In this special issue on The Arterial Pulse: Vascular Biology, Vascular Function, and Therapies, we have compiled five reviews, a clinical trial and a translational pilot study for the readership of Cardiology Research and Practice.Techniques and approaches for modern vascular function testing have evolved over time from invasive methods restricted to smaller studies in the research laboratory to more standardized noninvasive methods, which are suitable for use in large prospective cohort studies and clinical trials. E. A. Ellins and J. P. J. Halcox describe currently available methods for the assessment of endothelial function and their potential application in cardiovascular research and clinical practice. In the second contribution E. Patvardhan and co-authors present a clinical trial investigating the relationship of the augmentation index (AIx) obtained from pressure waveforms via arterial applanation tonometry and cardiovascular risk factors and coronary artery disease (CAD). The authors conclude that AIx may be a useful measure of assessing overall risk for coronary heart disease. J. Steppan and colleagues review the effects of age-associated increase in vascular stiffness on systolic blood pressure, pulse pressure, AIx, and cardiac workload in the third paper. In this paper they describe evidence for the use of pulse wave velocity testing to measure vascular stiffness as an index of vascular health and as a predictor of adverse cardiovascular outcomes. In the fourth paper, M. Weber and colleagues present data from a pilot study about the potential diagnostic role of microRNAs (miRNAs) in blood samples of patients with angiographically documented CAD and healthy controls. The authors show that a distinct miRNA expression profile discriminates patients with CAD from healthy controls, which in turn is altered by vasoactive medications such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. In the fifth paper, C. R. Martens and D. G. Edwards review the current literature pertaining to the potential mechanisms of peripheral vascular dysfunction in chronic kidney disease and propose possible targets for treatment. Vascular endothelial dysfunction is associated with a reduction in nitric oxide (NO) bioavailability, an increase in vasoconstrictors, including superoxide anions and endothelin-1 in parallel with a potential compensatory increase in other mediators of vasodilatation. This non-NO, non-prostaglandin-mediated endothelium-dependent vasodilatation has been partly attributed to endothelium-derived hyperpolarizing factors (EDHFs), the topic of the comprehensive review by M. A. Ozkor and A. A. Quyyumi who describe the role of endothelial hyperpolarization in human circulatory physiology. Finally, N. Ghasemzadeh and A. M. Zafari provide a historical review about the evolution of our knowledge of the arterial pulse from ancient times to the modern era. The authors describe the revolutionary scientific concepts and the technological innovations that provided the foundation of our current understanding of the arterial pulse as a wave that can be accurately measured with various noninvasive techniques in standardized fashion suitable for clinical patient-oriented research as well as clinical practice.A. Maziar ZafariArshed A. QuyyumiJulian P. J. HalcoxSanjay Rajagopalan


In a Perspective, Mark Caulfield discusses potential implications of using home blood pressure monitoring for diagnosis and treatment of hypertension.Please see later in the article for the Editors' Summary PLOS Medicine:This Perspective discusses the following new study published in doi:10.1371/journal.pmed.1001591Asayama K, Thijs L, Brguljan-Hitij J, Niiranen TJ, Hozawa A, et al. (2014) Risk Stratification by Self-Measured Home Blood Pressure across Categories of Conventional Blood Pressure: A Participant-Level Meta-Analysis PLoS Med 11(1): e1001591. Jan Staessen and colleagues compare the risk of cardiovascular, cardiac, or cerebrovascular events in patients with normal office blood pressure but elevated home blood pressure.Cardiovascular disease is now the leading cause of death and disability worldwide There are limited data on the use of home blood pressure monitoring (HBPM) to assess the cardiovascular risk of patients. An analysis as part of the 2011 UK National Institute for Health and Care Excellence guideline for hypertension suggested that ambulatory blood pressure monitoring (ABPM) was superior to HBPM and that both were superior to clinic blood pressure monitoring (CBPM) as a guide to adverse outcomes PLOS Medicine, Jan Staessen and colleagues undertook an individual-patient meta-analysis based on data from the International Database of Home Blood Pressure in Relation to Cardiovascular Outcome. The meta-analysis included 5,008 people who had home and conventional blood pressure measurements and were not being treated with antihypertensive medications that would have influenced prognostic outcomes As published in this week's In keeping with a previous analysis, the meta-analysis found no significant improvement in risk stratification in those defined as severely hypertensive (≥160/≥100 mm Hg); at these levels HBPM and CBPM are both strong predictors of outcomes. This is not unexpected; severe hypertension does not lack precision in risk stratification and is not difficult to decide to treat. On the other hand, at every level of blood pressure below severe hypertension, the additional measurements obtained from HBPM improved risk stratification, providing new evidence supporting the use of HBPM in routine assessment of risk. This result is important because it could refine risk stratification in people with optimal, normal, or high-normal blood pressure based on CBPM, who are not conventionally treated. In addition, HBPM showed improved stratification of risk in those with masked hypertension, that is, those who have normal clinic blood pressure but on HBPM or ABPM have periods of elevated blood pressure and may benefit from treatment These findings add depth to the evidence base in favour of electronic blood pressure monitoring in the form of HBPM. However, the authors do not have data to provide a head-to-head comparison of HBPM and ABPM, which would be valuable in assessing whether HBPM could be of sufficient diagnostic and prognostic precision to replace ABPM in the confirmation of a diagnosis informing a decision to treat. In addition, they were not able to standardise HBPM approaches, but that limitation would be more likely to dilute the observed improved risk stratification by HBPM than create a spurious association. To address this issue and validate these findings, the authors suggest further comparative, prospective randomised controlled trials would be valuable As the authors suggest, the use of electronic blood pressure monitoring (HBPM and ABPM) is likely cost-effective, allows more rapid diagnosis and treatment, saves consultation time, and may in some people avert treatment at least temporarily


Heart rate and plasma cortisol concentration are often used in evaluation of physiological reactions to stress and fear, but arterial blood pressure is rarely measured in farm animals. Goats are prey animals and can be expected to react strongly to a predator, especially when they have kids. We hypothesized that exposure to a dog elicits a flight response during pregnancy and a fight response when goats have kids to defend. Arterial blood pressure and heart rate should increase in both these cases, due to a synchronized discharge of the sympathetic nervous system.Seven goats were exposed to a dog for 15 minutes at 12 ± 3 days before, and again at 10 ± 1 days after, parturition. Arterial blood pressure, heart rate, and activity were registered by telemetry. Behavioral data were collected during 5 minute sessions, followed by blood samples obtained via intrajugular catheters. Plasma cortisol concentration was analyzed by radioimmunoassay.At the appearance of the dog, the mean arterial blood pressure of the goats increased from 90 ± 8 to 111 ± 8 mmHg (p < 0.001) during pregnancy and from 96 ± 8 to 108 ± 8 mmHg during lactation (p < 0.001). Heart rate did not change at dog exposure during lactation, but increased from 117 ± 6 to 126 ± 10 beats/min (p < 0.01) during pregnancy. Dog exposure resulted in plasma cortisol concentration increasing from 17 ± 1 to 43 ± 7 nmol/l (p < 0.01) during pregnancy and from 21 ± 1 to 49 ± 6 nmol/l (p < 0.01) during lactation. In response to the dog, goats vocalized at a higher frequency and started to ruminate later during lactation compared to pregnancy.When goats were exposed to a dog during pregnancy, their heart rate, blood pressure, and plasma cortisol increased, in contrast to lactation when only their blood pressure and plasma cortisol increased. However, when they were lactating, goats vocalized more and started to ruminate later compared to when they were pregnant. In the classic "fight or flight" response to a threatening event, the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis are activated ,2. If thGoats are prey animals and can be expected to react strongly to a predator, especially when they have kids ,8. This We hypothesized that exposure to a dog elicits a flight response during pregnancy and a fight response during lactation, when the goats have kids to defend, and that arterial blood pressure and heart rate increase on both occasions.Capra hircus) weighing 47 ± 2 kg (during lactation) were studied. Goats and kids were routinely kept together with the entire herd in a large, indoor pen. The goats were fed at 07:00 and 15:00 and had free access to water and mineral licks. Room temperature was kept at 17 ± 1°C.Seven 2-4-year-old Swedish domestic landrace goats  along the walls and an open floor area measuring 4.0 m × 4.0 m in the middle. Hay and water were available in the cages. The kids (six twins and one singleton) accompanied their mothers to the cages.The care of the animals and the experimental design were approved by the Local Ethical Committee in Uppsala, Sweden.The goats had previously implanted telemetric devices  for registering arterial blood pressure, heart rate, and activity. In brief, under full anesthesia, the transmitter body had been placed subcutaneously on the lateral side of the neck, and the fluid-filled catheter had been tunneled subcutaneously to the superficial temporal artery and, further, into the carotid artery . During ®, AstraZeneca, Södertälje, Sweden) was applied to the shaved skin covering the jugular veins. About 60 minutes later, a catheter  was inserted into one of the jugular veins in a maximum of four goats on one experimental day.The goats were exposed to the dog for 15 minutes at 12 ± 3 days before parturition and again at 10 ± 1 days after parturition. Telemetric registrations started when the goats arrived at the cages. At 07:30, a local anesthetic ointment  validated for caprine plasma. The lower detection limit was 1.10 nmol/l, the interassay coefficient of variance was < 1.6% (at 34 nmol/l), and the intraassay coefficient of variance was < 10% .The goats were lightly restrained while the blood was withdrawn. Blood samples were taken at 10:00 and 10:20. No sample was taken while the dog was in the room, but the third sample was withdrawn immediately thereafter, i.e., at 10:45, and again at 10:55, 11:05, 11:15, 11:45, and 12:15 Figure , arrows.The behavior of the goats was registered simultaneously by two observers (each of them observing one or two goats). The behavioral data were collected during 5 minute observation sessions, starting at 09:55 and at 10:15. The first sessions took place before the dog entered, three sessions occurred during dog presence, and thereafter the sessions started again at 10:50, 11:00, 11:10, 11:40, and 12:10. During each session, 15 sample points  were collected using an electronic timer. At each sample point, the activities walking, standing, lying down, climbing, stamping, eating, drinking, ruminating, and vocalizing (see below for Definitions) were recorded on a score sheet. In addition, all sessions were videotaped. If the goats took the piece of apple, this was noted, as was the time at which this took place .Walking: moving forward, lifting one foot after the other. This occurred rarely and has therefore been summarized together with standing.Standing: standing with all four feet on the floor.Lying down: lying with all four legs under the body and the head either held up or resting on the ground.Climbing: putting one or two front legs on the horizontal bars of the cages. The frequency was counted continuously during each 5 minute session.Stamping: abruptly lifting and putting down one front leg. The frequency was counted continuously during each 5 minute session.Ruminating: regurgitating and chewing previously swallowed food.Vocalizing: bleating. The frequency was counted continuously during each 5 minute session (145 or more bleats per 5 minute session = 100%).Eating: taking something edible into the mouth.Drinking: putting the mouth in a bucket of water (occurred rarely).