Proteomic investigations into hypertension: what's new and how might it affect clinical practice?

Introduction: Hypertension is a multifactorial disease that has, thus far, proven to be a difficult target for pharmacological intervention. The application of proteomic strategies may help to identify new biomarkers for the early diagnosis and prompt treatment of hypertension, in order to control blood pressure and prevent organ damage. Areas covered: Advances in proteomics have led to the discovery of new biomarkers to help track the pathophysiological processes implicated in hypertension. These findings not only help to better understand the nature of the disease, but will also contribute to the clinical needs for a timely diagnosis and more precise treatment. In this review, we provide an overview of new biomarkers identified in hypertension through the application of proteomic techniques, and we also discuss the difficulties and challenges in identifying biomarkers in this clinical setting. We performed a literature search in PubMed with the key words 'hypertension' and 'proteomics', and focused specifically on the most recent literature on the utility of proteomics in hypertension research. Expert opinion: There have been several promising biomarkers of hypertension identified by proteomics, but too few have been introduced to the clinic. Thus, further investigations in larger cohorts are necessary to test the feasibility of this strategy for patients. Also, this emerging field would profit from more collaboration between clinicians and researchers.

Efficacy and adverse effects of buprenorphine in acute pain management: systematic review and meta-analysis of randomised controlled trials.

Buprenorphine appears to have a ceiling effect on respiratory depression, but not analgesia in healthy young patients. However, the efficacy and side-effects of buprenorphine in the setting of acute pain are poorly characterized. The aim of this study was to characterize the analgesic efficacy and adverse effects of buprenorphine compared with morphine in the acute pain setting. A systematic review of five databases was performed. Randomised controlled trials (RCTs) comparing buprenorphine with morphine in acute pain management were included. Studies performed outside of the hospital setting were excluded. The a priori primary outcomes included pain, respiratory depression, and sedation. Secondary outcomes included requirement for rescue analgesia, time to rescue analgesia, nausea, vomiting, dizziness, hypotension, and pruritus. Twenty-eight RCTs with 2210 patients met the inclusion criteria. There was no difference in pain [visual analogue scale weighted mean difference (WMD)=-0.29; 95% confidence interval (CI)=-0.62 to 0.03; I2=99%; P=0.07], incidence of respiratory depression [odds ratio (OR)=2.07; 95% CI=0.78-5.51; I2=30%; P=0.14], or sedation (OR=1.44; 95% CI=0.76-2.74; I2=23%; P=0.26). There was only one secondary outcome with an overall significant difference; buprenorphine use was associated with significantly less pruritus (OR=0.31; 95% CI=0.12-0.84; I2=6%; P=0.02). Whilst a theoretical ceiling effect may exist with respect to buprenorphine and respiratory depression, in a clinical setting, it can still cause significant adverse effects on respiratory function. However, given that buprenorphine is an equally efficacious analgesic agent, it is a useful alternative opioid because of its ease of administration and reduced incidence of pruritus.

Reconciling research and community priorities in participatory trials: application to Padres Informados/Jovenes Preparados.

Background: Participatory research (PR) trials aim to achieve the dual, and at times competing, demands of producing an intervention and research process that address community perspectives and priorities, while establishing intervention effectiveness. Objective: To identify research and community priorities that must be reconciled in the areas of collaborative processes, study design and aim and study implementation quality in order to successfully conduct a participatory trial. We describe how this reconciliation was approached in the smoking prevention participatory trial Padres Informados/Jovenes Preparados (Informed Parents/Prepared Youth) and evaluate the success of our reconciled priorities. Methods: Data sources to evaluate success of the reconciliations included a survey of all partners regarding collaborative group processes, intervention participant recruitment and attendance and surveys of enrolled study participants assessing intervention outcomes. Results: While we successfully achieved our reconciled collaborative processes and implementation quality goals, we did not achieve our reconciled goals in study aim and design. Due in part to the randomized wait-list control group design chosen in the reconciliation process, we were not able to demonstrate overall efficacy of the intervention or offer timely services to families in need of support. Conclusion: Achieving the goals of participatory trials is challenging but may yield community and research benefits. Innovative research designs are needed to better support the complex goals of participatory trials.

