Patient and practice perspectives can inform development of team-based approaches to improving blood pressure control in primary care. We used a community-based participatory research approach to assess patient and practice perceptions regarding the value of team-based strategies for controlling blood pressure in a rural North Carolina population from 2010 through 2012.In-depth interviews were conducted with 41 adults with hypertension, purposely sampled to include diversity of sex, race, literacy, and blood pressure control, and with key office staff at 5 rural primary care practices in the southeastern US “stroke belt.” Interviews explored barriers to controlling blood pressure, the practice’s role in controlling blood pressure, and opinions on the use of team care delivery.Patients reported that provider strategies to optimize blood pressure control should include regular visits, medication adjustment, side-effect discussion, and behavioral counseling. When discussing team-based approaches to hypertension care, patients valued verbal encouragement, calls from the doctor’s office, and the opportunity to ask questions. However, they voiced concerns about the effect of having too many people involved in their care. Practice staff focused on multiple, broad methods to control blood pressure including counseling, regular office visits, media to improve awareness, and support groups. An explicit focus of delivering care as teams was a newer concept.When developing a team approach to hypertension treatment, patients value high-quality communication and not losing their primary relationship with their provider. Practice staff members were open to a team-based approach but had limited knowledge of what such an approach would entail. Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit.This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Preventing Chronic Disease. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Medscape, LLC designates this Journal-based CME activity for a maximum of 1 www.medscape.org/journal/pcd (4) view/print certificate.All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at Release date: April 24, 2014; Expiration date: April 24, 2015Upon completion of this activity, participants will be able to:Distinguish significant variables identified by patients as barriers to better blood pressure controlDistinguish significant variables identified by healthcare professionals as barriers to better blood pressure controlAnalyze what patients believe that healthcare professionals can do to help them improve their blood pressure controlEvaluate attitudes of patients and healthcare professionals toward team-based care for hypertensionEDITORSPreventing Chronic Disease. Disclosure: Rosemarie Perrin has disclosed no relevant financial relationships.Rosemarie Perrin, Technical Writer/Editor, CME AUTHORCharles P. Vega, MD, Associate Professor and Residency Director, Department of Family Medicine, University of California, Irvine. Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.AUTHORS AND CREDENTIALSDisclosures: Katrina E. Donahue, MD, MPH; Maihan B. Vu, DrPH, MPH; Jacqueline R. Halladay, MD, MPH; Cassandra Miller, MPH; Beverly A. Garcia, MPH; Doyle M. Cummings, PharmD; Crystal W. Cene, MD, MPH; Alan Hinderliter, MD; Edwin Little, MD; and Marjorie Rachide, FNP have disclosed no relevant financial relationships.Darren DeWalt, MD, MPH, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Merck.Affiliations: Katrina E. Donahue, Maihan B. Vu, Jacqueline R. Halladay Cassandra Miller, Beverly A. Garcia, Crystal W. Cene, Alan Hinderliter, Darren DeWalt, University of North Carolina, Chapel Hill, North Carolina; Doyle M. Cummings, East Carolina University, Greenville, North Carolina; Edwin Little, Marjorie Rachide, primary care practices in eastern North Carolina.Hypertension affects more than 68 million US adults and contributes to the excess mortality from heart disease, stroke, and chronic kidney disease . DespiteBlood pressure control initiatives that incorporate community-based participatory research (CBPR) approaches have been effective –11. CBPRThis study was part of a 5-year cardiovascular health intervention in a county and surrounding area in the heart of the stroke belt in rural North Carolina, where stroke mortality rates are 150% of the national average . Key praEligible participants were English-speaking patients aged 18 years or older) diagnosed and managed with hypertension who were attending 1 of 5 primary care practices in rural eastern North Carolina. Six to 10 patients per practice were eligible. Hypertension was defined as systolic blood pressure greater than140 mm Hg or diastolic blood pressure greater than 90 mm Hg . PatientAll area primary care practices (n = 8) in the study area were invited to join a collaborative effort to improve blood pressure control; 5 agreed to participate. Reasons for declining participation were lack of time or resources. To complement patient perspectives, providers and staff of each practice participated in an in-depth interview. The interviews within each practice were conducted in 2 groups; 1 with practice leadership  and the other with practice staff  to maximize diversity of perspectives and minimize single-source bias.Face-to-face semistructured interviews explored domains of overall health concerns, barriers to optimal blood pressure control, and perceptions of improving primary care delivery for hypertensive patients . We askeInterview transcripts were imported into ATLAS.ti 6.2 , and the study team created a codebook with operational definitions based on interview guide questions. Inductive coding techniques  and the Our final sample included interviews with 41 patients and 31 practice staff . ProvideOf the 41 patients who participated in the interviews, 41% reported their blood pressure was at the right level less than half the time. When patients were asked, “What makes it hard to keep your blood pressure under control?”, 2 main barriers were identified. First, patients said it was challenging to take medications regularly. Approximately 36% said they had missed a pill at least once in the past week. For some, remembering to take medications as scheduled was difficult. Some patients could not afford their medications. Others mentioned that they were “tired” of having to take medicine. This was influenced by the number and frequency of pills. As one patient said, “You know, what’s hard . . . to me really is sometimes I get tired [of taking medicine]. And I do know that I do need to take it. And sometimes I might not take it every day at the same time.” A second barrier for patients centered on their diet. They said that an unhealthy diet that used too much salt and overeating affected blood pressure levels. Patients appeared to recognize the link between nutrition and blood pressure, but they admitted that making behavior changes was challenging. For example, as one patient stated, “Sometimes you might overeat something you know you’re not supposed to be eating like fried foods. Drinking a little bit too much, and too much salt. Food got enough salt in it already. Gotta learn how to eat it with other seasoning.” Both provider and practice staff interviews showed agreement that patients’ inadequate adherence with medications affected their blood pressure. Providers recognized that patients did not take their medications because of cost or that they skipped doses to save money:Well, I’ll ask [them] directly about it. Are you taking [them] everyday? Are you taking [them] twice a day like you’re supposed to? . . . For example, I had a patient say, ‘I take the morning stuff but I may skip a dose.’ By the same token, I’ve also had patients say, ‘Yeah, I’ve been taking it every day,’ but a 1-month prescription lasts 3 months. You know no one gave [them] a refill so what happened there?” (Practice staff)There was consensus among patients, providers, and office staff that inadequate medication adherence and poor eating habits were important barriers to blood pressure control. However, from the provider and staff perspective, the larger barrier was patients’ lack of understanding of the importance of hypertension control. Practice staff reported that some patients held certain beliefs that may affect their treatment adherence. If the patients felt well, they did not make controlling their blood pressure as a high priority. As one provider explained, “I think patients really focus on symptoms, and when they don’t have symptoms, they are not sick. . . . If they feel very well with a blood pressure of 180 over 100, it’s very hard for me to sell the blood pressure medication, especially if it’s expensive and they had to pay for it. So I wish that high blood pressure would cause pain, because then patients would be buying.” (Provider)Another key barrier mentioned by providers and practice staff was patients’ belief that little could be done to prevent hypertension and its consequences. Providers and staff noted that some patients considered hypertension a problem that “runs in the family” or is “genetic” and were convinced that high blood pressure was inevitable. Practice staff shared, “We ask them their family history. They give their history and say ‘I’m sure I’m gonna have it too.’ They do think that, no matter what they do, they’re gonna get it cause their momma had it, their daddy had it, their grandma had it.” (Practice staff)Patients identified several strategies that doctors or nurses could use to help them control blood pressure. At the top of the list were regular office visits. They valued the periodic checkups during which providers could make adjustments in prescribed medications. For example, 1 patient explained how providers could help: “The nurse practitioner at (the practice) saw a need to change it, and I’ve always wanted like a diuretic for the fluid because I feel like that would help me. . . . She saw the need to add that right in with my blood pressure medicine. That’s good if a doctor would monitor (my medications), see the need if it’s not working or you need to change, and change you over on that.” Patients saw an important role for providers with antihypertensive medication management. They felt their doctors or nurses could help with medication adherence by prescribing medications that were “correct” for high blood pressure or “suited each individual.” Accessibility of refills and cost were also important factors related to adherence.A common theme that emerged from patient and provider interviews was the value of communication. Patients said it was important to have good communication with their doctors and nurses to keep their blood pressure under control. They wanted their providers to ask about how medications were working, to talk about possible side effects, and to give them information on managing their blood pressure. Providers echoed the importance of communicating with patients and observed that it was largely their job to “educate, educate, educate.” When providers and staff were asked “Where else should your patients get this message?” they discussed additional external communication strategies to reach patients. Providers mentioned the potential use of television, radio, and other media outlets given the credibility of these sources in the eyes of patients. One provider said that for his patients, “whatever comes on TV is believable.”“TV is where [patients] see a lot of the things that they’ll mention when they come in, even medications that they want to take. When they come in, they’ll say, ‘I saw this on TV. That’s something that would help me.’ They can’t read, but they can at least see TV, and they hear what it’s telling them so TV is a good resource for some that are undereducated and can’t read . . . for those that can’t [read], TV is probably where they get most of their information.” (Provider)Support groups and testimonies from individuals with high blood pressure were additional communication strategies that were deemed beneficial in influencing behavior change. Both practice and patient interviews showed agreement that although practices play an important role in blood pressure control, ultimately treatment success was up to the patient: “The doctor can prescribe or do whatever he needs to do. But if the patient’s not willing to go along with the program, then it’s not gonna do any good, regardless of what the doctor do.” During the interview, patients were given an example of team-based care . PatientFor some practices, the explicit use of teams in care delivery was a new concept. Providers and staff were accustomed to the physicians providing most of the patient care, although some practices were involving nurses more in a team-like approach, although not as a formal process of care delivery. “I take time to do it myself, but I may ask my nurse to sit down with a patient and talk to him about medicine or some other thing or give them literature. Or call them and see how they’re doing and emphasize the particular point of their treatment.” [Provider]Staff members also echoed these sentiments and noted some involvement between visits, specifically when a provider wanted to make a change in a patient’s medication regimen. “Sometimes [providers will] give us a message to send to the patient, and we’ll contact them that way. Like if there’s a change to the medication, we’d be the ones normally to talk to them.” [Practice staff]However some providers felt uneasy about giving up control and allowing other staff members to be involved in the use of a medication algorithm. “I’m comfortable with a nurse being involved in discussions with patients about medication changes that may be necessary to enhance a patient’s blood pressure control, but I would want to sign it (the new prescription) before it goes out . . . because I’m also liable . . . or without being in the communication but I would sign it before it goes out.”(Provider)We conducted structured interviews of patients and practice staff in 5 primary care practices to determine key components of an effective hypertension management intervention. Important factors in improving blood pressure control included adherence to medication, dietary habits, hypertension beliefs, and regular office visits. Patients may already understand much of what is required to control blood pressure but personal, community, and health system factors limit their ability to make sustained behavior changes. In this context, new strategies that are sensitive to both patient and community needs are needed. Our study suggests team-based care approaches that enhance efforts at improving medication adherence, lifestyle management, and communication with their provider could address patients’ concerns about blood pressure control.Team-based care models are being implemented across the country –25, and CBPR is an innovative approach to tailoring office-based interventions to improve hypertension care. This process engages both practices and community members in creating unique strategies to improve health care delivery that may be evidence-informed but uniquely tailored to local context. CBPR more often than not considers community-based or faith-based organizations as “the community” and as key stakeholders; health care providers are usually not considered the main community stakeholders in CBPR ,31. Our Findings from the CBPR approach have encouraged our research team to focus on how team-based care is implemented. For example, we created a standardized template for care delivery that allows practices to incorporate team strategies at each patient visit for hypertension care. We helped practices implement team approaches by providing on-site coaching and by gradually adding team care elements to care processes once previous activities have been vetted.Our study has several limitations. The study was limited to a sample of patients and primary care practices in a traditional rural community where team-based care is a new concept. Additionally, selection bias was a risk, because many patient participants were identified by the practices. However, the benefit of purposeful sampling allowed us to obtain information-rich cases. Finally, it is too early to tell whether using CBPR has resulted in improved care and better blood pressure control. Patients and practices in our study were open to exploring the challenges to blood pressure control and to considering multiple evidence-based approaches for improving hypertension management, including the use of team-based care. When developing a team-based approach to hypertension treatment, CBPR is a useful strategy to engage patients and practices in work to ensure that interventions are informed by local context. It is hoped that locally informed intervention design will then pave the way for sustained care delivery processes long after the support from research investigators and funds has ended.


Obstructive sleep apnoea (OSA) is frequently observed in severe asthma but the causal link between the 2 diseases remains hypothetical. The role of OSA-related systemic and airway neutrophilic inflammation in asthma bronchial inflammation or remodelling has been rarely investigated. The aim of this study was to compare hallmarks of inflammation in induced sputum and features of airway remodelling in bronchial biopsies from adult patients with severe asthma with and without OSA.An overnight polygraphy was performed in 55 patients referred for difficult-to-treat asthma, who complained of nocturnal respiratory symptoms, poor sleep quality or fatigue. We compared sputum analysis, reticular basement membrane (RBM) thickness, smooth muscle area, vascular density and inflammatory cell infiltration in bronchial biopsies.In total, 27/55 patients (49%) had OSA diagnosed by overnight polygraphy. Despite a moderate increase in apnoea-hypopnoea index , the prMild OSA in patients with severe asthma is associated with increased proportion of neutrophils in sputum and changes in airway remodelling. Severe asthma is a morbid condition, affecting about 3.6% to 10% of people with asthma. The probability of OSA is high for 26% of patients with severe asthma  and poorDespite the well-described association between asthma and OSA, the mechanisms that link the 2 diseases remain hypothetical. Obesity or gastroesophageal reflux disease (GERD) may have a role, with reciprocal interactions. Recently, the role of OSA-associated changes in airway inflammation and remodelling has been suggested: in ovalbumin-sensitized rats, chronic intermittent hypoxia modulated both inflammation (by decreasing eosinophil proportion) and remodelling in distal airways . In humaThe aim of this study was to compare features of airway inflammation and remodelling in both induced sputum and bronchial biopsies from patients with severe asthma with and without OSA.The study was prospectively conducted in adult patients referred to our Severe Asthma Clinic who were consecutively recruited during a 12-month period. The asthma diagnosis was confirmed by 2 pulmonary physicians trained in difficult-to-treat asthma. All patients with severe uncontrolled asthma according to Global Initiative for Asthma (GINA) guidelines and who complained of nocturnal respiratory symptoms , poor sleep quality and/or diurnal symptoms (fatigue or sleepiness) were enrolled in a sleep study. Patients receiving continuous positive airway pressure (CPAP) treatment at the time of the initial appointment and smokers or ex-smokers (>10 packs/year) were excluded. Fibre-optic bronchoscopy and induced sputum analysis are routinely performed for patients with severe asthma in our centre and are proposed to all patients investigated for difficult-to-treat asthma.Asthma control was evaluated by the Asthma Control Test. Atopy was defined as a positive skin prick test result and/or positive for specific IgE in the blood. Nasal polyposis was diagnosed by a laryngologist. Diabetes, depression and hypertension were considered if specific treatment was required. Data from the visit closest to the night recording were used.All patients gave written informed consent for follow-up in the COBRA cohort (Cohorte Obstruction Bronchique et Asthme) according to the procedure validated by the local Ethics Committee (Comité de Protection des Personnes d’Ile de France), which approved the study. Consent is usually retained in the patient’s medical file.Nocturnal polygraphy was performed with a portable, computerised data-acquisition system . The system records oronasal airflow from nasal pressure  and a mouth thermistor , chest and abdominal effort by inductance plethysmography, pulse oximetry, snoring, actimetry and body position . RecordiApnoea was defined as a decrease of > 90% in nasal airflow, lasting at least 10 s. Hypopnea was defined by ≥ 30% decrease in nasal flow associated with 4% desaturation (recommended definition) or ≥ 50% decrease associated with 3% desaturation or an arousal , as previously described .The number of apnoea-hypopnoea events per hour (AHI) was determined after the exclusion of periods with movements, considered periods of wakefulness. Sleep-disordered breathing was diagnosed as AHI ≥ 5/h. Nocturnal polygraphy was performed at least 2 weeks after recovery from any asthma exacerbation or intervention. The Epworth score and depression score  were collected. The 20 items in the CES-D scale measure symptoms of depression in 9 different groups on a scale from “0”  to “3” (nearly every day). A total score ≥ 17 for men and ≥ 24 for women indicates depression symptoms. Fatigue was measured by the Pichot questionnaire , consist2 were determined after α-actin and CD31 immunostaining, respectively. Eosinophil cationic protein (eosinophils), elastase (neutrophils), CD3 (lymphocytes) and tryptase (mast cells) were detected in bronchial submucosa by immunohistochemistry with the alkaline phosphatase method, and stained cells were counted were measured in a zone of 60-μm depth along the length of the basement membrane.Four biopsies were collected for each patient during fibre-optic bronchoscopy as described . BiopsieInduced sputum was analyzed, and macrophages, eosinophils and neutrophils were counted as described . In addiP≤0.05 was considered statistically significant. Original data are available as an Excel file in Data were analysed by using GraphPad Prism 5.01  and are expressed as number (%) or mean±SEM and range. Comparisons between 2 groups involved the Mann–Whitney test and Kruskall–Wallis test for continuous variables. Pearson chi-square test was used for comparing categorical variables. Univariate correlation (Spearman's rank-order method) was used for correlation analysis. In total, 55 patients consecutively referred for difficult-to-treat asthma and complaining of nocturnal symptoms, underwent overnight polygraphy . All had2 value was significantly lower for OSA than non-OSA patients. The Epworth score and depression score did not differ between OSA and non-OSA patients. The proportion of patients with Epworth score ≥11 was similar in the 2 groups. The mean Pichot fatigue score was higher for OSA than non-OSA patients (p = 0.006) and the proportion with a Pichot score ≥20 was higher for OSA patients (p = 0.04).Nocturnal polygraphy was performed in the hospital for 15 patients (9 non-OSA and 6 OSA) and at home for 40. Patient characteristics did not differ by the location of testing. In total, 27/55 patients (49%) had OSA. Among them, 9 patients (33%) had AHI ≥15/h and 3 had AHI ≥30/h . All patOSA and non-OSA patients did not differ in age, sex ratio, BMI, lung function, asthma control test or treatments , except A total of 31 patients underwent fibre-optic fibroscopy and bronchial biopsies. Reasons for not performing