® software . The repeated measurement analysis of variance (using the MIXED procedure) was applied to the various parameters. The statistical analysis included the fixed effects of mean arterial blood pressure, heart rate, activity, blood sample, behavior, and reproductive period, and the random effect of goat.The data were analyzed with SASTelemetry data were arranged in blocks of 15 minutes. The behavioral data were logarithmically transformed before the analysis. Values are presented as means ± standard error of the means (SEM) for behavior and cortisol data, and as least square means (LSM) and standard error (SE) of LSM for mean arterial blood pressure, heart rate, and activity data. Means were estimated and pairwise tests of significance were performed for the differences between the estimated means. Bonferroni adjustment was used to limit the risk for false mass significance. The significance level was set at p ≤ 0.05.As illustrated in Figure In Figure Overall comparison of blood pressure, heart rate, and activity between pregnancy and lactation revealed that the blood pressure was lowest during pregnancy , whereas the heart rate was highest during pregnancy . The goats were most active during pregnancy .The plasma cortisol concentration was elevated in the sample taken immediately after the dog left Figure . In pregBefore the dog came in, about 50% of the goats were lying down and had started to ruminate Figure  and 3B, Infrequent bleats were heard from pregnant goats in the presence of the dog (ns), but lactating goats started to vocalize as soon as they caught sight of the dog, and vocalized intensively while the dog was present (p < 0.001 vs. both before the dog and pregnancy). Lactating goats continued to vocalize after the dog had left .The goats climbed or stamped a few times during the experiments. Before the dog arrived, pregnant goats did not climb, but lactating goats climbed 3 ± 2% (ns) of the time. When the dog was present, only pregnant goats climbed, at a rate of 8 ± 2% . Pregnant animals stamped 6 ± 2% (p < 0.01 vs. before the dog), while lactating goats stamped 3 ± 2%, of the time (ns). After the dog had left, pregnant goats climbed 2 ± 2% of the time between 10:50 and 10:55 (ns).During pregnancy, four of the goats took the piece of apple; three goats did not touch it. During lactation, six of the goats took the apple piece at once, and one of them bit the hand of the owner before taking the apple.Before the dog came in, the kids were lying down most of the time. When the dog arrived, all the kids except the singleton and one twin kid stood up watching the dog. Two goats were suckled before dog exposure and one goat after.Arterial blood pressure and heart rate increased simultaneously when pregnant goats saw the dog. In lactating goats, blood pressure increased but the heart rate did not change, although the goats appeared as alarmed during lactation as they did during pregnancy.Many ruminants are pregnant or lactating most of the year and in addition, farm animals are kept for high production. One difference between pregnant and lactating animals is that the baroreceptor reflex is attenuated during pregnancy and returns to previous levels during lactation in most animals including goats ,11. ConsGoats are curious animals and do not easily panic if something unexpected happens . The goaAfter a few weeks, when the goats saw the dog for a second time, they may have recognized the situation and reacted differently for that reason. In another study, the first time that sheep were exposed to a sudden event they showed a startle response and tachycardia, but the response was smaller when the experiments were repeated . It may The activity counts were low when the dog was present, which shows that the signal strength from the sensor body on the neck of the goats varied only a little, i.e., the goats stood nearly still. This was supported by direct observations. During pregnancy, the goats climbed and stamped, but did not run around in the cage; during lactation, they stamped a few times but otherwise stood watching the dog. Pregnant goats uttered a few bleats, but lactating goats vocalized intensively with a high-pitched noise that sounded like a sneeze. This noise seems to be typical of alarmed goats .When animals stand still in response to a threatening event, activity in the sympathetic nervous system may increase blood pressure and redirect the blood to muscles and the brain to prepare the animal for fight or flight at the same time as activation of the parasympathetic innervation of the heart prevents a rise in heart rate .In lactating rats, aggressive behavior has been observed simultaneously with an attenuated responsiveness of the sympathetic nervous system as well as the HPA axis . In thisIt could be questioned how much the dog disturbed the goats in relation to other events that took place during the day. Eating is accompanied by a marked rise in heart rate in goats fed in the morning and afternoon , and theWhen goats were exposed to a dog during pregnancy, their heart rate, blood pressure, and plasma cortisol increased, in contrast to lactation when only their blood pressure and plasma cortisol increased. However, when they were lactating, goats vocalized more and started to ruminate later compared to when they were pregnant.The authors declare that they have no competing interests.EHS participated in the design and coordination of the study, in particular with regard to behavior, and drafted the manuscript. KO participated in the design of the study, performed the statistical analysis and discussed the draft of the manuscript. Both authors approved the final manuscript.


P < 0.05). In univariate analysis, IMT was positively and significantly associated with age , waist circumference , body mass index , systolic blood pressure , UAER , HbA1c  and, duration of diabetes . In multivariate linear regression analysis, UAER and HbA1c were independent predictors of IMT . In the two groups, the rate of soft plaques was higher than that of dense plaques and calcified plaques. In conclusion, there is a significant association between microalbuminuria and IMT which is regarded as the early sign of carotid atherosclerosis in type 2 diabetic patients.The aim of this study is to evaluate carotid atherosclerosis in patients of type 2 diabetes mellitus with microalbuminuria (MA) by high-frequency ultrasonography. Two hundred and fifty patients of type 2 diabetes mellitus were divided into two groups according to urinary albumin excretion rate (UAER): normoalbuminuria group (130 cases) and microalbuminuria group (120 cases). The intimal-medial thickness (IMT) and the atherosclerotic plaques of carotid artery were observed in both groups by high-frequency ultrasound. Fasting blood glucose (FBG), hemoglobin A1c, and lipid profiles were measured. The values of IMT of microalbuminuria group were significantly higher than those of normoalbuminuria group ( Diabetes mellitus is associated with aggressive vascular abnormalities in human subjects, and atherosclerosis is regarded as the leading cause of morbidity and mortality in diabetic patients . Microal The study included 250 patients of type 2 diabetes mellitus at the Department of Endocrinology of the second Affiliated Hospital of Dalian Medical University. Type 2 diabetes mellitus was diagnosed according to the 1999 World Health Organization criteria. The Ethics Committee of the second Affiliated Hospital of Dalian Medical University approved the study. All patients gave their informed consent to participate in the study. According to the level of urinary albumin excretion rate (UAER), 250 patients of type 2 diabetes mellitus were divided into two groups: normoalbuminuria group  and microalbuminuria group . Medical history was obtained and physical examination was performed in all patients. Blood was withdrawn from all subjects following 12 h of fasting. Type 1 diabetes mellitus, hypertension, history of ischemic heart disease, renal impairment (serum creatinine   > 150 umol/L), and valvular heart diseases were excluded. The clinical conditions that could cause transient elevations in urinary albumin excretion, such as exercise, urinary tract infection, febrile illness, were also excluded.Carotid artery ultrasonography was performed by an experienced specialist physician who was specifically trained for the vascular ultrasonography. A real-time ultrasound scanner was used: Hitachi EUB 7500 with a linear 3–15 MHz probe . The patients were examined in the supine position with the head turned 45° contralateral to the side of scanning. B-mode images were obtained in longitudinal section. IMT was defined as the distance between the lumen-intima and the media-adventitia ultrasound interfaces. The IMT on the far wall of the bilateral common carotid artery about 10 mm proximal to the bifurcation of the carotid artery was measured manually as previously described , 23. ThrThe following laboratory parameters were obtained: total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), hemoglobin A1c (HbA1c), fasting plasma glucose (FBG), and urinary albumin excretion rate (UAER). Serum concentrations of TC, TG, LDL, HDL, and FBG were measured by enzymatic method. HbA1C was measured by high performance liquid chromatography . UAER was obtained by a 24-hour urine collection. Body mass index (BMI) was calculated as weight in kilograms divided by height in meter squared. All the measurements were performed 3 times.χ2) test was used to compare groups regarding categorical variables. Correlation analysis including Pearson's for continuous and Spearman's for discrete variables and multiple linear stepwise regression analysis was used to show the influences of variables on IMT. All tests were performed with P < 0.05 considered statistically significant.The software of SPSS version 13.0 for Windows  was used for statistical analysis. Statistical significance between two groups was determined by the Wilcoxon rank-sum test. Continuous variables were expressed as median and range. Pearson's chi-square . In both normoalbuminuria and microalbuminuria groups, the rate of soft plaques was the highest. And the rate of soft plaque was higher than that of dense and calcified plaques. The rate of dense plaques was higher than that of calcified plaques. In detail, in normoalbuminuria groups, soft plaques rate (66.67) > dense plaques rate (25) > calcified plaques rate (8.33), and in microalbuminuria group, soft plaques rate (68.42) > dense plaques rate (24.21) > calcified plaques rate (7.37)  between two groups were shown in e (7.37) .r = 0.265, P < 0.05), waist circumference , body mass index , systolic blood pressure , UAER , HbA1c , and duration of diabetes . In multiple stepwise regression analyses, age, body mass index, systolic and diastolic blood pressure, waist and hip circumference, UAER, FBG, plasma HbA1C concentration, serum concentrations of triglycerides and total, HDL and LDL cholesterol, current smoking, and duration of diabetes mellitus were included in the model as independent variables. UAER and HbA1c were appeared to be significantly associated with IMT   .In the present study, we found that the values of IMT of type 2 diabetic patients with microalbuminuria was significantly higher than those without microalbuminuria. And UAER was an independent predictor of IMT. The results indicated that microalbuminuria was related to atherosclerosis in the early stage of diabetic nephropathy. Maybe there is a close relationship between atherosclerosis and diabetic nephropathy. But the mechanism underlying the relationship between microalbuminuria and atherosclerosis in type 2 diabetic patients is still unknown. Nand et al.  results Stehouwer et al.  found thIn the same time, our study showed that the value of HbA1c in type 2 diabetic patients with microalbuminuria was significantly higher than that in patients with normoalbuminuria. And IMT was positively and significantly associated with HbA1c. The result indicated that HbA1c maybe played an important role in the relationship between carotid atherosclerosis and microalbuminuria. HbA1c can accurately reflect longer-term glycemia. Clinically, HbA1c is now used to assess glycemic control in patients of diabetes mellitus, and it is regarded as a useful method of screening and diagnosing diabetes. And HbA1c has been accepted as the best marker for diabetic microvascular complications . MoreoveIn addition, the results showed that there were no significant difference in plaque incidence rate between normoalbuminuria and microalbuminuria groups. This result was in line with the previous studies . But theOur study has its limitations. First, the study population is small. Second, some type 2 diabetic patients have already been treated for diabetes and hyperlipidemia which may lead to inaccuracy of the results.Our data show that there is a significant association between microalbuminuria and IMT which is regarded as the early sign of carotid atherosclerosis in type 2 diabetic patients. Routine screening of carotid artery IMT and plaque presence in type 2 diabetic patients with microalbuminuria is necessary. It helps us not only to detect early atherosclerosis but to prevent further development of diabetic nephropathy and cardiovascular events by applying more intensive therapy. However, larger and further studies are needed to confirm our results.