Cultural Contributors to Smoking Susceptibility Outcomes Among Latino Youth: The Padres Informados/Jovenes Preparados Participatory Trial.

Padres Informados/Jovenes Preparados is a community-based participatory, family-focused tobacco prevention intervention for immigrant Latino families of adolescents. We conducted a participatory randomized controlled trial including 352 Latino families. Parents and youth in the intervention condition engaged in eight family skill building sessions. Participants completed baseline and 6-month postintervention surveys assessing smoking susceptibility and contextual factors. While the intervention did not affect smoking susceptibility overall, it resulted in lower smoking susceptibility among youth in families with less adherence to traditional Latino cultural values. This family cultural orientation is a key consideration for tobacco prevention interventions focused on Latino youth.

Honoring Roots in Multiple Worlds: Professionals' Perspectives on Healthy Development of Latino Youth.

PURPOSE: To obtain contextualized insights from professionals regarding factors that contribute to or inhibit the healthy development of Latino youth. METHOD: A community-engaged study in which semistructured in-depth interviews were conducted with 30 professionals who work extensively with Latino youth in urban clinics, schools, and other community-based settings. RESULTS: Every key informant expressed opinions regarding factors that contribute to healthy development of Latino youth, ranging from cultural identity and a sense of belonging to family connectedness and adult role models. Contributing and inhibiting factors were characterized by being either intrinsic to the individual (e.g., sense of belonging, hope) or extrinsic (e.g., family support and love, community support). CONCLUSION: Recognition of and appreciation for the importance of cultural influences in the lives of Latino youth is a critical starting point on which professionals must build to respectfully and successfully encourage healthy youth development. Factors that contribute to the healthy development of Latino youth range from cultural identity and cultural pride to family connectedness, adult role models, and a sense of belonging. In working with Latino young people, professionals must recognize and appreciate cultural influences as foundational to this population's health and well-being.

Sensorineural hearing loss following lumbar puncture, spinal anaesthesia or epidural anaesthesia: a case series and literature review.

BACKGROUND: Sensorineural hearing loss following spinal anaesthesia, epidural anaesthesia or lumbar puncture is a rare phenomenon that is thought to occur when reduced cerebrospinal fluid pressure is transmitted to the inner ear through an enlarged cochlear aqueduct. METHOD: This study presents two cases of sensorineural hearing loss following spinal anaesthesia for caesarean section as well as presenting results of a systemic review of the available literature using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Full-text articles from Medline, PubMed and Embase were used, as well as associated reference lists. Risk factors associated with poorer outcomes and an approach to management of this rare condition are also discussed. RESULTS: Twenty-one cases were identified. The literature was systematically reviewed showing presentations, investigations performed, treatments offered and outcomes. CONCLUSION: Sensorineural hearing loss following spinal anaesthesia, epidural anaesthesia or lumbar puncture is a rare occurrence that requires a high degree of clinical suspicion and prompt investigation and treatment.

Management of hypertension in the very old: aggressive reduction of blood pressure is harmful in most patients.

Arterial hypertension is particularly prevalent in the elderly and treatment is required according to the literature. Treatment in subjects between 65 and 80 years of age resembles by characteristics and results that obtained in younger population. The treatment of arterial hypertension in the very elderly differs in a relevant percentage of them. It is quite similar in those with a good physical fitness with or without cardiovascular disease. A series of factors as the presence of real sustained hypertension, orthostatic hypotension, frailty and disability, and the boundary of safety recommended by international recent guidelines analysed here are relevant to characterize a clearly elevated risk of complications in the remaining very elderly patients.

Intracellular calcium mishandling leads to cardiac dysfunction and ventricular arrhythmias in a mouse model of propionic acidemia.