these tests are in Among patients who had fibre-optic bronchoscopy, 29 underwent induced sputum analysis . InducedOSA patients showed a higher proportion of neutrophils along with higher IL-8 level in sputum as compared with non-OSA patients, but IL-5 and VEGF levels were higher in non-OSA than OSA patients . As expeElastase activity in sputum was low (under the detection level in many patients) and did not differ between the OSA groups. MMP-9 level in sputum was higher in OSA than non-OSA patients  and was 2, minimal SpO2, desaturation index) and other features of remodelling  or inflammation assessed in sputum or biopsies.RBM thickness was not correlated with eosinophil or neutrophil proportion in sputum or biopsies but was negatively correlated with OSA severity, as assessed by AHI  . In addiUsing induced sputum and bronchial biopsies, we found that OSA in patients with severe asthma is associated with specific features of airway inflammation and remodelling. The disease was characterized by a higher proportion of neutrophils and a lower proportion of macrophages as compared with non-OSA patients, elevated levels of IL-8 and MMP-9 in sputum, and thinner bronchial basement membrane, which was inversely correlated with AHI, a measure of OSA severity. These data suggest that OSA, although mild in most patients with asthma, may modulate airway inflammation and remodelling in the disease.in vitro to chronic intermittent hypoxia, produce IL-8, contributing to neutrophil recruitment [The hallmark of neutrophilic inflammation in airways of OSA patients was previously reported in induced sputum and exhaled breath condensate –18 and aruitment . Of noteruitment . In asthruitment  and contruitment . Smokersruitment . In asthruitment  25]. Th. Thin viOSA-related inflammation can drive tissue remodelling, mainly through increased oxidative stress. In the heart, atrial and ventricular remodelling is observed in OSA patients and can be reversed by continuous positive pressure. Myocyte hypertrophy, fibrosis and increased apoptosis are observed in animal models of chronic intermittent hypoxia . OSA patThe last observation in our study that may be related to OSA-associated neutrophilic inflammation is the greater prevalence of hypertension and cerebrovascular diseases in severe asthmatics with OSA without OSA. The causal association between OSA and cardiovascular disease has been linked to oxidative stress and intermittent hypoxia-induced vascular inflammation  and charTogether, all these findings support that patients with severe asthma with OSA may show a specific phenotype of neutrophilic asthma that needs to be identified to better target treatment. Indeed, increasing steroids doses may have a potential deleterious effect in the setting of neutrophilic /non-eosinophilic inflammation and should be cautioned in this setting. Steroids contribute to neutrophilic airway infiltration by decreasing neutrophil apoptosis, which could contribute to increased OSA risk in this population  and to iThe association between asthma and OSA is bidirectional, since asthma may contribute to OSA occurrence  and the The contribution of nasal obstruction in airway obstruction during OSA has been suggested in patients without asthma  and withOur study contains some limitations. First not all severe asthmatics from our clinic were explored but only those who complained of nocturnal symptoms or symptoms usually related to poor sleep . OSA was diagnosed in about half of these patients with uncontrolled severe asthma. This rate of OSA is high as compared to the general population, especially considering that most of our patients were female, but the proportion was lower than in a previous study of patients with severe asthma , 43, 44.To conclude, we demonstrate that OSA is associated with specific changes in airway inflammation associated with predominant neutrophilic inflammation with high levels of MMP-9 and IL-8 and low RBM thickness in patients with severe asthma. Whether CPAP, a specific treatment for this subgroup of patients, could affect these structural changes and therefore the asthma course remains to be investigated.S1 Original Data(XLS)Click here for additional data file.


Significant vascular sympathetic BRSinc and vascular sympathetic BRStotal slopes were obtained for 10 participants at both times of day. There was no significant difference in vascular sympathetic BRSinc between morning (−2.2 ± 0.6% bursts/mmHg) and afternoon  sessions. Similarly, vascular sympathetic BRStotal did not differ significantly between the morning (−3.0±0.5 AU/beat/mmHg) and afternoon . It is concluded that in healthy, young individuals baroreflex modulation of MSNA at rest does not differ between the morning and afternoon. The results indicate that recording MSNA at different times of the day is a valid means of assessing sympathetic function.The incidence of cardiovascular events is significantly higher in the morning than other times of day. This has previously been associated with poor blood pressure control via the cardiac baroreflex. However, it is not known whether diurnal variation exists in vascular sympathetic baroreflex function, in which blood pressure is regulated via muscle sympathetic nerve activity (MSNA). The aim of this study was to compare vascular sympathetic baroreflex sensitivity (BRS) in the same participants between the morning and afternoon. In 10 participants (mean age 22 ± 2.9 years), continuous measurements of blood pressure, heart rate and MSNA were made during 10 min of rest in the morning (between 0900 and 1000 h) and afternoon (between 1400 and 1500 h). Spontaneous vascular sympathetic BRS was quantified by plotting MSNA burst incidence against diastolic pressure (vascular sympathetic BRS The incidence of cardiovascular and cerebrovascular events is higher in the morning than at any other time of day Elliott, . The morThe baroreflex provides the principle means of buffering acute changes in blood pressure. It operates as a negative feedback loop responding to the activation of stretch sensitive receptors in the carotid sinus and aortic arch (baroreceptors), which project to the nucleus tractus solitarious (NTS) in the medulla via the glossopharyngeal and vagus nerves  in young healthy adults. When examining cardiac BRS we have previously employed the modified Oxford method, which is a pharmacological method for assessing baroreflex function  and those who smoked or took regular medication. Participants were instructed to abstain from alcohol or vigorous exercise 24 h prior and to not consume any caffeine on the day of both morning and afternoon experiments. Diet was otherwise uncontrolled; subjects studied in the morning had eaten their normal breakfast and those in the afternoon their typical lunch. The changes in hormone levels during the menstrual cycle have been shown to affect MSNA and vascular sympathetic BRS  inserted percutaneously at the level of the fibular head. Multi-unit neural activity was amplified  using an isolated amplifier  and stored on computer (10-kHz sampling) using a computer-based data acquisition and analysis system . A root-mean-square (RMS) processed version of this signal was computed, with a moving average of 200 ms. Blood pressure was recorded non-invasively via a finger cuff . Heart rate was recorded via electrocardiogram . Respiration was measured via a strain-gauge transducer  wrapped around the chest.Participants completed two trials, one beginning at 0800 h and one at 1300 h on two separate days. This was to ensure that, based on time to set up and obtain high quality nerve recordings (approximately 60–90 min), data collection coincided with the times of day associated with high (0900–1000 h) and low occurrence (1400–1500 h) of cardiovascular events during daylight hours  for systolic pressure, diastolic pressure, R-R interval, and MSNA. A custom-written LabView program was used to detect and measure the area of individual bursts of MSNA. The numbers of bursts per minute (MSNA burst frequency) and per 100 heartbeats (MSNA burst incidence) were determined for each individual.inc” in order to differentiate it from other methods of determining vascular sympathetic BRS.Vascular sympathetic BRS was quantified using methods previously described by Kienbaum et al. . For alltotal” in order to differentiate them from the MSNA burst incidence method for assessing vascular sympathetic BRS.The largest MSNA burst during the 10-min rest period was assigned a value of 1000 and the remaining MSNA bursts were calibrated against this to allow measures of MSNA to be normalized to individual resting values  and taking the average slope value for “up” sequences (cardiac BRSup), “down” sequences (cardiac BRSdown), and all sequences pooled (cardiac BRSpooled). Values of cardiac BRS were accepted when the number of sequences was ≥3 for both up and down sequences.Cardiac BRS was assessed using the sequence method, in which “up” and “down” sequences are identified. “Up” sequences consisted of three or more consecutive cardiac cycles for which there is a sequential rise in both systolic blood pressure and R-R interval. “Down” sequences consisted of three of more cardiac cycles for which there is a sequential fall in systolic blood pressure and R-R interval . For all statistical tests, a probability level of P < 0.05 (two-tailed) was regarded as significant. All values are expressed as means and standard error (SE).Vascular sympathetic BRS values were compared between morning and afternoon using Student's inc, vascular sympathetic BRStotal, and cardiac BRS values for both the morning and afternoon were acquired for all 10 participants. The mean age of these young, healthy participants was 22 ± 1 year and mean body mass index (BMI) was 23.8 ± 1.0 kg/m2.Twelve participants were recruited for the study. One participant, who reported a family history of hypertension, had a resting blood pressure of 150/82 mmHg and was therefore excluded from the study. Nerve recordings were successfully obtained in all experiments except one afternoon experiment; this participant was excluded from the analysis. Baroreflex sensitivity was therefore assessed on two occasions for 10 participants. Significant vascular sympathetic BRSP = 0.02). However, there were no significant differences in resting diastolic pressure, heart rate or MSNA between the morning and afternoon (P > 0.05). Figure Resting cardiovascular variables for the 10 participants at both times of day are presented in Table inc between the morning and afternoon sessions (P = 0.68). Similarly, there was no significant difference in vascular sympathetic BRStotal between the morning and afternoon (P = 0.89). These results are summarized in Table There was no significant difference in vascular sympathetic BRSpooled, cardiac BRSup, or cardiac BRSdown between morning and afternoon sessions , “up” sequences  or “down” sequences .There was no significant difference in cardiac BRSIn this study diurnal variation in vascular sympathetic baroreflex sensitivity has been examined for the first time. Previous research indicates that there are two sites for modulation of MSNA: one responsible for burst incidence and the other burst amplitude . All authors were involved in the design of the experiments and/or acquisition and analysis of the data, as well as the writing or editing of this manuscript. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work.No authors (or their institutions) of this manuscript received payment or services from a third party for any aspect of this manuscript. We have no financial relationships with entities perceived to influence the research presented in this manuscript, nor do we have patents or copyrights to declare. We are unaware of any other potential relationships or activities that might have influenced the writing of this manuscript.