Hypertension affects about 65 million individuals in the United States. In adult patients, primary aldosteronism and renovascular causes are described as most prevalent. Vesicoureteral reflux as a cause of hypertension, while commonly described in pediatric populations, is less prevalent in the adult population especially in the absence of proteinuria. We present the case of a 31-year-old female presenting with early onset hypertension. Workup for renovascular hypertension was unrevealing. She was found to have right-sided vesicoureteral reflux with a unilateral scarred kidney. Patient underwent a nephrectomy with marked improvement in blood pressure control. The absolute number and percentage of adults with hypertension was estimated to be at least 65 million and 31.3%, respectively, in the US from years 1999-2000 [Vesicoureteral reflux (VUR) is a less recognized cause of hypertension in the adult population. It is a congenital anomaly of the ureterovesical junction due to deficiency of the submucosal longitudinal muscle that predisposes the individual to retrograde urine reflux. Adult presentation of primary VUR occurs in patients who have had VUR since childhood that has remained undetected and presents in adulthood with complications or patients who develop VUR in adulthood de novo with no prior history of UTI . PrimaryA 31-year-old female with onset of hypertension in adolescence initially presented to us with a recent history of hypertensive urgency and prior history of systolic blood pressure of 220 mm of Hg. She had been started on Amlodipine 10 mg once daily by her primary care physician and referred to the University Nephrology Clinic. Past medical history was significant for workup for secondary hypertension through a local nephrology practice approximately nine years ago. At that time, renal artery stenosis was considered the most likely diagnosis and was pursued with invasive testing. She underwent a renal arteriogram at that time which did not reveal stenosis. Careful history by us, however, revealed recurrent urinary tract infections and back pain accompanying these episodes which aroused our suspicion for a diagnosis of pyelonephritis and vesicoureteral reflux. Her family history was significant for middle age onset of primary hypertension in her father; her mother was diagnosed with autosomal dominant polycystic kidney disease leading to end-stage renal disease. She was sexually active with no use of oral contraceptives. On presentation to us, her physical examination revealed blood pressure of 153/97 mmHg, equal in both arms, and with strong pulses in upper and lower extremities. The remainder of the physical examination was essentially unremarkable; no femoral, carotid, or abdominal bruits were appreciated. Urinalysis revealed 2+ leukocyte esterase, positive for nitrites, trace protein, trace blood, and white blood cell count of 47. Her complete blood count and basic metabolic panel were unremarkable. Serum creatinine was 0.7 mg/dL, and 24-hour urine protein was 0.24 gm/24 hours (<0.2 gm/24 hours). Ultrasound of the kidneys showed a right kidney measuring 7.8 cm with severe cortical thinning and the left kidney measuring 13.2 cm with normal cortical echogenicity. There was no evidence of hydronephrosis or renal calculi. Real-time sonographic, duplex, and color Doppler images of the kidneys demonstrated a scarred right kidney. Doppler of renal arteries did not show renal artery stenosis. A voiding cystourethrogram demonstrated grade-3, right vesicoureteral reflux. There was also focal narrowing of the right ureterovesical junction. The bladder was within normal limits. Nuclear imaging to evaluate renal flow showed prompt radiopharmaceutical uptake within the left kidney. The right kidney was not clearly visualized on flow phase or functional images. On delayed imaging, there was reflux into the right collecting system. She was started on hydrochlorothiazide 25 mg once daily by mouth. Angiotensin converting enzyme inhibitors were not used due to the patient being sexually active without use of contraception. Subsequently, surgical opinion was sought regarding possible nephrectomy. The patient underwent a laparoscopic right nephrectomy and partial ureterectomy successfully. Microscopic analysis of the kidney revealed chronic pyelonephritis and extensive cortical atrophy. At four month followup, the patient demonstrated excellent blood pressure control at 118/88 mm of Hg while maintained on hydrochlorothiazide 12.5 mg once daily by mouth.Secondary hypertension is more common in the pediatric population. 60–80% of secondary hypertension is caused by renal parenchymal disease . VUR, muVUR was noted in 29% to 50% of children with UTIs, often the initial presentation . The preIncidence of hypertension in adults with reflux nephropathy has been reported to be anywhere between 38–60% –9. A retTo our knowledge, only one study in adults so far has reported serious consideration of VUR as a secondary cause hypertension in the absence of renal injury markers. In a study by Barai et al., 19.1% of adult patients with hypertension who do not have any evidence of renal involvement had VUR and are often labeled as having essential hypertension . An editIn the absence of proteinuria, the underlying cause of how VUR and a scarred kidney cause hypertension is unclear. Past studies have suggested that reflux nephropathy can activate the renin angiotensin system. In children, it has been shown that patients with VUR have high circulating or selective renal vein renin levels . One stuGuidelines for diagnosis of VUR in the adult population have been devised with reference to the screening for VUR in the pediatric population . A recenTreatment options can be surgical or medical. Medical treatment consists of antimicrobial treatment or prophylaxis of UTI and treatment of hypertension; however, long-term antibiotic prophylaxis may not be an ideal option for a younger patient in whom more definitive treatment would be preferred . Surgical options have been well studied in the pediatric population. Primary ureteral reimplantation, extravesical and intravesical surgical techniques, ureteroneocystotomy, and endoscopic subureteral injections are some of the techniques employed in the correction of VUR in the pediatric population with success rates of 92–98% . In adulThe only two indications for surgical correction of unilateral reflux in adults are a history of pyelonephritis with unsuccessful medical treatments or in women of childbearing age . Recent Our patient's workup was significant for recurrent urinary tract infections, grade 3 vesicoureteral reflux, minimal proteinuria, and a scarred kidney. Ultrasound with Doppler and voiding cystourethrogram were used for diagnosis. Medical treatment was not an ideal option in our young patient of child bearing age. A nephrectomy was performed primarily for persistent hypertension felt to be secondary to the unilaterally scarred kidney. After nephrectomy, our patient demonstrated markedly improved blood pressure control. Through this case we hope to highlight VUR as a cause of secondary hypertension. Markers of renal injury such as elevated creatinine and proteinuria may be absent; however, a scarred kidney probably is the cause of patient's hypertension through an unknown mechanism. Medical management may not be ideal, and stenting is not the optimal treatment for a scarred kidney. Nephrectomy may be therapeutic in these cases. The long-term benefits remain to be seen, and randomized control trials are needed to study the efficacy of surgical versus medical management of VUR in the adult population.