Propionic acidemia (PA) is a rare metabolic disease associated with mutations in genes encoding the α and ß subunits of the enzyme propionyl-CoA carboxylase. The accumulation of toxic metabolites results in mitochondrial dysfunction, increased reactive oxygen species production and oxidative damage, which have been associated with the disease pathophysiology. Clinical symptoms are heterogeneous and include cardiac complications, mainly cardiac dysfunction and arrhythmias, which are recognized as one of the major life-threatening manifestations in patients. We aimed to investigate the molecular mechanisms underlying the cardiac phenotype using a hypomorphic mouse model (Pcca-/-(A138T)) that recapitulates some biochemical and clinical characteristics of PA. We demonstrate that Pcca-/-(A138T) mice present with depressed cardiac function along with impaired cell contractility when compared to the wild-type mice. Cardiac dysfunction in Pcca-/-(A138T) mice was associated with lower systolic Ca2+ release ([Ca2+]i transients), impairment in the sarcoplasmic reticulum (SR) Ca2+ load and decreased Ca2+ re-uptake by SR-Ca2+ ATPase (SERCA2a). These functional changes correlated well with the depressed activity of SERCA2a, the elevated ROS levels and SERCA2a oxidation rate in cardiomyocytes isolated from Pcca-/-(A138T) mice. In addition, decreased SR-Ca2+ load in Pcca-/-(A138T) cardiomyocytes was associated with increased diastolic Ca2+ release. The increase in Ca2+ sparks, Ca2+ waves and spontaneous [Ca2+]i transients in Pcca-/-(A138T) cardiomyocytes could be responsible for the induction of ventricular arrhythmias detected in these mice. Overall, our results uncover the role of impaired Ca2+ handling in arrhythmias and cardiac dysfunction in PA, and identify new targets for the development of therapeutic approaches for this devastating metabolic disease.

Microvascular injury and the kidney in hypertension.

Renal macrocirculation participates in the development of arterial hypertension. The elevation in systemic blood pressure (BP) can damage the kidney starting in the microcirculation. Established arterial hypertension impinge upon the large arteries and stiffness develops. As a consequence central BP raises and BP pulsatility appear and contribute to further damage renal microcirculation by direct transmission of the elevated BP.

[Cardiovascular risk study in patients with renin-angiotensin system blockade by means of the proteone of circulating extracellular vesicles]. / Estudio del riesgo cardiovascular en pacientes con bloqueo del sistema renina-angiotensina a través del proteoma de las vesículas extracelulares circulantes.

INTRODUCTION: Extracellular vesicles (EVs) are released to the bloodstream by certain cell types due to transport, activation and cell death processes. Blood count of EVs from platelet and endothelial origin has been proved to be a cardiovascular risk biomarker. Thus, EVs proteome might reflect the underlying cellular processes in hypertensive patients with albuminuria. MATERIAL AND METHODS: Protein content of circulating EVs was analyzed by liquid chromatography coupled to mass spectrometry. EVs were isolated by an ultracentrifugation protocol optimized in order to avoid contamination by blood plasma proteins. Purity of the isolated fraction was verified by electronic and confocal microscopy, and by flow cytometry. RESULTS: We hereby show a method to isolate circulating EVs from hypertensive patients with/without albuminuria with high yield and purity. Besides, we provide a reference proteome of the EVs of these patients, composed of 2,463 proteins, and prove that the proteins carried by these vesicles are associated with crucial processes involved in the inherent cardiovascular risk. CONCLUSION: The proteome of circulating EVs is an interesting source of indicators in the evaluation of cardiovascular risk in hypertensive patients with renin-angiotensin system blockage.

A Tale of Two Community Networks Program Centers: Operationalizing and Assessing CBPR Principles and Evaluating Partnership Outcomes.

BACKGROUND: Community Networks Program (CNP) centers are required to use a community-based participatory research (CBPR) approach within their specific priority communities. Not all communities are the same and unique contextual factors and collaborators' priorities shape each CBPR partnership. There are also established CBPR and community engagement (CE) principles shown to lead to quality CBPR in any community. However, operationalizing and assessing CBPR principles and partnership outcomes to understand the conditions and processes in CBPR that lead to achieving program and project level goals is relatively new in the science of CBPR. OBJECTIVES: We sought to describe the development of surveys on adherence to and implementation of CBPR/CE principles at two CNP centers and examine commonalities and differences in program-versus project-level CBPR evaluation. METHODS: A case study about the development and application of CBPR/CE principles for the Missouri CNP, Program for the Elimination of Cancer Disparities, and Minnesota CNP, Padres Informados/Jovenes Preparados, surveys was conducted to compare project versus program operationalization of principles. Survey participant demographics were provided by CNP. Specific domains found in CBPR/CE principles were identified and organized under an existing framework to establish a common ground. Operational definitions and the number of survey items were provided for each domain by CNP. CONCLUSION: There are distinct differences in operational definitions of CBPR/CE principles at the program and project levels of evaluation. However, commonalities support further research to develop standards for CBPR evaluation across partnerships and at the program and project levels.