Hypertension is a modifiable risk factor for cognitive impairment, although the relationship between hypertension and cognitive impairment is not fully understood. The objective of this study was to investigate the effect of age on the relationship between blood pressure and cognitive impairment.Blood pressure and global cognitive function information was collected from 1799 participants (age 40–85) who lived in a village in the suburbs of Xi'an, China, during in-person interviews. Cognitive impairment was defined as a Mini-Mental State Examination (MMSE) score lower than the cutoff value. The effect of age on the relationship between blood pressure parameters  and cognitive impairment was analyzed by logistic regression models using interaction and stratified analysis. Blood pressure and age were regarded as both continuous and categorical data.P = 0.011); however, the age by SBP interaction term was negatively correlated with cognitive impairment , indicating that the relationship between SBP and cognitive impairment was age-dependent (OR = 1.130×0.989(age-55.5) per 10mmHg,40 ≤age≤85). When the blood pressure and age were considered as binary data, the results were similar to those obtained when they were considered as continuous variables. Stratified multivariate analysis revealed that the relationship between SBP (when regarded as continuous data) and cognitive impairment was positive for patients aged 40–49 years  and 50–59 years , whereas it tended to be negative for patients aged 60–69 years  and ≥70 years . Results similar to those for SBP were obtained for DBP, MABP and HBP as well. Subsequently, SBP, DBP and MABP were transformed into categorical data , and the stratified multivariate analysis was repeated. This analysis showed that the age-dependent association continued to exist and was especially prominent in the SBP≥160 mmHg, DBP≥90 mmHg and MABP≥110 mmHg groups.A total of 231 participants were diagnosed as having cognitive impairment based on our criteria. Interaction analysis for the total population showed that SBP (when regarded as continuous data) was positively correlated with cognitive impairment (OR = 1.130  per 10mmHg, Elevated blood pressure is positively correlated with cognitive impairment in the middle-aged, but this positive association declines with increasing age. These results indicated that specific blood pressure management strategies for various age groups may be crucial for maintaining cognitive vitality. As a leading risk factor for stroke, hypertension is also an important risk factor for vascular cognitive impairment (VCI) . TraditiThe study was designed as a cross-sectional study to evaluate the effect of age on the relationship between blood pressure and cognitive impairment in a Chinese population. From October 8, 2014, to March 30, 2015, we selected individuals from a village in the suburbs of Xi'an, which is located in northwestern China, as our research sample. The population composition of this village is similar to that of rural areas of Xi'an, and the villagers’ lifestyles are similar to the lifestyles of residents of rural areas of Xi'an. Therefore, this sample reasonably represents rural areas of Xi'an, China. Our inclusion criteria were the following: 1) 40 or more years old; 2) permanent resident of the village, meaning that the subject was currently a resident of the village and had lived there for more than 3 years; 3) agreed to participate in the study and completed the questionnaire survey.Individuals who suffered from medical conditions that could interfere with normal cognitive function but that were not caused by neurodegeneration as well as those with VCI were excluded. More specifically, medical conditions that resulted in exclusion included brain trauma, past craniocerebral operation, nervous system tumor, congenital malformation of the nervous system, epilepsy , organic psychosis, schizophrenia, affective psychosis, congenital mental retardation, untreated hypothyroidism, secondary hypertension, and acute or end-stage chronic disease. Individuals with a history of stroke were also excluded. The study protocol and the selection of subjects are shown in Global cognitive function was evaluated in a quiet room using the Mini-Mental State Examination (MMSE). Examiners accepted uniform training before the beginning of the study, and consistency between the examiners (kappa: 0.76–1) was evaluated in a pilot study. We chose an MMSE score lower than the cutoff value set by Ming-yuan Zhang et al.  as the cBlood pressure was measured 2 times in a seated position using a mercury sphygmomanometer. The measurements were conducted after 10 minutes of rest. In addition, no vigorous exercise was allowed during the 30 minutes before each measurement. The mean of the 2 measurements was used as the blood pressure for each participant. High blood pressure (HBP) was defined as systolic blood pressure (SBP)≥140 mm Hg and/or diastolic blood pressure (DBP)≥90 mmHg . Four vaCovariates included demographic information , lifestyle , comorbidities , physical examination parameters  and biochemical test parameters . Fasting blood glucose and fasting blood lipids were tested by the biochemical laboratory of the First Affiliated Hospital of Xi'an Jiao Tong University.P value of less than 0.05 was considered significant, and tests were 2 sided. The characteristics of the participants were reported as the mean±SD for approximately normally distributed continuous variables, as the median  for severely skewed continuous variables, and as numerical values (percentages) for categorical variables. In the univariate analysis, differences were evaluated using t tests for normally or approximately normally distributed variables, rank tests for severely skewed variables and χ2 tests for categorical variables. In the multivariate analysis, we calculated the ORs and 95% confidence intervals (CIs) of the blood pressure parameters and interaction terms using logistic regression models to correct for confounding factors. In the logistic regression models, cognitive impairment (yes or no) was the dependent variable, and the blood pressure parameters and confounding factors were independent variables.Statistical analysis was performed with SPSS 18.0 statistical software. A To understand the effect of age on the relationships between the blood pressure parameters and cognitive impairment, the following analysis steps were performed for the data collected from the entire population. First, we conducted the univariate analysis to test for correlations between the 4 blood pressure parameters and cognitive impairment. Potential correlations between the confounding factors and cognitive impairment were also analyzed. Then, based on the results of the univariate analysis, we established multivariate models to correct for the confounding factors. Interaction and stratified analysis were critical parts of the multivariate analysis. For the former, age by blood pressure parameter interaction terms  were included in the multivariate logistic regression models established for the total population. For the stratified analysis, we divided the total population into 4 subgroups according to age  and established a multivariate model for every subgroup to evaluate whether the correlations changed with age.The participants included in this study were aged 40–85 years (mean 55.5±9.9 years) and were divided into 4 subgroups according to age . SBP (131.73±18.39 mmHg), DBP (81.90±10.17 mmHg) and MABP (98.51±11.97 mmHg) were approximately normally distributed. A total of 776 subjects met the criteria for HBP. The MMSE scores [27] showed a skewed distribution, and 231 participants were diagnosed as having cognitive impairment according to the criteria described above. Detailed information about the total population and each age-based subgroup is presented in In the total population, there were significant differences in the prevalence of cognitive impairment between the two groups based on SBP, DBP, MABP, and HBP . The ageTo better understand the relationship between the blood pressure parameters and cognitive impairment, we established 4 logistic regression models for the total population to correct for potential confounding factors . The selP = 0.011). However, the age by SBP interaction term was negatively correlated with cognitive impairment . Thus, the OR for SBP was 1.130 per 10mmHg for the participants of average age  but decreased to 0.989 times its prior value with each additional year. In other words, the OR for SBP for a subject of a specific age can be expressed by OR = 1.130×0.989(age-55.5) per 10mmHg for 40≤age≤85. The relationships between DBP and cognitive impairment and between MABP and cognitive impairment were similar to that between SBP and cognitive impairment  and age on cognitive impairment in the total population; detailed information of the model is shown in P = 0.018). However, the interaction term age by SBP was negatively correlated with cognitive impairment , indicating that the OR of SBP was approximately 3.013 in the participants who were 40–59 years old but was decreased by approximately 0.546 times in participants who were 60–85 years old. The effect of the interaction of HBP and age on cognitive impairment was similar to that of SBP and age on cognitive impairment . The steps of the statistical analysis and the results are shown in As described above, it appears that elevated blood pressure is positively correlated with cognitive impairment in middle-aged individuals but that this positive association declines with increasing age. It is unclear whether this association is applicable across the entire range of blood pressures. To address this issue, SBP, DBP and MABP were transformed into categorical data . Model 6 was established using dummy variables, which were defined based on the blood pressure parameters ; with respect to analysis steps and confounding variables considered, model 6 was the same as model 5. Model 6 demonstrated that individuals with SBP≥160 mmHg had larger ORs (OR>1) than subjects with SBP<140 mmHg among middle-aged subjects but that ORs reduced as the age increased; among individuals older than 60 years, the ORs were lower than 1.0 . For sub(age-55.5) per 10mmHg for 40≤age≤85. Further analysis indicated that this age-dependent association was particularly prominent in the SBP≥160 mmHg, DBP≥90 mmHg and MABP≥110 mmHg groups . Moreover, in most studies that have employed multivariate models, blood pressure parameters have generally been considered as categorical data so that it is easy for the readers to understand the result of the studies. However, this approach leads to information loss and reduces statistical power. Even more seriously, the results of a study may depend on the blood pressure cutoff value employed. In the multivariate model used in this study, the blood pressure parameters were taken into account as both continuous variables and categorical data. The interaction terms, age by blood pressure parameters, were also considered in the multivariate model to evaluate the effects of the interaction between age and blood pressure on cognition. An equation was also developed quantitatively describe the age-dependent relationship. To make the results easy to understand, we conducted stratified multiple logistic regression.The cognitive function of the participants was evaluated using the MMSE, which was