The prevalence of type 2 diabetes is rising, and most of these patients also have hypertension, substantially increasing the risk of cardiovascular morbidity and mortality. The majority of these patients do not reach target blood pressure levels for a wide variety of reasons. When a literature review provided no clear focus for action when patients are not at target, we initiated a study to identify characteristics of patients and providers associated with achieving target BP levels in community-based practice.We conducted a practice- based, cross-sectional observational and mailed survey study. The setting was the practices of 27 family physicians and nurse practitioners in 3 eastern provinces in Canada. The participants were all patients with type 2 diabetes who could understand English, were able to give consent, and would be available for follow-up for more than one year. Data were collected from each patient's medical record and from each patient and physician/nurse practitioner by mailed survey. Our main outcome measures were overall blood pressure at target (< 130/80), systolic blood pressure at target, and diastolic blood pressure at target. Analysis included initial descriptive statistics, logistic regression models, and multivariate regression using hierarchical nonlinear modeling (HNLM).Fifty-four percent were at target for both systolic and diastolic pressures. Sixty-two percent were at systolic target, and 79% were at diastolic target. Patients who reported eating food low in salt had higher odds of reaching target blood pressure. Similarly, patients reporting low adherence to their medication regimen had lower odds of reaching target blood pressure.When primary care health professionals are dealing with blood pressures above target in a patient with type 2 diabetes, they should pay particular attention to two factors. They should inquire about dietary salt intake, strongly emphasize the importance of reduction, and refer for detailed counseling if necessary. Similarly, they should inquire about adherence to the medication regimen, and employ a variety of patient-oriented strategies to improve adherence. The age-standardized prevalence of type 2 diabetes in Canada rose by a relative 21% from 2003 to 2007 to 6.2% overall . As comoAlthough effective treatments exist for hypertension, most patients with type 2 diabetes do not reach target blood pressures. In the earlier baseline phase, only 27.1% of patients were at target (< 130/80) -10.A review of the literature revealed a wide array of patient, physician, and health system factors contributing to the success or failure in reaching target BP goals. Many, such as patient age ,11-17 anThe literature review provided no clear guidance to our team of eight community family physicians that had collected the baseline phase data regarding where to focus their attention when patients are not at target blood pressures. With the support of university colleagues, they initiated a study to identify characteristics of patients and providers associated with achieving target BP levels in patients with type 2 diabetes in typical community-based practice. This paper will outline which characteristics were found to be significant and provide suggestions for increased attention in office practice.This practice-based, cross-sectional study which included both observational and mailed survey components was conducted in family physician and nurse practitioner practices in the Maritime Family Practice Research Network in 3 eastern provinces in Canada. The study was first approved by our institutional Research Ethics Board (CD-2004-221); it was subsequently approved by six more Research Ethics Boards with jurisdiction over participating practices. Data for this phase of our study was collected between January 2008 and June 2010. All participants signed informed consent forms.Potential participants included all patients of each practice with diagnoses of type 2 diabetes and hypertension who could understand English, were able to give consent, and were expected to be available for follow-up for more than one year. Patients were included if they had their most recent BP measurement taken with a BpTRU™ within the past six months in order to relate that pressure with the results of the patient survey. Because antihypertensive drug prescribing was one of our study variables, only patients taking those medications were included in the analysis.Data was obtained from three sources: the patient's medical record, a self-administered survey mailed to each patient and a survey completed by each participating provider. Measures  from all sources were guided by a modification of the Andersen conceptual model of health service utilization  and inclCompendium of Pharmaceuticals and Specialties [Clinical data relevant to the diagnosis and management of type 2 diabetes and hypertension were extracted from each patient's medical record. Individual level patient characteristics included predisposing characteristics  and factors associated with the identification of evaluated need such as the durations of diabetes and hypertension, targeted clinical factors  , renal scialties . The sumThe main outcomes of interest, or evaluated health status, were overall BP at target, systolic blood pressure (SBP) at target and diastolic blood pressure (DBP) at target. BP readings extracted from the patient medical record were the most recent measures taken with an automated oscillometric machine (BpTRU™). The BpTRU™ readings were done according to a protocol provided with the machine, using the average of the second through fifth readings. Blood pressure at target was defined as less than 130/80 mmHg, consistent with the CHEP recommendations ,27. DetaInformation pertaining to patients not normally found in the medical record was obtained directly from them using a survey questionnaire developed for this study. Survey administration was by mail and followed a modified Dillman's method . Each elTo account for clustering of patients within provider practices across the three provinces, contextual information pertaining to the practice and the system they operate within were collected through a survey mailed to each participating provider using the same method as that for the patient survey. Items in this provider survey solicited responses regarding provider demographics and practice information.Following initial descriptive statistics, bivariate regression models were used to evaluate the crude association between each potential predictor variable and all outcomes of interest. This was followed by multivariate analysis where hierarchical nonlinear modeling (HNLM) was utilized in order to account for the clustering of patients associated with a provider. Predictors found to be significant at p ≤ 0.2 in the bivariate analyses were considered for inclusion in the hierarchical multivariate modeling. For the hierarchical analyses, all predictors were tested for random or fixed slopes and accounted for in the regression equations as required.A manual stepwise procedure was used for the addition of individual predictors to build the model. Individual level patient predictors (Level 1) were tested first, followed by contextual system and provider predictors (Level 2). Predictors were considered statistically significant in the final model with a p-value ≤ 0.05.HLM version 6.03  was usedIn total, 656 patients met the inclusion criterion of this study and were asked to complete the self-administered survey. Of these eligible patients, 588 completed the patient survey for a response rate of 89.6%. Eighteen respondents were removed from analyses due to missing critical information, such as incomplete survey information from their provider or antihypertensive medications not being prescribed. This resulted in a final cohort of 570 for analysis. These 570 patients had been recruited by 27 providers who represented a diverse group of family physicians (n = 25) and nurse practitioners (n = 2) from urban and rural settings, and various practice types and payment methods , an evaluated need factor  and personal health practices (medication adherence and BP self-monitoring). All were associated with lower odds of attaining SBP target. Age greater than 75 years was associated with lower odds for reaching target as were patients diagnosed with overt nephropathy, with low medication adherence and often self-monitoring their BP.The attainment of DBP target was significantly associated with age and gender (predisposing characteristics), controlled low-density lipoprotein cholesterol (LDL-CHOL)  and salt intake . Female patients had twice the odds of being at DBP target as males  while patients 65 years of age and older were more than three times as likely as patients < 55 years. Also associated with greater odds of attaining DBP target were patients with controlled LDL-CHOL  and those reporting eating foods low in salt .Contextual factors pertaining to the system or providers (level 2) did not add significantly to the final multivariate models. However there was significant variability in BP at target across providers, which justified the use of the multi-level method.Of the 570 patients included in this analysis, 54.4% had achieved both SBP and DBP targets (< 130/80), much higher than the 27.1% reported in the baseline phase and comparable to a large study in Ontario, Canada, which also used BpTRU™ measurements (50.3%) ,36, and The remainder of the discussion will focus on three significant factors found by our study that potentially can be modified by interventions of health practitioners caring for hypertension. Patients who reported low medication adherence and self-monitoring of blood pressure were less likely to have achieved overall BP target levels while patients eating foods low in salt were more likely. These factors can be influenced by a wide array of health care providers.Our results are in keeping with other studies that report an association between medication adherence and blood pressure control. In a study by Casson et al., poor adherence was associated with increases in systolic blood pressure when patients were monitored over an 18 month period . Morris http://hypertension.ca/chep/therapy-tables/#table 5. Further research could clarify which of these strategies is most effective in improving adherence and lowering blood pressure.A review of strategies to enhance hypertensive medication adherence found that no single intervention has emerged as superior to others. It is recommended that a patient-centered approach that is tailored to overcome specific patient barriers may be the best strategy to improve adherence to hypertensive medication . A varieThe association of self-monitoring of blood pressure with a lower likelihood of achieving BP targets contrasts with much of the literature on the topic. Bray et al. reported on a review of 25 randomized controlled trials that had been published by 2009 that included self-monitoring and self-management of blood pressure as an intervention . Twelve Our study was an observational study, with no explicit intervention for self-monitoring. The data presented came from the patient survey response to the question "Do you check your blood pressure outside of your doctor's office?" Response options were "No," "Sometimes," or "Often." Those who responded "often" were less likely to be at target . We have no evidence to determine how many patients were advised to self-monitor by their doctor or nurse practitioner as a component of "usual care," or how many chose to do it themselves at home or in a setting such as a pharmacy. There was no structured co-intervention. Our study design did not provide us with evidence to explain the apparent difference with previous literature. We have speculated that individuals who were not at target might be more likely to be concerned about their BP and therefore check it between office visits. It may also be that, without a co-intervention, self-monitoring alone offers a small  to no 5 advantagOur finding that patients who report a low salt diet are more likely to be at overall target and diastolic BPs comes as no surprise and gives support to current guidelines . It stroOur "real world" community practice setting, in rural and urban locations with a variety of available resources and supports for patients, is a strength of this study. A small number of academic practices (10) contributed only 8% of the patient cohort. None of the practices had a special focus on diabetes; all were broad primary care practices of physicians and