New insights into the role of angiotensin-converting enzyme obtained from the analysis of genetically modified mice

Angiotensin-converting enzyme (ACE) has been well-recognized for its role in blood pressure regulation. ACE is made by many tissues, though it is most abundantly expressed on the luminal surface of vascular endothelium. ACE knockout mice show a profound phenotype with low blood pressure, but also with hemopoietic and developmental defects, which complicates understanding the biological functions of ACE in individual tissue types. Using a promoter-swapping strategy, several mouse lines with unique ACE tissue expression patterns were studied. These include mice with ACE expression in the liver (ACE 3/3), the heart (ACE 8/8), and macrophages (ACE 10/10). We also investigated mice with a selective inactivation of either the N- or C-terminal ACE catalytic domain. Our studies indicate that ACE plays a role in many other physiologic processes beyond simple blood pressure control.     

Morphological Aspects and Viremia Analysis of BALB/c Murine Model Experimentally Infected with Dengue Virus Serotype 4

Ever since its brief introduction in the Brazilian territory in 1981, dengue virus serotype 4 (DENV-4) remained absent from the national epidemiological scenario for almost 25 years. The emergence of DENV-4 in 2010 resulted in epidemics in most Brazilian states. DENV-4, however, remains one of the least studied among the four DENV serotypes. Despite being known as a mild serotype, DENV-4 is associated with severe cases and deaths and deserves to be investigated; however, the lack of suitable experimental animal models is a limiting factor for pathogenesis studies. Here, we aimed to investigate the susceptibility and potential tropism of DENV-4 for liver, lung and heart of an immunocompetent mice model, and to evaluate and investigate the resulting morphological and ultrastructural alterations upon viral infection. BALB/c mice were inoculated intravenously with non-neuroadapted doses of DENV-4 isolated from a human case. The histopathological analysis of liver revealed typical alterations of DENV, such as microsteatosis, edema and vascular congestion, while in lung, widespread areas of hemorrhage and interstitial pneumonia were observed. While milder alterations were present in heart, characterized by limited hemorrhage and discrete presence of inflammatory infiltrate, the disorganization of the structure of the intercalated disc is of particular interest. DENV-4 RNA was detected in liver, lung, heart and serum of BALB/c mice through qRT-PCR, while the NS3 viral protein was observed in all of the aforementioned organs through immunohistochemistry. These findings indicate the susceptibility of the model to the serotype and further reinforce the usefulness of BALB/c mice in studying the many alterations caused by DENV.     

Exercise rehabilitation for neurogenic thoracic outlet syndrome: a scoping review

Exercise rehabilitation has been proposed for the management of Neurogenic Thoracic Outlet Syndrome (NTOS). To date there have been no reviews of the literature regarding exercise rehabilitation for NTOS and their proposed clinical rationale. Understanding various exercise protocols and their clinical rationale may help guide rehabilitation clinicians in their exercise selection when managing NTOS. A scoping review was conducted on exercise rehabilitation for NTOS from inception to March 2021 in the PubMed database. Forty-seven articles consisting of literature reviews, non-randomized control trials, prospective and retrospective cohort studies, case series, case studies and clinical commentaries met the inclusion criteria. This scoping review provides a broad overview of the most common exercise protocols that have been published and examines the purported clinical rationale utilized in the management of NTOS.     

Building political will for HIV response: an operational model and strategy options

As global programs for HIV response look to transfer responsibility and financing increasingly to country governments, the political will to take on these responsibilities becomes increasingly prominent. However, defining and assessing political will are problematic; it involves intent and motivation, and thus is inherently difficult to observe. It is intimately connected to capacity and is contextually embedded. This article describes an operational model of political will comprised of seven components that are observable and measurable. Two case studies illustrate the application of the model and shed light on the interconnections among commitment, capacity and context: South Africa and China. Strategy options to build political will for HIV response identify possible actions for both government and civil society. Political will as a concept is most usefully viewed as integrated within larger political and bureaucratic processes, as a product of the complex array of incentives and disincentives that those processes create. However, this conclusion is not a recipe for discouragement or inaction. Agent‐based conceptualizations of policy change offer a solid grounding for building political will that supports HIV policy and programs. Copyright © 2015 John Wiley & Sons, Ltd.     

Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome

Context  Analysis of predictors of cardiac events in hereditary long-QT syndrome (LQTS) has primarily considered syncope as the predominant end point. Risk factors specific for aborted cardiac arrest and sudden cardiac death have not been investigated. Objective  To identify risk factors associated with aborted cardiac arrest and sudden cardiac death during adolescence in patients with clinically suspected LQTS. Design, Setting, and Participants  The study involved 2772 participants from the International Long QT Syndrome Registry who were alive at age 10 years and were followed up during adolescence until age 20 years. The registry enrollment began in 1979 at 5 cardiology centers in the United States and Europe. Main Outcome Measures  Aborted cardiac arrest or LQTS-related sudden cardiac death; follow-up ended on February 15, 2005. Results  There were 81 patients who experienced aborted cardiac arrest and 45 who had sudden cardiac death; 9 of the 81 patients who had an aborted cardiac arrest event experienced subsequent sudden cardiac death. Significant independent predictors of aborted cardiac arrest or sudden cardiac death during adolescence included recent syncope, QTc interval, and sex. Compared with those with no syncopal events in the last 10 years, patients with 1 or 2 or more episodes of syncope 2 to 10 years ago (but none in the last 2 years) had an adjusted hazard ratio (HR) of 2.7; (95% confidence interval [CI], 1.3-5.7; P<.01) and an adjusted HR of 5.8 (95% CI, 3.6-9.4; P<.001), respectively, for life-threatening events; those with 1 syncopal episodes in the last 2 years had an adjusted HR of 11.7 (95% CI, 7.0-19.5; P<.001) and those with 2 or more syncopal episodes in the last 2 years had an adjusted HR of 18.1 (95% CI, 10.4-31.2; P<.001). Irrespective of events occurring more than 2 years ago, QTc of 530 ms or longer was associated with increased risk (adjusted HR, 2.3; 95% CI, 1.6-3.3; P<.001) compared with those having a shorter QTc. Males between the ages of 10 and 12 years had higher risk than females (HR, 4.0; 95% CI, 1.8-9.2; P = .001), but there was no significant risk difference between males and females between the ages of 13 and 20 years. Among individuals with syncope in the past 2 years, -blocker therapy was associated with a 64% reduced risk (HR, 0.36; 95% CI, 0.18-0.72; P<.01). Conclusions  In LQTS, the timing and frequency of syncope, QTc prolongation, and sex were predictive of risk for aborted cardiac arrest and sudden cardiac death during adolescence. Among patients with recent syncope, -blocker treatment was associated with reduced risk.      

Borg's rating of perceived exertion scales: do the verbal anchors mean the same for different clinical groups?

OBJECTIVE: To examine the interpretation of the verbal anchors used in the Borg rating of perceived exertion (RPE) scales in different clinical groups and a healthy control group. DESIGN: Prospective experimental study. SETTING: Rehabilitation center. PARTICIPANTS: Nineteen subjects with brain injury, 16 with chronic low back pain (CLBP), and 20 healthy controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Subjects used a visual analog scale (VAS) to rate their interpretation of the verbal anchors from the Borg RPE 6-20 and the newer 10-point category ratio scale. RESULTS: All groups placed the verbal anchors in the order that they occur on the scales. There were significant within-group differences ( P >.05) between VAS scores for 4 verbal anchors in the control group, 8 in the CLBP group, and 2 in the brain injury group. There was no significant difference in rating of each verbal anchor between the groups ( P >.05). CONCLUSIONS: All subjects rated the verbal anchors in the order they occur on the scales, but there was less agreement in rating of each verbal anchor among subjects in the brain injury group. Clinicians should consider the possibility of small discrepancies in the meaning of the verbal anchors to subjects, particularly those recovering from brain injury, when they evaluate exercise perceptions.     

'But is the difference clinically significant?'

The statement that a difference or change found in a research study is statistically significant is frequently met with the response, 'but is it clinically significant?'. This question seems entirely reasonable and uncontentious until one asks how to determine or define clinical significance. Significance must always have an object; significant to whom? Furthermore it needs elaboration; significant in what way? Once these questions are raised, it becomes apparent that the slick, apparently sensible question is in fact extremely difficult to answer and may have multiple answers: the patient may value being free of discomfort, but the payer may only value achieving less cost in long-term care and the clinician may wish to see change in activities. The use of this question by funding organizations may disadvantage rehabilitation. This Editorial explores the substance of this question, concluding that the question can only be answered by the individual patient concerned, and that research studies should perhaps explore more fully what is actually of significance to patients.