA to PV, compared to the mean activation time from RA to LA. During vagus_stim or dual_stim, ERP decreased significantly at all sites, and baseline interatrial activation times changed from 20±4 ms to 30±10 ms and from 21±5 ms to 31±11 ms, respectively (p10 s a arritmia terminou imediatamente após interrupção da estim_vagal. Conclusões: No coração de coelho inervado in vivo, a estimulação autonómica aguda encurta a refractariedade auricular e das VP, e modifica a velocidade de condução auricular, potenciando a indução e duração de FA. Os resultados sugerem que as variações agudas e a interacção da actividade autonómica podem desempenhar um papel importante na fisiopatologia da FA. Keywords: Animal model, Vagus, Sympathetic, Refractoriness, Conduction velocity, Atrial fibrillation, Palavras-chave: Modelo animal, Vago, Simpático, Refractariedade, Velocidade de condução, Fibrilhação auricular