established by Folstein in 1975 . In mostMany previous studies have provided support for the hypothesis that mid-life hypertension is a risk factor for cognitive impairment ,12,13. HThe results of previous studies that have investigated whether lowering blood pressure protects cognitive function are inconsistent ,31–34. OThe mechanisms underlying the correlation between blood pressure and cognitive impairment are complex. As far as we know, high blood pressure can damage cognitive function through multiple pathways. High blood pressure alters cerebrovascular structure and function, which leads to brain lesions such as cerebral atrophy, stroke, lacunar infarcts, diffuse white matter damage, microinfarcts, and microbleeds and finally results in cognitive impairment. This pathway is crucial for VCI . High blWe expended considerable effort to obtain reliable data and results, but deficiencies are unavoidable. Non-response bias and survival bias likely affected the results of our study. Non-response bias occurs in statistical surveys if the answers of respondents differ from those of potential non-respondents. We tried our best to improve the response rate by conducting home-based interviews with those who were unwilling to participate in interviews at the designated site. Survival bias is caused by the death of subjects who meet the inclusion criteria. In our study, elderly individuals who suffer from both hypertension and cognitive impairment may die at an early age, and this may have impacted our results. Moreover, our study utilized a cross-sectional design, which makes it difficult to determine causal relationships. As noted above, it is essential to conduct prospective cohort studies and reasonably designed RCTs for the treatment of the blood pressure disorders to confidently identify the causality of the two diseases of interest.In conclusion, elevated blood pressure is positively correlated with cognitive impairment in the middle-aged individuals, but this positive association declines with increasing age. These results indicated that specific blood pressure management strategies for various age groups may be crucial for maintaining cognitive vitality.S1 File(PDF)Click here for additional data file.


IL-13 is one of many cytokines responsible for the chronic inflammation of asthma.The aim of this study was to determine the effect of combined therapy ICS/LABA and ICS/LABA plus Montelukast in patients with uncontrolled severe persistent asthma by analyzing of serum IL-13 and FEV1 before the treatment and after 6 months of therapy.In study we included two groups. First group with 27 patients were treated with ICS/LABA. Second group with 29 patients were treated with ICS/LABA plus Montelukast. In each of them were measured serum IL-13 levels by the ELISA method and FEV1 before and after 6 months of treatment. Results were statistically analyzed according to the Wilcoxon Pairs Test and T-test.The obtained results in both groups showed that the serum IL-13 before the start of therapy were much higher and after 6 months of treatment significantly reduces their value, which in the second group were more expressed. The difference in the average value of FEV1 in both groups before and after therapy was statistically significant.Treatment with ICS/LABA plus Montelukast proved superior compared to therapy of ICS/LABA in patients with uncontrolled severe persistent asthma and allows achievement of well controlled of asthma with subjective clinical improvement. If the 20-th century was underlined with an “explosion” of allergic diseases and asthma, the 21-th century is already called epidemic century for allergic diseases and asthma. Asthma is a worldwide problem and also is one of the most common chronic diseases worldwide —300 millions or 7.2% patients suffered from asthma. Prevalence was increasing in many countries, especially in children — 6% and in adult 10%. There are 250,000 deaths annually. It is estimated that the number of people with asthma will grow by more than 100 million by 2025 . In the Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role . These mediators act on cells in the airway, leading to contraction of smooth muscle, oedema due to plasma leakage and mucus plugging. The chronic inflammation is associated with airway hypersponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment , 7, 8.In this chronic inflammation are involve more than 100 mediators and the Interleukins take central place in this inflammation , 10. TheT cells play a key role in coordinating the immune response in asthma. The key to the functioning of T cells is a molecule that binds to the antigen: T cells receptor. Generally the T cells which have the CD4 + act as helper cells (Th2-Ly), and CD8+ act as cytotoxic cells (Tc-Ly). CD4 + helper cells, differentiate into subpopulations of T cells in Th1, Th2, Th9, Th17, Th22 and T follicular effectors cell. Th2 cells produce, IL-4, IL-5, IL-9, IL-13, GM-CSF and IL-25, IL-31, IL-33 that are responsible for chronic eosinophilic inflammation, inflammation in allergic diseases, including and asthma .Interleukin 13 (IL-13) is one of many cytokines responsible for the chronic inflammation of asthma. IL-13 is synthesized by activated Th2 CD4 and CD8 cells in response to antigen specific stimulus. It has a similar function as IL-4. This is due to the ability to connect to a common receptor IL4R , 17.Patients with asthma who have increase values of serum IL-13, lead to airway hyperresponsiveness, mucus hypersecretion, activation of fibroblasts and hyperplasia and hypertrophy of smooth muscle of the airways and if they do not use preventive anti-asthma treatment, may cause irreversible airway remodelling .The National Asthma Education and Prevention Program have classified asthma as: intermittent, mild persistent, moderate persistent and severe persistent. These classifications are based on severity, which is determined by symptoms and lung function tests. You should be assigned to the most severe category in which any feature occurs .Asthma is considered severe persistent if without treatment any of the following are true . SymptomFEV1 - Forced expiratory volume in the first second is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration expressed. FEV1 should be measured from a series of at least three forced expiratory curves that have an acceptable start of test and are free from artefact, such as a cough. The largest FEV1 should be recorded after examining the data from all of the usable curves, even if they do not come from the same curve. The calculated values than are converted to a percentage of normal, based on date of birth, height, weight, gender and race. FEV1 is a marker for the degree of airway obstruction in asthma. Reversibility with the use of a bronchodilator is defined as an increase in FEV1 of 12% or 200 ml , 20, 40.The aim of this study was to determine the effect of double combined therapy of inhaled corticosteroid and long-acting beta agonist - ICS/LABA and triple combined therapy ICS/LABA plus LTRA: leukotriene receptor antagonist (Montelukast) in patients with uncontrolled severe persistent asthma by analyzing of IL-13 and FEV1 before and after 6 months of therapy.We have examined 56 patients with a diagnosis of uncontrolled severe persistent asthma treated at the Clinic of Pulmonology and Allergology. The available subjects were divided at random into two groups. First group with 27 patients were treated with combined therapy of ICS/LABA (500/50 mcg-twice daily). Second group with 29 patients were treated with ICS/LABA (500/50 mcg-twice daily) plus Montelukast (10 mg-daily).In each of them were measured serum IL-13 levels by the ELISA method before the treatment and after 6 months of therapy at the Institute of Immunobiology and Human Genetics, Faculty of Medicine, Ss Cyril and Methodius University of Skopje. The reference values for IL-13 are 0 to 6.9 pg/ml. Spirometry was done with spirometer Schiller SP-1 according to the standard methodology at the Clinic of Pulmonology and Allergology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje. We were analyzed FEV1- Forced expiratory volume in the first second.uncontrolled severe persistent asthma patients. The classification was according to the actual version of the GINA guidelines   and Guidpregnancy, severe diseases of the immune, endocrine, haematological cardiac, renal, gastrointestinal, neurological system, psychiatric disorders, and neoplastic diseases.The results were statistically analyzed according to the Wilcoxon Pairs Test. The significances value were taken p < 0.05 and a highly significant p < 0.01.First group with 27 patients were treated with combined therapy of ICS/LABA (500/50 mcg-twice daily). The average serum levels of IL-13 before the treatment were 907.37 ± 601.95 pg/ml and after 6 months treatment were 527.47 ± 577.25 pg/ml. In this group were registered highly significant difference in the values of IL-13 before and after the treatment for a period of 6 months  .In this group the average values of FEV1 before the treatment were 37.33 ± 10.57%, and after 6 months treatment they were increased on 57.33 ± 13.27%. Statistically, this difference of 12.00 and is highly significant (p < 0.001), with significantly increased the values of FEV1.Second group with 29 patients were treated with ICS/LABA (500/50 mcg-twice daily) plus Montelukast (10 mg-daily). Before the start of therapy with ICS/LABA (500/50 mcg-twice daily) plus Montelukast (10 mg-daily), were registered much higher values of serum IL-13 (the average was 1028.21 ± 621.02 pg/ml) and after 6 months of treatment significantly reduces their value (the average was 252.21 ± 427.23 pg/ml), Z = 4.7; p < 0.001 .The patients who were treated with a combination of ICS/LABA and Montelukast, average values of FEV1 before the treatment were 36.76 ± 10.26, and after 6 months therapy were 51.75 ± 11.74. The difference in the average value before and after therapy 14.99 confirmed as statistically highly significant (p < 0.001) .The goal of asthma treatment is to achieve and maintain clinical total control. Combination therapy with ICS/LABA represents the gold standard in the treatment of asthma, safe and effective treatment which is recommended by the Global Initiative for Asthma in the treatment of uncontrolled severe persistent asthma in the step 3 and 4. Combination high dose of ICS/LABA, generally provides additional benefit but it is well recognized that not in all patients will achieve well-controlled asthma despite an appropriately high dose of ICS or ICS/LABA combination therapy, in such patients, there is a need for additional add-on therapy such as treatment with a LTRA. Addition of a leukotriene receptor antagonist (LTRA) to patients who have considered to be insufficiently controlled resulted in a significant clinically improvement in asthma control, pulmonary function and quality of life , 21-24.In our study serum IL-13 was increased in all patients before the treatment. After 6 mounts therapy with combination of ICS/LABA in patients with uncontrolled severe persistent asthma we found decreases of serum IL-13, but added the Montelukast in this combination proved superior effect and allow achievement of total control of asthma with subjective clinical improvement. Unfortunately there are not available studies that analyze the level of IL -13 from the effect of adding of montelukast to