Genetic predisposition to albuminuria is associated with increased arterial stiffness: role of elastin.

BACKGROUND AND PURPOSE: The Munich Wistar Frömter (MWF) rat strain represents an experimental model to study cardiovascular alterations under conditions of progressive albuminuria. The aim of this study was to evaluate the association between genetic predisposition to albuminuria and the development of arterial stiffness and/or vascular remodelling. EXPERIMENTAL APPROACH: Experiments were performed in mesenteric arteries from 12-week-old MWF, Wistar Kyoto (WKY) and consomic MWF-6(SHR) and MWF-8(SHR) rats in which chromosomes 6 or 8 associated with albuminuria from MWF were replaced by the respective chromosome from spontaneously hypertensive rats (SHR). KEY RESULTS: Incremental distensibility, wall stress and strain were reduced, and arterial stiffness was significantly increased in albuminuric MWF compared with WKY. Albuminuria suppression in both consomic strains was associated with lower ß-values in MWF-8(SHR) and MWF-6(SHR) compared with MWF. Moreover, elastin content was significantly lower in MWF external elastic lamina compared with WKY and both consomic strains. In addition, a reduction in arterial external and internal diameter and cross-sectional area was detected in MWF compared with WKY, thus exhibiting an inward hypotrophic remodelling. However, these alterations remained unchanged in both consomic strains. CONCLUSION AND IMPLICATIONS: These data demonstrate that albuminuria in MWF is associated with increased arterial stiffness due to a reduction of elastin content in the external elastic lamina. Moreover, inward hypotrophic remodelling in MWF is not directly associated with albuminuria. In contrast, we demonstrated that two major genetic loci affect both the development of albuminuria and arterial stiffness, thus linking albuminuria and impairment of mechanical properties of resistance arteries.

Mild caloric restriction reduces blood pressure and activates endothelial AMPK-PI3K-Akt-eNOS pathway in obese Zucker rats.

Genetic obesity models exhibit endothelial dysfunction associated to adenosine monophosphate-activated protein kinase (AMPK) dysregulation. This study aims to assess if mild short-term caloric restriction (CR) restores endothelial AMPK activity leading to an improvement in endothelial function. Twelve-week old Zucker lean and obese (fa/fa) male rats had access to standard chow either ad libitum (AL, n=8) or 80% of AL (CR, n=8) for two weeks. Systolic blood pressure was significantly higher in fa/fa AL rats versus lean AL animals, but was normalized by CR. Endothelium-dependent relaxation to acetylcholine (ACh, 10(-9) to 10(-4) M) was reduced in fa/fa AL compared to control lean AL rats (p<0.001), and restored by CR. The AMPK activator AICAR (10(-5) to 8·10(-3) M) elicited a lower relaxation in fa/fa AL rings that was normalized by CR (p<0.001). Inhibition of PI3K (wortmannin, 10(-7) M), Akt (triciribine, 10(-5) M), or eNOS (L-NAME, 10(-4) M) markedly reduced AICAR-induced relaxation in lean AL, but not in fa/fa AL rats. These inhibitions were restored by CR in Zucker fa/fa rings. These data show that mild short-term CR improves endothelial function and lowers blood pressure in obesity due to the activation of the AMPK-PI3K-Akt-eNOS pathway.

[23 observations of subungual exostosis]. / Veintitrés observaciones de exostosis subungueal.

Twenty-three cases of subungual exostosis are described, representing an incidence of 0.031% in our setting. Children and adolescents were most frequently affected, with a clear predominance of females. Eight lesions were observed in exceptional locations, three on the fingers and five on the third and fourth toes. The results of the surgical technique employed to excise the exostosis are evaluated.

[Infantile acro-localized papulo-vesicular syndromes]. / Síndromes pápulo-vesiculosos acrolocalizados infantiles.

