Cystatin C is growing to be an ideal indicator for renal function and cardiovascular events. The aim of this study was to investigate the relationship between serum cystatin C levels and peripheral arterial disease and to explore its diagnostic value for lower limb ischemia (LLI) in type 2 diabetic population.A total of 1609 T2DM patients were included in this cross-sectional study. Their clinical and biochemical characteristics, ankle-brachial index (ABI), carotid and lower extremity arterial ultrasound were detected. LLI was defined by ABI <0.9 and lower extremity arterial stenosis >50% by ultrasound examination. Patients were divided to two groups: with LLI and without. The risk factors of LLI were explored by binary logistic regression analysis., the presence of hypertension , age , GA  and diabetes duration . The prevalence of coronary artery disease, cerebral infarction and LLI increased with cystatin C (P<0.01), and the prevalence of LLI in patients with cystatin C >1.2 mg/L was much higher than other three quartile groups. Receiver operating characteristic curve analysis revealed the cut point of cystatin C for LLI was 1.2 mg/L. The risk of LLI dramatically increased in patients with cystatin C >1.2 mg/L . After adjusting for sex, age, duration, HbA1c, GA and hypertension, its OR still remained 3.395 .The serum concentrations of cystatin C were 1.53±0.60 and 1.08±0.30 mg/L in patients with and without LLI, respectively. Binary logistic regression analysis showed that the significant risk factors were cystatin C There was a strong and independent association between cystatin C and limb arterial disease in diabetic population, and cystatin C >1.2 mg/L indicated a great increased risk of LLI. Lower limb ischemia (LLI) caused by peripheral arterial disease (PAD) is the major risk factor of foot ulceration and amputation which severely impairs the patients’ life quality. In the diabetic population, the onset of vascular abnormalities, atherosclerosis and plaque may be earlier and more obvious. Cystatin C, an endogenous marker of renal function, is becoming to be more sensitive than creatinine in estimating glomerular filtration rate (GFR).The study was approved by the Ethics Committee of Shanghai Jiaotong University Affiliated Sixth People’s Hospital and in accordance with the principle of the Helsinki Declaration. Written informed consent was obtained from all subjects.A total of 1609 patients with type 2 diabetic mellitus (T2DM) were recruited from Shanghai Clinical Center of Diabetes at Shanghai Jiaotong University Affiliated Sixth People’s Hospital from July 2011 to June 2012. The diagnosis of diabetes mellitus was performed according to the 1999 World Health Organization criteria and 2012 American diabetes association standards. 99mTc-DTPA renal dynamic imaging using Siemens Signature e.cam SPECT .Clinical information, including sex, age, diabetes duration, height, weight, systolic blood pressure, diastolic blood pressure, previous history of smoking habit, hypertension (HTN), coronary artery disease (CAD), cerebral infarction (CI) and medication of aspirin or lipid lowering drugs was collected. Body mass index (BMI) was calculated as body weight (in kg) divided by the square of the height (in m). HTN was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg or history of antihypertensive medicine administration. CAD was defined as a history of myocardial infarction or coronary arterial stenosis >50%. CI was defined as a history of ischemia attack showed by cerebral CT or MRI scan. Ankle-brachial index (ABI) was calculated by dividing the higher systolic blood pressure in the dorsalis pedis and posterior tibial artery by the higher of the brachial systolic blood pressure. The lower value of ABI in either limb was used for analysis. The arterial lesion of carotid and lower extremity artery were evaluated by color Doppler ultrasound examination, and the carotid and femoral intima-media thickness (IMT) were collected. LLI was defined by ABI <0.9 and lower extremity arterial stenosis >50%. The patients with ABI ≥0.9 and <1.0 or ABI >1.3 were excluded due to uncertainty status about blood supply. Glomerular filtration rate (GFR) was measured by the Serum cystatin C concentration was determined by high sensitive latex-enhanced immune-turbidimetric method with an automatic biochemical analyzer . The distribution of serum cystatin C levels was at a median of 1.0 mg/L (inter-quartile range 0.3 mg/L). Patients were also subdivided into four groups by cystatin C quartile: ≤0.8 (n = 259), 0.8–1.0 (n = 502), 1.0–1.2 (n = 368) and >1.2 (n = 479).White blood cell (WBC), red blood cell (RBC), hemoglobin (Hb), platelet (PLT) and neutrophils (N) were measured by an automated blood analyzer . C-reactive protein was measured by Dad Behring Nephelometer II System . Fasting plasma glucose (FPG) and 2-h postprandial blood glucose (PPG) were measured by glucose oxidase method . Glycosylated hemoglobin (HbA1c) was estimated by high-pressure liquid chromatography using the Variant™ II machine . Glycosylated serum albumin (GA) was determined by the liquid enzymatic assay using the Glamour 2000 automatic biochemical analyzer . Total protein (TP), albumin (Alb), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), γ-glutamyl