combination therapy ICS/LABA in patients with uncontrolled severe persistent asthma.Shimbori C, Montelukast treatment also decreased mRNA levels of IL-6, IL-10, IL-13, and TGF-β1, all of which were elevated in fibrotic lungs [It is known that the significant elevations in IL-13 are found in the airways of patients with both allergic and nonallergic asthma . In the ic lungs .In several studies have confirmed that Montelukast add-on therapy with ICS or ICS/LABA treatment is effective for managing asthma in achieving control and reducing asthma symptoms in patients who were previously uncontrolled asthma symptoms with ICS or ICS/LABA treatment who had uncontrolled -29.In our study the value of FEV1 at the start of therapy were lower in both groups and after 6 months of therapy confirmed as statistically significant improvement of lung function, increase especially in the group which used Montelukast and ICS/LABA.That is referenced in other studies when added to ICS, Montelukast induced further improvement in symptoms and pulmonary function, particularly in patients still symptomatic despite treatment with ICS. Although in short-term studies the combination of ICS plus LABA was more effective on symptoms and pulmonary function than ICS plus Montelukast -34.Virchow et al in a recent article from an observational study on 1681 patients not controlled by ICS, or ICS plus LABA, showed that the addition of Montelukast improved both asthma control and asthma-related quality of life , 34.In a 6-week study in symptomatic patients on high-dose ICS and short-acting b2-agonists, the addition of an LTRA significantly improved lung function and reduced exacerbations. In addition, in a smaller, open label study of 313 patients with insufficiently controlled patients on fixed combination therapy with ICS and LABAs, Dupont et al. observed an improvement in asthma symptoms and pulmonary function with add-on LTRA therapy after 2 months of therapy , 35, 36.Many long-term studies on large groups of adult and pediatric patients, showed clinical and laboratory safety profile for Montelukast because no reported significant or considerable side effects observed for placebo or active control/usual care therapies. The safety profile of Montelukast did not change with long-term -39.The relatively small number of participants may be considered a limitation factor.In conclusion, treatment with ICS/LABA plus Montelukast proved to be superior compared to therapy of ICS/LABA in patients with uncontrolled severe persistent asthma, leading to reduced inflammation and allows achievement of well controlled of asthma with subjective clinical improvement. The reduced values of IL-13 after 6 month treatment with ICS/LABA led to clinical improvement, achieving good control of the disease and certainly able to reduce the dose of ICS/LABA. This suggests that IL-13 is an important marker for monitoring of evolution and success of therapy in patients with asthma.In the future, research in the field of therapy in asthma, may be directed to discover a new molecules which specifically inhibited the activity of Th2 cytokines, which actually indirectly reduce mediators and markers of inflammation.


The prevalence of chronic kidney disease (CKD) is on the rise and constitutes a major health burden across the world. Clinical presentations in early CKD are usually subtle. Awareness of the risk factors for CKD is important for early diagnosis and treatment to slow the progression of disease. We present a case report of a 17-year-old African American male who presented in a life threatening hypertensive emergency with renal failure and the highest reported serum creatinine in a pediatric patient. A brief discussion on CKD criteria, complications, and potential red flags for screening strategies is provided. Prevalence of chronic kidney disease (CKD) is increasing significantly and it has poor outcomes if not diagnosed and treated early in its course . CKD is The National Kidney Foundation (NKF) created the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines and definition of CKD to facilitate the diagnosis and management by primary care physicians. Serum creatinine, a product of muscle metabolism, has been widely used as a marker for glomerular filtration rate (GFR). We describe a clinical case of an adolescent male with the highest serum creatinine reported in a pediatric patient. The primary aim of this case report was to create awareness of chronic kidney disease among general practitioners and to stress that clinical manifestations could be subtle in the early stages of the disease.µmol/L) and was transferred to our pediatric intensive care unit for further evaluation and treatment.A 17-year-old African American male who was previously healthy with the exception of high blood pressure presented to a referring hospital with a 4-day history of coughing, vomiting, headache, facial edema, and lower extremity cramping. One day prior to admission, he also had noticed decreased urine output. At the referring hospital, he was found to be hypertensive with a serum creatinine of 52 mg/dL  of 203 mg/dL and serum creatinine of 52 mg/dL, measured by enzymatic method. He had severe metabolic acidosis with bicarbonate of 10 mmol/L. Patient also had severe electrolyte imbalances including hyponatremia (126 mmol/L), hyperkalemia (6.3 mmol/L), hyperphosphatemia (10.5 mg/dL), hypocalcemia (5.3 mg/dL), and severe anemia with hemoglobin at 5.1 g/dL. Parathyroid hormone levels were elevated at 682 pg/mL . Urine dipstick showed 3+ protein and 2+ blood and a urine protein to creatinine ratio was elevated at 14 . Serological workup including complement levels, antinuclear antibodies, antinuclear cytoplasmic antibodies, and antiphospholipid antibodies was negative. Chest X-ray was significant for cardiomegaly and pulmonary edema. Echocardiogram showed severe left ventricular hypertrophy. Renal ultrasound revealed bilateral small, echogenic kidneys  consistent with dysplastic kidneys. Patient emergently underwent hemodialysis for fluid overload and to correct electrolyte imbalance. His anemia and electrolyte imbalances were slowly corrected. He is currently transitioned to peritoneal dialysis awaiting kidney transplant.CKD is a heterogeneous group of diseases with altered structure and function of the kidneys with varying manifestation based on underlying etiology. Based on KDIGO guidelines, CKD is classified into various stages using GFR and the degree of albuminuria (Tables  K (height in centimeters)/Serum creatinine with the constant K value being 0.413.eGFR = GFR varies with age, gender, and body size and increases from infancy to adulthood. Normative data of GFR based on age is presented in The modified Schwartz formula used to calculate GFR is derived from the CKiD (chronic kidney disease in children)  and usesMost epidemiological information on adult CKD is available from data on ESRD patients . This reThe etiology for ESRD varies with age. Structural anomalies contribute to a large degree to ESRD in younger children, while it is predominantly glomerular diseases in older children. As per NAPRTCS 2011 review data, about 14.2% of all pediatric dialysis patients had ESRD secondary to hypoplastic/dysplastic kidney with obstructive uropathy at 12.6% .Prematurity and being small for gestational age.Congenital abnormalities of the kidney and urinary tract.H/o poor growth or failure to thrive.Family history of kidney diseases and relatives on dialysis or transplant.Electrolyte or acid-base abnormalities.Body mass index (BMI) > 95th percentile.Blood pressure greater than the 95% recorded on multiple visits.Polyuria or inappropriately dilute urine.Gross hematuria.Dysfunctional voiding, urinary incontinence, or prolonged enuresis.H/o recurrent UTI.A thorough history and physical examination during well child visits could help us in identifying these children with high risk for kidney disease. Once identified, these children should have their urine checked for proteinuria, their renal function analyzed by measuring creatinine, and their blood pressure regularly screened. Children with evidence of kidney damage should be sent to a specialist for further investigation and treatment. For our patient, blood pressure > 95% and the BMI > 95% should have prompted a screening for potential kidney disease.Screening strategies are aimed at early detection and intervention for CKD so as to slow the progression of disease. Though routine urine screening for CKD has not been found to be cost effective in the general population and has not been recommended by AAP, it is important to identify and screen children at high risk. Some of the high risk populations at risk for CKD are mentioned below:Cardiovascular disease accounts for most deaths in pediatric CKD similar to adult onset CKD. In contrast to adult CKD patients, where atherosclerosis and coronary vascular disease are much more common, arrhythmias account for the majority of cardiovascular death in children (19.6%) . TraditiAnemia is a common complication in CKD secondary to impaired erythropoiesis. As CKD progresses, so does the prevalence of anemia in these children. Factors such as malnutrition, blood loss, iron deficiency, inadequate dialysis, and uncontrolled secondary hyperparathyroidism should always be kept in mind while managing resistant anemia. KDIGO recommends maintaining hemoglobin levels between 10 and 12 g/dL to reduce need for transfusion. Iron levels should be checked and adequately supplemented in all CKD patients before initiating or increasing dose of erythropoiesis stimulating agents.Metabolic bone disorder (CKD-MBD) is a major complication in CKD. This occurs secondary to the inability of kidneys to excrete phosphorus and synthesize active vitamin D. Net result is secondary hyperparathyroidism. Disorders in calcium phosphorus balance and secondary hyperparathyroidism play a major role in vascular calcification in CKD and subsequent cardiovascular mortality and morbidity.Fluid and electrolyte imbalances are especially common in children with CKD secondary to congenital anomalies of the kidneys and urinary tract (CAKUT). In CAKUT impaired urinary concentrating ability could present with polyuria and can present with dehydration. Disorder of sodium, potassium, and acid-base balance is also very common in these children due to impaired tubular handling. As the normal tubular response to ADH is not present, special attention should be paid to the fluid and electrolyte replacement in these children in the setting of dehydration.Growth failure and neurocognitive delay are important concerns for young children with CKD , 13. ProOur patient had bilateral dysplastic kidneys and ultimately progressed to ESRD. Though he had potential red flags including obesity and high blood pressure noted on multiple occasions, the thought of kidney disease was not entertained. A screening urine dipstick could have prevented this life threatening admission with hypertensive emergency, severe anemia, and multiple electrolyte imbalances. Earlier detection of kidney disease and control of hypertension and proteinuria could have slowed the progression of disease and also would have allowed the time to plan for his renal replacement therapy in a safe manner. Chronic kidney disease is a growing health burden and awareness of it among primary care physicians is essential in early diagnosis and treatment.