nurse practitioners interested in contributing to research. As well, our high patient survey response rate (89.6%) reinforces the value of our data and enhances the generalizability of our findings. An additional strength is the use of hierarchical nonlinear modeling which allowed us to control for the clustering of patients within practices and the variance between providers.One of the limitations of our study is that the population is less ethnically diverse than the general Canadian population. Some measures were derived from a self-reported mailed survey and may be subject to over- or under-reporting. However, commonly biased self-report measures  all came from the provider, not the patient. Additionally, 8% of the data for medication adherence was missing. Only patients with an available BpTRU™ measurement were included in analysis and because of this, a small number of patients could not be included. Their providers could not obtain a BpTRU™ reading due to the size and shape of the arm. These were very high BMI patients with a "conically" shaped arm.Although numerous factors have been shown to be associated with achieving BP targets, our study identified two specific issues that health practitioners should focus on when treating patients who are still not at target. They should emphasize salt-restriction, possibly with referral to a nutritionist, and employ patient-centered strategies to assess and enhance medication adherence.The authors declare that they have no competing interests.WP and BL participated in the conception and design of this study, the analysis and interpretation of results, and drafting and revising the manuscript. FB, MG, RAG, JH, KL, and IM participated in the conception and design of the study, acquisition of data, the interpretation of results, and the revising of the manuscript for intellectual content. FIB, NN, IS, BM, PD took part in the conception and design of the study, the interpretation of the results, and the revising of manuscript for intellectual concept. KVA took part in the analysis and interpretation of the results and the drafting and revising of the manuscript. MSG participated in the interpretation of the results and the revising of the manuscript. All authors have approved the final version.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/12/86/prepub


The GD showed a higher frequency of C-reactive protein above laboratory cutoff (P = 0.044), higher frequency of male gender, and a non significant higher value of VO2max (P = 0.099). The CA-IMT was similar. Only better aerobic capacity was associated with lower frequency of high C-reactive protein when adjusted to diabetes and gender in a logistic regression model. In conclusion, aerobic capacity was associated with inflammatory state, in CKD patients, independently of diabetes presence.The persistent inflammatory state is common in diabetes and chronic kidney disease (CKD). These patients present exercise intolerance and increased arterial stiffness. Long-term aerobic exercise has been associated with better arterial compliance, antidiabetic and antiinflammatory benefits. We assessed the hypothesis that in patients with diabetes and CKD, better aerobic capacity is associated with less inflammatory state and arterial stiffness. Thirty-nine CKD patients  were evaluated. According to CKD etiology two patient groups were obtained: group of diabetics (GD) was formed by 11 patients and nondiabetics (GND) formed by 28 patients. Central blood pressure and arterial stiffness were evaluated by Sphygmocor device. Carotida intima-media thickness (CA-IMT) was evaluated by ultrasonography. Aerobic capacity was measured by estimated VO Chronic kidney disease (CKD), characterized by irreversible loss of renal function , is a maOne of the major risk factors for development of CKD is diabetes, which causes, in addition to kidney damage, several cardiovascular comorbidities and visual and peripheral vascular complications. Persistent chronic microinflammatory state is very common in diabetic and CKD patients. It is associated with malnutrition and cardiovascular disease and is a potent predictor of mortality .Increased arterial stiffness has been recognized as important predictors of CV diseases in patients with CKD and diabetes patients and is associated with chronic inflammatory state . Like pu2max), muscle gain in mass and capillary density, velocity of nerve conduction, and blood pressure (BP) [CKD patients usually manifest symptoms of exercise intolerance such as muscle weakness and fatigue and are less active, exhibiting muscle atrophy even when compared to inactive normal subjects . CKD pature (BP) –11.Recent evidence had shown that physical activity can ameliorate inflammatory state in CKD . Two intTherefore, the aim of this study is to evaluate the association between aerobic capacity and presence of diabetes, inflammation, arterial stiffness, and CA-IMT in chronic kidney disease patients.Were included hemodialysis patients for at least six months or CKD predialysis patients. All subjects were aged more than 18 years. Subjects unable to perform exercise testing, with coronary heart disease or previous coronary artery bypass, active infection, cancer, or liver cirrhosis were excluded. Informed consent was obtained from each patient. This study was approved by Research Ethics Committee of the Botucatu Medical School with the protocol 3083/2009.Clinical data evaluated were age, gender, body mass index, and kidney disease etiology. The following laboratorial data was evaluated: hemoglobin, calcium, phosphorus, parathyroid hormone, albumin, iron, ferritin, transferrin saturation, C-reactive protein, creatinine, and creatinine clearance. All laboratorial evaluations were performed in the morning while fasting. The hemodialysis patients were evaluated in the morning while fasting in the interdialytic day.The C-reactive protein was evaluated by dry chemistry , and test sensitivity was 0.1 mg/dL. Elevated CRP was defined when a patient had values superior to 1 mg/dL, as defined by superior limit of our laboratory.Patients who met the inclusion criteria underwent Sphygmocor CPV  evaluation for CBP, PWV, and AIx. The measurements were performed in supine position. The BP stabilization was considered when the difference between three consecutive measurements in five-minute interval was not greater than 5 mm Hg. Average and maximum of left and right CA-IMT by ultrasonography according to Mannheim carotid intima-media consensus  were eva2max, the patients were submitted to a treadmill test (Bruce protocol [2max = (time × 3.29) + 4.07 for men, and VO2max= (time × 3.36) + 1.06 for women. All evaluations were performed on the same day in the same sequence. Hemodialysis patients underwent their examinations on interdialytic days.For the estimation of VOprotocol ), and thAccording to the kidney disease etiology, two patient groups were obtained. Group D (GD) formed by diabetic patients and group ND (GND) formed by nondiabetic patients. The groups were compared regarding age, body mass index, and laboratorial data, systolic, diastolic and pulse CBP, PWV, Aix, and CA-IMT.t-test or Mann-Whitney was used when appropriate. Multiple logistic regressions were performed to identify variables independently associated with inflammation and selected variables with statistical probability of <0.1 between groups. Values were expressed as mean ± standard deviation to parametric variables or median (first–third quartile) when appropriate. A P < 0.05 was considered statistically significant.For comparison between groups, P = 0.725). Other clinical and laboratorial variables of the groups are shown in Tables P = 0.011. There were included 39 patients . Clinical and laboratory characteristics are shown in P = 0.044; Diabetic group had a CRP value of 1.50 (0.32–2.72) mg/dL and GND 0.5 (0.20–0.75) mg/dL. When patients were divided according to the inflammatory status (CRP > 1 mg/dL or CRP ≤ 1 mg/dL) a significantly greater number of chronic inflammatory state patients was found in GD  and 23.5 ± 7.44 mL/kg/min (P = 0.042) in diabetic group (n = 13 diabetic men), so, reinforcing the difference in VO2max between diabetics and nondiabetics. Thickness of the intimae-media right carotid artery showed a trend of higher values in diabetic patients , other indexes of carotid thickness were similar between groups. Comparing the values of arterial stiffness indexes, GD had similar values of GND.Was observed a trend of higher VO2max (P = 0.024). Gender and diabetes were not independently associated with inflammatory state . 2max, in all patients, where the higher the aerobic capacity, the lower their inflammatory state .In multiple logistic regression, with CRP as dependent variable , the mai2 level and that the VO2 level had a strong association with CRP independently of diabetes. We can speculate that it is possible that the inflammatory state of chronic kidney disease diabetic patients would be caused, in grand part or at least in part, by physical deconditioning. This speculative possibility must be confirmed in other studies with a great number of individuals and especially in longitudinal and interventional studies.The C-reactive protein is a sensitive marker of inflammation, and an increase in its levels has been associated with higher risk of vascular disease . Diabeti2max have lower levels of CRP compared with basal values [The long-term exercise training increases the nitric oxide availability and diminishes the oxidative stress, inflammation and blood pressure, which improves the endothelial function and consequently cardiovascular mortality –23. Patil values . Nitric l values .In the elderly, training also decreased the concentration of CRP , 25. TheAccording to the American College of Sports Medicine and American Heart Association, to reduce risk of cardiovascular events, individuals with chronic illnesses should perform moderate-intensity physical activity, 30 min, 5 times weekly .2max superior to 17.5 mL/kg/min had a higher survival compared to individuals with lower peak VO2 [2max of the current study was 26.6 ± 8.02 mL/kg/min.Physical capacity proved to be an important predictor of survival. In a study that evaluated patients with CKD and followed them over three years, patients with a VOpeak VO2 . The mea2max as a principal determinant of C-reactive protein. Our results were in accordance with previous studies [Although the benefits of physical training have been demonstrated in CKD patients , 34–36,  studies –39 and r2max. So, better physical aerobic capacity was associated only with the metabolic marker of inflammation and not with structural or functional properties of arteries. However, these data do not exclude that long-term assisted physical training could have an impact on those parameters not observed in this transversal study.In the present study, measures of intima-media thickness of carotid arteries and arterial stiffness did not correlate with VO2max was indirectly measured.In the current study, some limitations must be recognized. First, a small number of subjects was evaluated, nevertheless this number was sufficient to detect statistically significant correlations. This is a transversal study, so it submits to limitations inherent to this design and must be confirmed in a longitudinal and interventional study. However, we evaluated the confounding variables and took into account those in multiple analysis. Finally, the VO2max was associated with lower frequency of elevated CRP levels in subjects with chronic kidney disease. The current study strengthens previous findings and reinforces the hypothesis of cardiovascular benefits with a better aerobic capacity in CKD diabetic patients.In conclusion, better VO