Seven observations of papulo-vesicular acrolocated syndromes in males between 6 months and three years age. Clinical, histological and nosological aspects are commented in according to Gianotti's words and last reports about this disease.

Pharmacogenetic analysis of SNPs in genes involved in the pharmacokinetics and response to lopinavir/ritonavir therapy.

Despite the known benefits and the experienced use of lopinavir/ritonavir (LPV/r) in the management of HIV infection, important interindividual variability in the pharmacokinetics (PKs) and the response to treatment with standard doses of this drug has been observed. Host genetic factors have been recently suggested as being responsible for part of this variability as they may affect the expression and functional activity of many proteins involved in the kinetic behavior, the immune recovery or the adverse effects related to LPV/r. Here, we present a genetic association study in 106 HIV-infected individuals collected over a period of 5 years with the aim of identifying and confirming single nucleotide polymorphisms (SNPs) with a significant influence on the PK parameters of LPV/r, the immunovirological response or toxicity derived from treatment with the studied drug. Genotyping was performed by MALDI-TOF and KASPar; LPV/r plasma concentrations were quantified using high-performance liquid chromatography with an ultraviolet detection system and the PK parameters were estimated using Bayesian algorithms. Genetic association analysis was performed with SPSS. The most significant associations were found between SNPs in the dopamine receptor D3 gene and the PK of LPV/r. Additionally, other suggestive relationships were established between genetic factors and the response during treatment with this drug. Thereby, identifying HIV-infected individuals who are at increased risk of achieve non-optimal LPV/r plasma concentrations with the emergence of toxicity, drug resistance or absence of clinical response could be helpful as a tool to optimize the LPV/r-based antiretroviral therapy.

The developmental stages of a community-university partnership: the experience of Padres Informados/Jovenes Preparados.

BACKGROUND: Strong and sustained community-university partnerships are necessary for community-based participatory translational research. Little attention has been paid to understanding the trajectory of research partnerships from a developmental perspective. OBJECTIVE: To propose a framework describing partnership development and maturation based on Erikson's eight stages of psychosocial development and describe how our collaboration is moving through those stages. METHODS: Collaborators engaged in three rounds of iterative reflection regarding characteristics and contributors to the maturation of the Padres Informados/Jovenes Preparados (Informed Parents/Prepared Youth [PI/JP]) partnership. LESSONS LEARNED: Each stage is characterized by broad developmental partnership tasks. Conflict or tension within the partnership is often a part of achieving the associated tasks. The strengths developed at each stage prepare the partnership for challenges associated with subsequent stages. CONCLUSIONS: This framework could provide a means for partnerships to reflect on their strengths and challenges at a given time point, and to help understand why some partnerships fail whereas others achieve maturity.

Immigrant family skills-building to prevent tobacco use in Latino youth: study protocol for a community-based participatory randomized controlled trial.

BACKGROUND: Despite declines over recent years, youth tobacco and other substance use rates remain high. Latino youth are at equal or increased risk for lifetime tobacco, alcohol, marijuana, and other illicit drug use compared with their white peers. Family plays an important and influential role in the lives of youth, and longitudinal research suggests that improving parenting skills may reduce youth substance use. However, few interventions are oriented towards immigrant Latino families, and none have been developed and evaluated using a community-based participatory research (CBPR) process that may increase the effectiveness and sustainability of such projects. Therefore, using CBPR principles, we developed a randomized clinical trial to assess the efficacy of a family-skills training intervention to prevent tobacco and other substance use intentions in Latino youth. METHODS/DESIGN: In collaboration with seven Latino community-serving agencies, we will recruit and randomize 336 immigrant families, into intervention or delayed treatment conditions. The primary outcome is youth intention to smoke 6 months post intervention. The intervention consists of eight parent and four youth sessions targeting parenting skills and parent-youth relational factors associated with lower smoking and other substance use in youth. DISCUSSION: We present the study protocol for a family intervention using a CBPR randomized clinical trial to prevent smoking among Latino youth. The results of this trial will contribute to the limited information on effective and sustainable primary prevention programs for tobacco and other substance use directed at the growing US Latino communities. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01442753.