Encephalopathy and altered higher mental functions are common clinical complications of acute kidney injury. Although sepsis is a major triggering factor, acute kidney injury predisposes to confusion by causing generalised inflammation, leading to increased permeability of the blood–brain barrier, exacerbated by hyperosmolarity and metabolic acidosis due to the retention of products of nitrogen metabolism potentially resulting in increased brain water content. Downregulation of cell membrane transporters predisposes to alterations in neurotransmitter secretion and uptake, coupled with drug accumulation increasing the risk of encephalopathy. On the other hand, acute brain injury can induce a variety of changes in renal function ranging from altered function and electrolyte imbalances to inflammatory changes in brain death kidney donors. Acute kidney injury (AKI) is a worldwide problem, associated with increasing morbidity and mortality, and can be considered as a systemic inflammatory condition that may have substantial effects on various distant organs -3.Patients with AKI commonly develop confusion, which may be present at the onset of AKI or develop subsequently. The cause of neurological disturbance is often multifactorial, as the majority of patients who develop AKI do so on a background of small vessel disease associated with cardiac failure, diabetes and hypertension – resulting in a spectrum of fluctuating clinical signs ranging from headache, visual abnormalities, tremor and asterixis through to multifocal myoclonus, chorea, seizures and coma. As such, many older patients who develop AKI may already have established small vessel ischaemic brain disease characterised by white matter changes, lacunar infarcts and disturbed cerebral autoregulation, so predisposing them to additional cerebral injury. Moreover, neurological problems in AKI may not only be directly related to uraemic toxin accumulation, but may also develop due to electrolyte imbalance, drug toxicity, thiamine deficiency, and also additionally the effects of renal replacement therapy, including dialysis disequilibrium . EncephaOn the other hand, acute brain injury can lead to neurohumeral changes that directly affect the kidney by increasing renal sympathetic nervous system activity, so altering renal blood flow and glomerular filtration, and by altering vasopressin release lead to changes in sodium and water balance. In addition, acute brain injury is also a cause of cerebral salt wasting, and also severe brain injury leading to brain death results in haemodynamic instability, hormonal disturbance and increased immunologic response, triggering an inflammatory cascade in several organs, including the kidney. Clinically, studies have reported a link between brain death and increased inflammatory response in the kidneys used for organ donation, leading to donor graft dysfunction ,6. SimilAlthough there is overlap between encephalopathy in patients with AKI and those with end-stage chronic kidney disease (CKD), this review will concentrate mainly on the effects of AKI on the brain, and conversely the effects of acute brain injury on the kidney, rather than discussing the effects of CKD on cerebral function or the insults that affect the brain and kidney.vice versa. The interactions between the liver and the kidney  for human glutamate dehydrogenase, so resulting in oxidative deamination of glutamate ..61].Acute cerebral injury is often associated with increased visceral sympathetic nervous system activity and plasma catecholamines resulting in systolic hypertension. Although this may be a compensatory mechanism to preserve perfusion to areas of damaged brain, increased visceral sympathetic nervous system activation results in reduced renal glomerular perfusion with increased renal sodium reabsorption. Sustained severe hypertension may lead to red cell fragmentation, haemolysis and AKI secondary to red cell thrombi in the glomeruli, similar to that found with thrombotic thrombocytopenic purpura.+ regulatory T cells [The increasing use of cadaveric kidneys from brain-dead donors has led to research into the effects of brain death on renal function. Sanchez-Fructuoso and colleagues reported that the renal allograft survival rate from deceased donors was significantly lower than that for living related donors . Further T cells , leading T cells .The majority of patients with acute traumatic brain injury are young and have normal pre-existing renal function, but even so the reported incidence of AKI stage 1 has been reported to be around 23%, with only a small minority requiring renal replacement therapy. However, the mortality in some studies increased fivefold for patients with AKI . In otheAlthough patients with acute subarachnoid haemorrhage are usually older with a past history of hypertension, the incidence of AKI has also been reported to be around 23%, but with a twofold increase in worse functional recoveries and the mortality increasing with severity of AKI class . SomewhaThe majority of patients with acute traumatic brain injury are young and have normal renal function. However, they may be at risk of AKI secondary to blood loss from multiple trauma, exposure to radiocontrast agents and prescription of nephrotoxic antibiotics to treat sepsis and nonsteroidals for analgesia. On the other hand, patients admitted with subarachnoid haemorrhage and acute stroke are usually older and more likely to have a background of CKD secondary to hypertension and small vessel disease associated with diabetes and cardiovascular disease. As such, maintaining adequate hydration is an important clinical goal for preventing AKI, particularly for reducing the risk of contrast-induced nephropathy. In addition, multiple contrast exposure should be minimised by selecting other imaging techniques wherever possible, and nephrotoxic drugs should be similarly avoided if possible.Although renal replacement therapy can help improve encephalopathy due to uraemia, by removing azotaemic retention products and reducing toxic drug levels, too rapid a fall in serum urea may paradoxically cause cerebral oedema.Intermittent haemodialysis using modern-day high-efficiency dialysers coupled with dialysates containing supraphysiological levels of bicarbonate can exacerbate underlying brain damage. Urea is rapidly removed from the plasma water during intermittent haemodialysis, but there is a delay in urea moving out of cells, including neurons and cerebrospinal fluid . This leIt is equally important to avoid intradialytic hypotension to minimise iatrogenic episodes of cerebral ischaemia . The risper se, affecting distant organ injury mediated by increased circulating cytokines and other inflammatory mediators, due to a combination of increased production and reduced clearance. Increased circulating cytokines and other inflammatory mediators predispose to alterations in the BBB, leading to increased permeability and changes in neuronal homeostasis. This is exacerbated by changes in excitatory and inhibitory neurotransmitter concentrations. AKI leads to the retention of azotaemic products of nitrogen metabolism and metabolic acidosis, which lead to changes in intracellular osmolality and further disturb intracellular homeostasis. Alterations in drug pharmacokinetics in patients with AKI may then lead to parent drug or metabolite accumulation, which may further alter higher mental functions and increase the risk for cerebral dysregulation.Cerebral dysfunction is a common finding in patients with AKI. Although alterations of mental status are more likely to occur in the older patient with pre-existing small vessel cerebrovascular disease, sepsis is probably the most common triggering factor. However, AKI is an inflammatory state Patients admitted with acute cerebral dysfunction are at risk of AKI primarily secondary to hypovolaemia, reduced intrarenal glomerular perfusion, and exposure to radiocontrast and nephrotoxic drugs. As such, achieving adequate hydration and avoiding or minimising nephrotoxin exposure is key to preventing AKI. For patients who develop progressive AKI requiring renal replacement therapy, modifying the dialysis prescription may minimise further brain injury. These modifications would include continuous renal replacement therapy or intermittent haemodialysis with reduced blood flow rate, a longer daily dialysis session time in combination with smaller surface area biocompatible dialysers, and cooled dialysate with increased sodium and reduced bicarbonate dialysate concentrations.AKI: Acute kidney injury; BBB: Blood–brain barrier; BCSFB: Blood–cerebrospinal fluid barrier; CKD: Chronic kidney disease; IL: Interleukin; OAT: Organic anion transporter; OCT: Organic cation transporter.The authors declare that they have no competing interests.


Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease (CVD) with poor parasympathetic function being implicated as an underlying factor. Factors related to parasympathetic function, commonly assessed by heart rate recovery (HRR) following maximal exercise, are currently not known in RA. We aimed to explore the association between HRR with CVD risk factors, inflammatory markers, and wellbeing in patients with RA.Ninety-six RA patients  completed a treadmill exercise test, during which heart rate (HR) was monitored. HRR1 and HRR2 were defined as the absolute change from HR peak to HRR 1 min post HR peak and 2 min post HR peak, respectively. Cardiorespiratory fitness, CVD risk factors, and serological markers of inflammation were measured in all patients. The Framingham Risk Score (FRS) was used as an assessment of global risk for CVD events, and wellbeing was assessed by questionnaires.p = 0.009, p = 0.001 respectively), however no individual measure was independently associated with HRR1 or HRR2.Mean HRR1 and HRR2 were 29.1 ± 13.2 bpm and 46.4 ± 15.3 bpm, respectively. CVD risk factors as well as most inflammatory markers and measures of wellbeing were inversely correlated with HRR1 and HRR2. Multivariate regression analyses revealed that 27.9 % of the variance in HRR1 and 37.9 % of the variance in HRR2 was explained collectively by CVD risk factors, measures of inflammation, and wellbeing (Parasympathetic activation was associated with overall CVD risk, arthritis-related burden and wellbeing in patients with RA.ISRCTN04121489][Exercise, cardiovascular disease and rheumatoid arthritis,  Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic systemic inflammation affecting approximately 1 % of the general population . AlthougThe autonomic nervous system (ANS) is divided into the sympathetic and the parasympathetic system, which, in a healthy state, work together to maintain cardiovascular autonomic balance. Autonomic dysfunction, an increased activity of the sympathetic tone and less parasympathetic tone at rest , has beeA common method to assess autonomic function, and in particular parasympathetic tone, is heart rate recovery (HRR). The rapid fall in heart rate immediately following an exercise tolerance test (ETT) is suggested to represent reactivation of the parasympathetic tone . HRR is Ninety-six RA patients (fulfilling the revised American College of Rheumatology criteria ), were r2 consumption were recorded for two minutes while seated, followed by an ETT and six minutes post ETT recovery period.Participants were invited to visit the research laboratory on two different occasions. During visit one, a fasted blood sample was taken and questionnaires were given. During visit two, brachial blood pressure was taken using electronic sphygmomanometer  while the patient was seated. Height was measured to the nearest 0.5 cm using a standard height measure (Seca 214 Road Rod), weight and BMI were measured using a Tanita BC 418 MA Segmental Body Composition Analyser . Subsequently, the patients were fitted with an appropriate size mask to cover the nose and mouth securely for the purpose of inspired and expired gas analysis, and electrocardiography (ECG)  electrodes were attached. Resting heart rate and volumes of OETT was performed on a treadmill . All patients performed an individualized treadmill ETT which was modified according to their fitness and physical abilities . The sta2 uptake (VO2 peak). ECG was recorded throughout the exercise task and recovery period. The test was terminated if patients reached volitional exhaustion, or any of the relative or absolute contraindications of ACSM’s guidelines [After two minutes warming up at the preferred speed, the test started. The inclination increased by one percent every minute while keeping the speed constant. Breath by breath gas analyses  were recorded throughout the exercise task, which was used to calculate peak volume of Oidelines  were metHRR was measured at 1 and 2 min following peak heart rate during exercise. Heart rate recovery 1 min (HRR1) was defined as the absolute change from peak heart rate to heart rate 1 min post peak heart rate (HRR1 = peak heart rate – heart rate at 1 min post peak heart rate). Similarly, heart rate recovery 2 min (HRR2) was calculated as the absolute change from peak heart rate to heart rate 2 min post peak heart rate. Peak heart rate was identified as the maximum heart rate during the exercise protocol.2 peak) was measured during treadmill ETT via a breath by breath gas analyser. The inspired and expired gases data from the analyser were averaged every 2 s. To avoid spikes and fluctuations of the VO2 ml/min readings, these data were smoothened by taking the average of VO2 every 28 s (taking the average of 14 readings of VO2 ml/min). VO2 peak was defined as the highest VO2 during the test and was expressed as ml/min/kg.Aerobic capacity , low density lipoprotein (LDL), and triglycerides. Homeostasis models assessment (HOMA) was utilized to assess insulin resistance . InflammIn order to measure the probability of occurrence of cardiovascular events within 10 years period, the Framingham risk score was utilized .Functional ability, psychological and general wellbeing were assessed using health assessment questionnaire (HAQ) , hospitaStatistical analysis was performed using SPSS20 . Kolmogorov-Smirnov test was used to test the normality of all variables. Log-transformation was performed for non-normally distributed variables . All normally distributed variables were presented as mean and standard deviation, whereas, non-normally distributed variables were presented as median and interquartile range. To assess the relationship between HRR at both time points and other normally distributed variables, bivariate correlation (correcting for gender as a possible confounder) using Pearsons moment. Bivariate correlation was performed on normally distributed variables and after log transformation for the skewed variables. To assess factors associated with HRR at both time points, two multivariate linear regression were used using enter method (correcting for gender) where HRR (HRR1 and HRR2 separately) was the dependent variable, while the independent variables were all the variables that came out significantly associated with HRR1 and HRR2 separately in our correlation analysis. The level of significance for all analyses was set at .05.2 max 20.6 ± 5.1 ml/min/kg [Demographic characteristics as well as CVD risk, markers of inflammation and wellbeing of the 96 RA patients  are presented in Table l/min/kg .Table 1Dr (87) = − .27, p = .009). VO2 peak was positively associated with HRR1 and HRR2 (r (93) = .33, p = .001 and r (93) = .41, p < .001, respectively). HRR1 and HRR2 were both inversely related to FRS. WBC, Fibrinogen, hsCRP, and ESR were all inversely associated with HRR1, and, albeit somewhat weaker, with HRR2 with the exception of CRP (Table r (90) = .26, p = .01 and r (88) = .30, p = .004), respectively, whereas, only vitality was significantly associated with HRR2 (r (88) = .21, p = 0.05). Additional non-parametric correlational analyses (Spearman correlation) were conducted between HRR and those variables which were not normally distributed. These analyses revealed similar associations as the Pearsons correlations reported on the log-transformed data (data not reported).Correlational analyses were conducted to explore the associations between HRR and risk factors for CVD and wellbeing. With regards to CVD risk factors, results revealed that HRR1 and HRR2 were inversely associated with age and triglycerides, whereas resting SBP was only inversely associated with HRR2 Table . HRR2 waHRR2  = 2.57, p = .009, R2 = 0.29). However, even though almost a third of the variance in HRR1 was explained by these variables, none of the variables were independently associated with HRR1. For HRR2, using the same method, a model which included age, resting systolic blood pressure, triglycerides, HOMA, VO2 peak, Framingham risk score, WBC, ESR, fibrinogen and vitality accounted for 37.9 % of the variation in HRR2  = 3.6, p = .001, R2 = 0.37). Similar to HRR2, none of the variables were independently associated with HRR2. Data was checked for collinearity, but this revealed not to influence the data. Additionally, in a different analyses, using age as a confounding factor along with gender did not change the model presented in Table In order to identify if the variables were independently associated with HRR, all variables which were significantly correlated with HRR were subsequently entered in multivariate linear regression analyses  and HRR in RA. The effect size of the associations between global CVD risk and HRR were greater than the effect sizes of the associations between individual risk factors and HRR. Given that FRS comprises of multiple variables, this association, together with the finding that none of the individual risk factors were independently associated with HRR in multivariate analyses, suggests that rather than individual risk factor, the overall RA- and CVD related burden is an important factor that associates with parasympathetic function.In line with cross-sectional and experimental studies in other populations , 57, disThere were subtle differences in the associations between inflammation and HRR1 and HRR2 in the current study; CRP was associated with HRR1 which is related to parasympathetic reactivation, but not HRR2, which is reflective of sympathetic withdrawal . SimilarThe first two minutes of HRR are the most validated  and commTo our knowledge, this is the first study to explore associations between markers of psychological wellbeing and autonomic function in RA. This is surprising given that psychological factors have been associated with CVD and autonomic function has been implicated as an underlying pathway by which psychological wellbeing contributes towards the pathogenesis of CVD . Indeed,There are number of limitations in this study. The cross-sectional design does not allow for the assessment of causality between variables. The current study did not have a comparison group, however, as the aim of the current study was to explore factors associated with parasympathetic activity in RA, the focus was specifically on RA patients. Without a control group, a direct comparison between parasympathetic activity in RA and other populations is not possible. Comparing HRR in this well-controlled cohort of RA patients from this study to HRR reported in healthy participants in other studies , 68, revIn conclusion, the results of this study showed that CVD risk, disease related inflammations, and wellbeing associate with HRR in RA. As there is ample evidence that HRR is related to CVD mortality in other populations , furtherThis data forms part of a larger ongoing study, it is therefore not possible to share the data at this stage.