To control blood pressure (<140/<90 mm Hg), bisoprolol and amlodipine could be doubled (10 mg per day) and α-methyldopa (0.5–2 g per day) added. Sitting blood pressure fell by 19.5/12.0 mm Hg in R patients and by 24.8/13.2 mm Hg in E patients and heart rate decreased by 9.7 beats per minute in R patients with no change in E patients (–0.2 beats per minute). The between-group differences (R minus E) were 5.2 mm Hg (P<0.0001) systolic, 1.3 mm Hg (P=0.12) diastolic, and 9.6 beats per minute (P<0.0001). In 57 R and 67 E patients with data available at all visits, these estimates were 5.5 mm Hg (P<0.0001) systolic, 1.8 mm Hg (P=0.07) diastolic and 9.8 beats per minute (P<0.0001). In R compared with E patients, 45 vs 37% (P=0.13) proceeded to the higher dose of randomised treatment and 33 vs 9% (P<0.0001) had α-methyldopa added. There were no between-group differences in symptoms except for ankle oedema in E patients (P=0.012). In conclusion, new compared with old drugs lowered systolic blood pressure more and therefore controlled hypertension better in native African black patients.To address the epidemic of hypertension in blacks born and living in sub-Saharan Africa, we compared in a randomised clinical trial (NCT01030458) single-pill combinations of old and new antihypertensive drugs in patients (30–69 years) with uncomplicated hypertension (140–179/90–109 mm Hg). After ⩾4 weeks off treatment, 183 of 294 screened patients were assigned to once daily bisoprolol/hydrochlorothiazide 5/6.25 mg ( They also indicated that the majority of hypertensive patients require multiple drugs to achieve control.10 Modern guidelines for the management of hypertension13 endorse the use of single-pill combinations of antihypertensive drugs to initiate treatment. Recommendations for the management of hypertension in native black African patients are to a large extent extrapolations of studies conducted in blacks living in the United States or Europe and do not account for differences in selection in previous generations,14 ethnic admixture,15 and lifestyle.16 We therefore designed the newer versus older antihypertensive agents in African hypertensive patients (NOAAH) to compare in native black African patients a single-pill combination of newer drugs, not involving a diuretic, with a combination of older drugs, including a diuretic.Sub-Saharan Africa is facing an epidemic of cardiovascular disease,17 The sponsor  and all participating centres obtained ethical clearance from their local Institutional Review Boards and/or National Regulatory Authorities. Patients provided written or witnessed informed consent at screening.The NOAAH trial was an open, randomised, investigator-led multicentre trial complying with the guidelines for good clinical practice.18 treatment-naïve or previously treated patients of either sex, aged 30–69 years with uncomplicated grade 1 or grade 2 hypertension and a maximum of two additional risk factors qualified for enrolment. Previously treated patients should not have a compelling indication to continue treatment and should be on a single drug. After a 4-week run-in period off treatment, eligible patients had a sitting blood pressure ranging from 140 to 179 mm Hg systolic or from 90 to 109 mm Hg diastolic, or both. These blood pressure thresholds were averages of three consecutive readings obtained by means of validated19 Omron 705IT monitors  fitted with a cuff adjusted to arm circumference. To exclude orthostatic hypotension, systolic blood pressure measured immediately after standing up had to be at least 110 mm Hg. In addition to major illness and high cardiovascular risk, the exclusion criteria encompassed atrial fibrillation, electrocardiographic left ventricular hypertrophy with strain pattern, a serum creatinine concentration higher than 1.4 mg dl−1 in women or 1.5 mg dl−1 in men, overt diabetes mellitus and proteinuria or haematuria on a dipstick test.As outlined in detail in the published protocol,The Studies Coordinating Centre (SCC) in Leuven randomised eligible patients, using permuted blocks of four consecutive patients within each centre, to a single-pill combination of 6.25 mg hydrochlorothiazide plus 5 mg bisoprolol (older drugs) or the combination of valsartan 160 mg plus amlodipine 5 mg (newer drugs). To achieve blood pressure control, the study medication could be up titrated to 6.25 mg hydrochlorothiazide plus 10 mg bisoprolol in the reference group and to 160 mg valsartan plus 10 mg amlodipine in the experimental group. If blood pressure remained uncontrolled, doctors could add α-methyldopa up to 2 g per day to the study medication. SCC shipped all medications to the recruiting clinical sites. To assess drug accountability and adherence, each medicine package carried a unique identification number. Patients had to return unused medications at the next visit. Investigators counted the number of unused pills.21 For analysis, the scores of the 34 questions were averaged into an overall score and into organ-specific scores summarising neurosensory, circulatory, gastrointestinal, respiratory and urogenital symptoms , an assessment of symptoms and side effects, measurements of haemoglobin, haematocrit, serum sodium, potassium, creatinine and total cholesterol, and blood glucose, and a dipstick test on a fresh urine sample. Patients graded symptoms on a 5-point scale  by means of a validated questionnaire.P of 0.01 and 90% power, 180 randomised patients, 90 per group, were required. Secondary outcomes were time to blood pressure control and incidence of adverse events. Controlled hypertension was a sitting blood pressure below 140 mm Hg systolic and below 90 mm Hg diastolic (average of three consecutive readings).The primary outcome was the baseline-adjusted between-group difference in the sitting systolic blood pressure. To demonstrate a 5 mm Hg difference  with a two-sided t test, Mann-Whitney's U, the χ2 statistic, and the log-rank test, respectively. Treatment effects on continuous variables were analysed using a mixed model with baseline blood pressure and follow-up time as fixed effects and centre as random effect. Cox regression was used to compare time with blood pressure control. Statistical significance was a two-sided P-value of 0.05 or less.SAS software , version 9.3, was used for database management and statistical analysis. Group statistics include means (s.d.), medians (interquartile range (IQR)) and frequencies (per cent). The main analysis included all randomised patients with at least one follow-up visit according to the intention-to-treat principle. The cohort analysis only included patients who had data at each scheduled visit. Between-group comparisons of means, medians, proportions and Kaplan–Meier survival estimates relied on Student's P⩾0.06) as well as among those in the cohort analysis (P⩾0.19), with the exception of body mass index (P=0.009) in the cohort analysis. There were no differences among patients included or not included in the cohort analysis (P⩾0.17). The study comprised 96 (52.5%) women and 128 (69.9%) treatment-naïve patients. Age (±s.d.) averaged 51.2±9.0 years, ranging from 30.5 to 68.9 years. None of the patients had a fall in systolic blood pressure exceeding 20 mm Hg on standing.P=0.24). In patients on old drugs, compared with those assigned new drugs, 45 vs 37% (P=0.13) proceeded to the higher dose of randomised treatment and 33 vs 9% (P<0.0001) had α-methyldopa added (P=0.13) and 38.6 vs 7.5% (P<0.0001), respectively  and similar in both groups (pa added . In the ectively . The medP⩾0.07). The overall tablet count averaged (±s.d.) 90±18% . Heart rate decreased (P<0.0001) in the patients randomised to old drugs with no changes in the new-drug group (P⩾0.12), resulting in a significant (P<0.0001) between-group differences at all follow-up visits in all patients  after randomisation, irrespective of whether blood pressure was measured in the sitting or standing position. Sitting systolic blood pressure decreased more in patients randomised to new drugs. In all patients (P=0.013) at the last visit and to 5.2 mm Hg (P<0.0001) for all visits combined. In the cohort analysis, the corresponding differences were 5.4 mm Hg (P=0.035) and 5.5 mm Hg (P<0.0001), respectively. The P⩾0.32) and in the standing systolic and diastolic blood pressures (P⩾0.07) were not different between the study groups  had reached blood pressure control. Disregarding visits at which patients were taking α-methyldopa, these numbers were 53 (61.6%) and 27 (45.0% P=0.047), respectively. The median time interval from randomisation to blood pressure control was 12 weeks  on new drugs and 18 weeks  on old drugs (P=0.011). In Cox regression with adjustments applied for the blood pressure at randomisation, the probability to achieve blood pressure control was 52% greater on new than old drugs . Findings in the cohort analysis were confirmatory  and 40 allocated to old drugs (44.9% irmatory .P⩽0.010) with no between-group difference (P⩾0.29). After randomisation, the between-group differences in the organ-specific and individual symptom scores were not significant (P⩾0.057), with the exception of ankle oedema that achieved a higher score in patients on new drugs (P=0.012). The within-group changes (P⩾0.10) and the between-group differences (P⩾0.08) in the haematological and biochemical measurements and in the ECG Cornell index did not reach statistical significance . Analyses involving blood pressure changes from baseline to the last follow-up visit were confounded by the threefold higher usage of α-methyldopa in the old-drug group. In general, standing blood pressure readings are less standardised than in the sitting position, because of the varying time intervals between the last sitting and the first standing blood pressure measurement. There were no significant between-group differences in the sitting or standing diastolic blood pressures. Adherence was excellent as exemplified by tablet counts and, more objectively, by the lower heart rate on the β-blocker in the old-drug group and the higher score for ankle oedema in patients randomised to amlodipine in the new-drug group. Symptom scores improved during follow-up with no between-group differences, whereas no changes occurred in the Cornell voltage index. Missing data were addressed in two ways: (i) by carrying the last information forward in the intention-to-treat analysis of all randomised particpants and by a cohort analysis, which included only patients with information available at all scheduled visits.The key NOAAH finding was that over 6 months of follow-up the sitting systolic blood pressure decreased by ∼5 mm Hg more on a single-pill combination of new drugs compared with old drugs. Blood pressure control was achieved sooner on new drugs with less need of the addition of α-methyldopa. Over the whole follow-up, the standing systolic blood pressure also decreased by 4.6 mm Hg. In analyses of the blood pressure changes from randomisation to the last follow-up visit, sitting systolic blood pressure was 5.2 mm Hg lower on new drugs, but only 3.9 mm Hg in the standing position , or even months (grade 1), before antihypertensive drug treatment is initiated. All NOAAH patients received counselling on lifestyle. Second, combination therapy was used to initiate antihypertensive treatment. In single-pill combinations, both components potentiate one another. The advantages of combination therapy28 are earlier and tighter blood pressure control than monotherapy or sequential combination therapy; simplification of the therapeutic regimen and therefore better adherence; avoidance of dose-dependent adverse effects experienced with higher doses of single agents; and attenuation of the adverse effects of some agents when used alone. For instance, angiotensin II receptor blockers reduce the prevalence of ankle oedema associated with dihydropyridine calcium-channel blockers.29 Third, blacks have a higher sensitivity to salt intake and an impaired ability to excrete ingested salt. This leads to an overall expansion of the intravascular volume. According to the AB/CD algorithm,12 both treatment arms of NOAAH included a drug class that addressed the low-renin volume component of hypertension (hydrochlorothiazide and amlodipine) as well as an agent  interfering with the high-renin vasoconstrictor component. Diuretics and calcium-channel blockers potentiate the efficacy of renin system inhibitors in black low-renin patients.30In several design aspects, the NOAAH trial closely followed current US,9 These considerations should be accounted for when current guidelines for the treatment of black hypertensive patients are updated. One limitation of the current study is that it did not include a formal cost-effectiveness analysis.Cost containment is important in the management of common chronic diseases, such as hypertension, especially in resource-poor settings, where out-of-pocket medical expenditure is usual practice. In the countries, in which NOAAH was running, many cheap generics are being sold, however, with minimal quality requirements or even without any regulation via illegal channels. While the older drugs are cheaper, their chronic use contributes to the development of side effects such as the metabolic syndrome, diabetes mellitus, gout and dyslipidaemia. More importantly, treatment with new antihypertensive drugs results in lower morbidity and mortality.31 Furthermore, NOAAH demonstrated that a simple therapeutic regimen consisting of a single-pill combination of either old or new drugs efficiently lowered blood pressure in black patients born and living in sub-Saharan Africa, thereby extending and generalising previous findings in African Americans32 and South African blacks.22 NOAAH therefore revealed an enormous potential to curb the epidemic of premature cardiovascular mortality and morbidity,2 mainly caused by hypertension,4 in sub-Saharan Africa. Several African countries, such as Nigeria, implement programmes, in which patients with HIV or tuberculosis are being followed up and treated free of cost. The time might have come to consider similar approaches to screen for hypertension, the leading cause of death in the developing world,2 and to provide patients access to antihypertensive treatment at low or no cost.Over 6 months, the new compared with the old drugs lowered systolic blood pressure ∼5 mm Hg more. If sustained over years, a 5-mm Hg lower systolic blood pressure might be associated with a 20% reduction of cardiovascular mortality and a 30% decrease in major cardiovascular complications.4–2013) to proceed from planning to publication. To our knowledge, NOAAH is the first successful randomised clinical trial of antihypertensive treatment in developing countries located in sub-Saharan West Africa. The skills learnt by local investigators should be useful for much more demanding studies in the future. Such trials might have intermediate or hard endpoints rather than change in blood pressure and must address the cost-effectiveness of various pharmacological options to treat the legions of hypertensive patients in sub-Saharan Africa.In addition to its scientific objectives, NOAAH also intended to build capacity among sub-Saharan investigators to conduct randomised clinical trials in the field of cardiovascular medicine. NOAAH showed that conducting such trials in this region of the world met problems related to regulations, logistics, infrastructure and know how. It took 5 years (2008


Identification of an inflammatory asthma phenotype currently requires sputum induction. This technique is invasive, has a high variability, is time-consuming and a burden for patients. Therefore, there is a strong need for a routine blood test to establish the inflammatory phenotype of asthma. We designed a clinical cohort study  in 115 asthma patients visiting the outpatient clinic to compare the results of such a blood test to sputum analysis. This abstracts focuses at the preliminary results in 21 patients.To assess whether expression of active FcgammaRII (CD32) and MAC-1( CD11b) on neutrophils and eosinophils in peripheral blood enables the diagnosis of an inflammatory phenotype of asthma.21 asthma patients were recruited at the outpatient clinic of the University Medical Centre Utrecht. Clinical parameters were gathered and FENO , sputum induction and blood tests were performed. Eosinophils and neutrophils in whole blood were stained with a FITC labeled antibody against active FcgammaRII receptor (clone A17) and a PE-labeled antibody against CD11b in the absence and presence of the activator fMLP (1 µM). Subsequently, fluorescence intensity was measured by flowcytometry.Expression of Mac-1 (CD11b) and activeFcgammaRII (CD32) on eosinophils at basal level and after stimulation (fMLP) showed refractory cells (low responsiveness for fMLP) in case of granulocytic asthma . FENO values were overall lower in paucigranulocytic asthma compared to granulocytic asthma .‘activation prone’ eosinophils migrated to the lung.Refractory blood eosinophils determined by a simple blood test were found in those patients that were more likely to suffer from granulocytic asthma . Therefore, paucigranulocytic asthma can be distinguished from other phenotypes purely based on blood analysis and FENO measurement. A low expression of activation epitopes on eosinophils in peripheral blood might indicate that


Objective. The aim of this study was to identify patients with Parkinson's disease who showed loss or decrease of nocturnal blood pressure fall (nondipper patients) as a marker of autonomic dysfunction. Presence or absence of orthostatic hypotension was considered to investigate whether alterations in circadian blood pressure pattern are associated with posture-related dysregulation of blood pressure. Methods. 40 patients with Parkinson's disease underwent 24-hour blood pressure monitoring. 21 patients were diagnosed with arterial hypertension and received anti-hypertensive drugs. Nondipper patients were defined as having nocturnal decrease of mean systolic and diastolic blood pressure less than 10%. Presence or absence of orthostatic hypotension was determined by Schellong's test. Results. We identified 35 nondipper patients (88%). Nondipping was detected in 20 patients with orthostatic hypotension (95%) and in 15 patients without orthostatic hypotension (79%). 18 patients with hypertensive and 22 patients with normal blood pressure values were detected. Conclusions. In conclusion 24-hour blood pressure monitoring showed a high prevalence of nondipping in 40 patients with Parkinson's disease with and without orthostatic hypotension independent of coexisting arterial hypertension and antihypertensive treatment. 24-hour blood pressure monitoring may be useful to identify non-dipping as a marker of autonomic dysfunction in patients with Parkinson's disease. Parkinson's disease is a multisystem degeneration . Beside Involvement of the autonomic nervous system (ANS) occurs in the early stages of the disease . Cardiovascular dysautonomia, especially orthostatic hypotension, is frequently reported in Parkinson's disease .Involvement of peripheral components of the ANS can be demonstrated by MIBG scintigraphy.MIBG scintigraphy shows reduced cardiac uptake of MIBG (meta-[123I]iodobenzylguanidine) representing loss of postganglionic myocardial sympathetic nerve fibers in patients with Parkinson's disease and autonomic failure . HoweverFurther effects of autonomic cardiovascular dysfunction are demonstrated in earlier studies such as baroreceptor reflex dysfunction, alterations in circadian blood pressure regulation, and supine hypertension –15. FindAmbulatory blood pressure monitoring is frequently used in the diagnosis and therapy monitoring of arterial hypertension and allows an evaluation of the circadian blood pressure evaluation , 18.The aim of this study was to identify patients with Parkinson's disease who showed loss or decrease of nocturnal blood pressure fall (non dipper patients) as a potential marker of autonomic dysfunction.Presence or absence of orthostatic hypotension was considered to investigate whether alterations in circadian blood pressure pattern are associated with posture-related dysregulation of blood pressure.40 patients with Parkinson's disease underwent ambulatory 24-hour blood pressure monitoring. Parkinson's Disease was diagnosed according to the criteria of the United Kingdom Parkinson's disease Society Brain Bank . None ha20 of the patients were male, 20 were female; they were aged 41 to 82 years ; disease duration (Parkinson's disease) was 1 to 152 months (mean disease duration 49 months) . 21 patiLong-term blood pressure measurements were performed with “Mobilograph,” an oscillometric recorder . Patients were asked to maintain their normal physical activity. Nondipper patients were defined as having nocturnal decrease of mean systolic and diastolic blood pressure less than 10%. Presence or absence of orthostatic hypotension was determined by Schellong's test ; orthostatic hypotension was defined as a minimum decrease in systolic and/or diastolic blood pressure of 20 mmHg or 10 mmHg, respectively, on standing at the third minute .Results are presented as mean values (± standard deviation (SD)). A correlation analysis was performed between the presence of loss of nocturnal blood pressure fall and disease duration, age and presence of arterial hypertension/use of antihypertensive medication.Ambulatory blood pressure was recorded without interruption in all patients with a mean measurement period of 23 hours . The average number of measurements obtained during the 24-hour recording was 88% (± 11). Results of the mean diurnal arterial pressure showed 18 patients with hypertensive blood pressure values and 22 patients with normal blood pressure. Beside the 21 patients who were already diagnosed with arterial hypertension 6 patients showed hypertensive blood pressure values in ambulatory blood pressure recording; thus a total of 27 patients (68%) had arterial hypertension .We identified 35 non dipper patients (88%) among 40 examined patients with Parkinson's disease; 25 patients (63%) showed nocturnal increase of blood pressure . CorrelaAutonomic test results showed 21 patients with orthostatic hypotension. Loss of nocturnal blood pressure fall was detected in 20 patients with orthostatic hypotension (95%); this was also detected in 15 patients without orthostatic hypotension (79%). We found 11 patients with supine hypertension who were non dipper (100%) and 24 patients without supine hypertension who were non dipper (83%) .We investigated ambulatory blood pressure monitorings in patients with Parkinson's disease to evaluate the circadian blood pressure profile, especially the presence or absence of loss of nocturnal blood pressure fall (non dipper). Results of earlier studies show a variable percentage of non dipper patients , mainly Our results show that most of our examined patients with Parkinson's disease were non dipper (88%); this was even found in 79% of the patients without orthostatic hypotension. In conclusion, ambulatory blood pressure monitoring could be useful to detect autonomic dysfunction even in the early stages of Parkinson's disease when orthostatic hypotension is not present. α-adrenergic receptors due to sympathetic denervation in patients with Parkinson's disease may contribute to supine hypertension during the night due to exaggerated vasoconstriction [The alterations in the circadian blood pressure profile may be caused by impairment of the autonomic regulatory mechanisms, possibly through postural dysregulation of blood pressure as mentioned in earlier reports . This dytriction , 23, 24.Presence or absence of arterial hypertension was additionally investigated in our patients  to evaluate a possible association with loss of nocturnal blood pressure fall; there was no correlation between the presence of non-dipping and the presence of arterial hypertension or use of antihypertensive medication. 27 patients were additionally diagnosed with arterial hypertension or had hypertensive blood pressure values in ambulatory blood pressure recording (68%). 24-hour blood pressure monitoring should be performed in patients with Parkinson's disease and coexisting arterial hypertension, who are treated with antihypertensive medication. For prevention of an increased prevalence of end-organ damage we propose treatment of nocturnal hypertension in patients with Parkinson's disease. Treatment with antihypertensive drugs in patients with orthostatic hypotension may be complicated by worsening of the postural blood pressure fall in the upright position in these patients and thus may cause syncopes or cerebral ischemia. Consequently, vasoactive drugs should be used carefully in patients with Parkinson's disease and autonomic dysfunction. Alternatively sleeping in a 12° head-up tilt position may be helpful . Concerning an increased cardio—and cerebrovascular risk in patients with nondipping, Cornélissen et al. showed that—compared with dipping—abnormal chronobiological end points such as reduced circadian standard deviation of heart rate or elevated pulse pressure are more useful to discriminate between patients who are at a higher risk and who are not . HoweverIn conclusion 24-hour ambulatory blood pressure monitoring showed a high prevalence of non-dipping in 40 patients with Parkinson's disease with and without orthostatic hypotension independent of the coexisting arterial hypertension, and antihypertensive treatment. Our data strengthens the role of ambulatory blood pressure recording for detection of non-dipping not only in patients with orthostatic hypotension, but also in patients without orthostatic hypotension. Beside other autonomic tests  24-hour blood pressure monitoring may be helpful to support the detection of autonomic dysfunction in patients with Parkinson's disease even in the early stages of the disease.


Objective. The objective of this study was to investigate the effect of bromocriptine (BEC) on left ventricular mass index (LVMI) and residual renal function (RRF) in chronic kidney disease (CKD) patients with type 2 diabetes (T2D). Research Design and Methods. A 6-month double-blind randomized controlled trial was conducted in 28 patients with T2D and stage 4 CKD with increased LVMI. Fourteen patients received BEC  and 14 received a placebo . Cardiovascular changes were assessed by monitoring 24 h ambulatory blood pressure, two-dimensional-guided M-mode echocardiography, and N-terminal brain natriuretic peptide (NT-proBNP) plasma levels. RRF was evaluated by creatinine clearance and cystatin-C plasma levels. Results. Both BEC and PBO groups decreased blood pressure—but the effect was more pronounced in the BEC group. Average 24 h, diurnal and nocturnal blood pressures, and circadian profile showed improved values compared to the PBO group; LVMI decreased by 14% in BEC and increased by 8% in PBO group. NT-proBNP decreased in BEC (0.54 ± 0.15 to 0.32 ± 0.17 pg/mL) and increased in PBO (0.37 ± 0.15 to 0.64 ± 0.17 pg/mL). Creatinine clearance did not change in the BEC group and decreased in the PBO group. Conclusions. BEC resulted in a decrease on blood pressure and LVMI. BEC also prevented the progression of CKD while maintaining the creatinine clearance unchanged. Cardiovascular diseases (CVD) are the most frequent cause of morbidity and mortality in patients with chronic kidney disease (CKD) , 2. HighAdequate control of fluid overload is a key point in the prevention and handling of blood pressure and LVH. Nevertheless, in predialysis patients, when salt and fluid restriction is not sufficient, the need arises for pharmacological support. Although there are several classes of antihypertensive drugs available, the use of renin-angiotensin-aldosterone system (RAAS) blockers is considered the most effective renal and cardioprotective treatment , 11. CKD is characterized by an increase in sympathetic activity, which appears to be triggered by the unhealthy kidney –14, withIn addition to its cardioprotective effects, BEC also has important metabolic effects, reducing insulin resistance and improving glycemic control in overweight and patients with T2D. Quick-release BEC has been accepted by the US Food and Drug Administration for the treatment of T2D –26. Takihttp://www.ANZCTR.org.au/ACTRN12610000779077.aspx). All patients signed a written informed consent form before beginning the study.  A single-center, double-blind randomized controlled trial (RCT) was conducted in diabetic patients with stage 4 CKD. The protocol was approved by the scientific and ethics boards of the hospital and was performed according to the Helsinki Declaration. The protocol was also registered in the Australian New Zealand Clinical Trials Registry  was calcium channel blockers , α-1 blocker , furosemide (13 versus 10), thiazides (1 versus 0), and spironolactone (0 versus 1). Prevalent CKD patients from the out-patient clinic for diabetes and hypertension were invited to participate. Inclusion criteria were age 18–80 years, blood pressure ≥140/90 mmHg or on antihypertensive therapy, creatinine clearance (CrCl) ≤30 mL/minute, and LV mass index >116 gmPatients underwent an initial baseline evaluation, demographic and clinical data, measurements of biochemical parameters, glomerular filtration rate (GFR), echocardiography, and 24-hour ambulatory blood pressure were recorded. Patients were then randomized to receive an initial dose of 2.5 mg a day (tablet) of bromocriptine mesylate (BEC), or placebo (1 tablet) with a subsequent increase to 2 tablets per day after one week and 3 tablets from the third week. Patients were followed each week during the first four weeks and every month thereafter, for a total of 6 months. Antihypertensive drug doses were adjusted when necessary. Patients were prescribed a diet containing less than 100 mmol/day of sodium and reduced content of phosphorus according to current clinical guidelines.Overnight-fasting blood samples were taken following 30 minutes of complete rest in recumbent position from the antecubital vein without stasis between 7:00 and 8:00 a.m. at baseline and at each visit. Samples were centrifuged, and plasma and serum were separated and kept at −70°C until assay. 24-hour urine collection was obtained for urinary volume and creatinine clearance (CrCl) analysis. Blood glucose, urea, creatinine, cholesterol, and triglycerides were measured by routine, standard techniques in automatic equipment. Cystatin-C levels were measured by immunoturbidimetric technique . Prolactin , aldosterone , and NT-proBNP  were measured in plasma by commercial RIA kits. GFR was calculated using the cystatin-C values and validated formulas . Echocardiography was performed in M mode and bidimensional mode by the same blinded cardiologist  and sectorial transducer  following recommendations of the American Society of Cardiology. 24-hour systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) were assessed using a Space Labs 90207 recorder . Recording began at 7:00 a.m. and ended at 7:00 a.m. the following day. The monitor was programmed to measure the blood pressure every 30 minutes during the day and night.t-test; changes intragroup in the studied variables along the time were analyzed with a general linear model for repeated measures. To determine if the effects on LVM and renal function of BEC were independent of blood pressure and metabolic control an ANCOVA analysis was performed. Statistical significance was considered with a P value <0.05. The data were processed with SPSS 18.0 .Data are presented as mean ± SE for continuous variables and percentage for discontinuous variables. Data were analyzed as an intention-to-treat analysis. Differences between groups were analyzed by independent Student Thirty-two patients were initially included in the study. Of these, two declined to participate in the study and two started peritoneal dialysis just after the deadline for the initial evaluation. Fourteen patients from each group were included in the final analysis. 24-Hour Ambulatory Blood Pressure. Twenty-four hour ambulatory blood pressure profiles were similar in both groups at baseline and showed loss of circadian rhythm, Patients in the BEC group showed significant reductions in LV mass and interventricular wall thickness after 3 and 6 months of treatment, whereas in patients in the PBO group these parameters tended to increase, resulting in significant differences between the groups at 3 and 6 months,  In the PBO group, creatinine and cystatin C increased whilst CrCl declined significantly, and GFR calculated by cystatin-C values also tended to decline. In contrast, although there was an observed increase in creatinine and cystatin C, CrCl remained statistically unchanged in the BEC group, Significant reductions in glucose and cholesterol were observed in the BEC group at three months; in the PBO group these parameters increased; at this point the antidiabetic treatment was modified  after this modification the glucose and cholesterol levels decreased in both groups without significant difference between the groups at the end of the study. Hemoglobin levels and hematocrit did not change along the study in any group, Data from this randomized controlled trial can be summarized as follows: oral administration of BEC for 6 months in patients with T2D and CKD resulted in: reduced blood pressure, restored circadian rhythm of blood pressure, reduced LV mass, delayed decline of RRF, and improved metabolic control. The results of the current study support the importance of targeting the overactivity of the sympathetic system and increased levels of NE in patients with CKD as suggested by previous reports from clinical and experimental studies –19. HighThe nephroprotective effect of BEC with better preservation of renal function as measured by CrCl was observed in the current study; the pathophysiological pathways that explain this effect have not been sufficiently explored, and we cannot assure that there are some other independent factors not directly related to the heart or the kidney. However, there are some experimental studies reporting that circulating levels of PRL are elevated in an NZB/NZW murine model of systemic lupus erythematous (SLE) and that the treatment with BEC prevents or retards the development of lupus nephropathy in mice , 37, 38.Previous studies, including some RCT's testing the effect of quick-release BEC formulations, have shown a beneficial effect of BEC in the control of glycaemia and glycated hemoglobin levels, and the frequency of serious adverse events and cardiovascular events was lower in the BEC treated group when compared with placebo controls –26, 40. Some limitations of the current study should be noted. Only surrogate markers of clinical outcomes were monitored; a longer follow-up period analyzing all-cause and cardiovascular mortality in a larger group of patients is needed to provide definitive proof of the beneficial effects of BEC. The study enrolled a small number of patients; however, significant results were still obtained with an acceptable level of confidence. In conclusion, the results of this RCT show that BEC treatment of stage 4 CKD patients resulted in reduction of LV mass, improved blood pressure control, and lowered NT-proBNP and PRL levels; it also prevented the decline of RRF, and improved the metabolic control. These promising results deserve to be tested in a more open setting resembling the day-to-day conditions to be validated. Additional studies are needed to clarify the pathophysiological mechanisms involved that are regulated by BEC. From a cost-effectiveness point of view, BEC should be advantageous as it is cheaper than most of the common drugs currently used as cardio- and renal protection. To test previously reported benefits of BEC for metabolic control in patients with type 2 diabetes and for reducing left ventricular mass in CKD, an RCT was conducted for six months in patients with stage 4 CKD and increased LV left ventricular mass. The main findings include a better control of blood pressure, measured by 24-hour ambulatory monitoring. Echocardiography showed significant reduction in left ventricular mass, paralleled by a reduction in NT-proBNP levels. BEC also improved blood glucose and lipid control and lowered PRL levels. No significant adverse events of BEC were observed.