transpeptidase (γ-GT), blood urea nitrogen (BUN), serum creatinine (Cr), uric acid (UA) and serum lipids, including total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) were assessed by enzymatic method with an automatic biochemical analyzer .U test and categorical variables were compared by the χ2 test. Binary logistic regression analysis was used to find the independent risk factors for LLI. Receiver operating characteristic curve (ROC) was made to find the cut-off point of cystatin C for predicting LLI. Binary logistic regression analysis was used to calculate the ORs and 95% confidence intervals for LLI by cystatin C quartiles. P<0.05 was considered statistically significant.All the statistical analysis was performed using SPSS 16.0 . Data were expressed as mean ± SD for continuous variables, and as percentages for categorical variables. Between LLI and without LLI, and among cystatin C quartiles, continuous variables were compared by the Mann-Whitney P<0.01) and HbA1c, AST, medication of aspirin and lipid lowering drugs  between patients with and without LLI. There was no difference in BMI, FPG, PPG, PLT, WBC, UA, TG and γ-GT between two groups . The serum concentrations of cystatin C were 1.53±0.60 and 1.08±0.30 mg/L in patients with and without LLI, respectively.The clinical characteristics between patients with and without LLI were showed in , the presence of hypertension , age , GA  and diabetes duration   .As the concentration of cystatin C rose, the levels of age, diabetes duration, carotid and femoral IMT, systolic blood pressure, neutrophils, BUN, Cr, UA and CRP increased, but RBC, Hb, PLT, albumin, FPG, PPG and GFR decreased . The proP<0.001). After adjusting for sex, age, duration, HbA1c, GA and hypertension, its OR was 3.395 .ROC curve analysis was performed to verify the diagnostic accuracy of cystatin C for LLI. The area under curve (AUC) was 0.794 ; the optimal cut point of cystatin C was 1.2 mg/L . And senThis cross-sectional study including 1609 Chinese type 2 diabetic patients at the first time investigated the relationship between serum cystatin C levels and lower extremity arterial disease in T2DM population. It was revealed that cystatin C was strongly and independently associated with the prevalence of diabetic lower arterial lesion. Moreover, cystatin C higher than 1.2 mg/L indicated a dramatically increased risk of LLI. Therefore, cystatin C was believed to be a sensitive biomarker for screening out PAD in the type 2 diabetic populations.LLI is one of the manifestations of PAD in diabetes, caused by arteriosclerosis, plaque formation and arterial occlusion. As we all know, in diabetic population, the traditional risk factors for PAD are smoking, elder age, advanced duration of diabetes, poor blood glucose control, hypertension and hyperlipidemia. We also revealed that renal function indicators in those with LLI were much higher than those without renal dysfunction and the degree of peripheral arterial lesion was significantly correlated with renal function and GFR. Several previous studies reported a close association between chronic renal insufficiency and PAD.Cystatin C is a small-molecular-weight non-glycosylated basic protein produced steadily by human nucleated cells. Because cystatin C is freely filtered at the glomerulus at a constant rate and is less affected by sex, age and diet, Although the mechanism linking cystatin C with cardiovascular disease was currently not well known, numerous studies tried to explain it. Urbonaviciene et al. observed a significant correlation of cystatin C and high-sensitivity C-reactive protein (hs-CRP) suggesting chronic low-grade inflammation was one of mechanism concerned, Diabetic lower extremity arterial disease was one of the major causes for foot ulceration and amputation. Early detection and treatment of lower extremity disease is critical to prevent amputation and mortality for diabetic population. From the results of the present study, cystatin C levels were strongly associated with PAD. The prevalence of CAD, CI and LLI increased with cystatin C quartiles, especially the prevalence of LLI, suggesting that cystain C was more suitable to be a PAD predictor. From the aforementioned results, cystatin C was not only an ideal marker reflecting early phase impairment of renal function, but also has great potential advantages to predict the progression of arteriosclerosis in diabetic population. Although the present study couldn’t provide explicit answer to the detailed mechanism linking cystatin C and peripheral arterial disease, further follow-up and basic research will be carried out to reveal its related mechanism. The exploration of the possible mechanisms underlying cystatin C and cardiovascular disease may provide more approaches to prevent and treat macrovascular disease in the future.99mTc-DTPA renal dynamic imaging rather than estimated from serum creatinine, which was more accurate and avoided the impact from serum creatinine. One of the limitations was the relatively small sample size, especially the patients with critical limb ischemia, thus the patients could not be further divided to several subgroups based on low ABI values. Another limitation was that it was a cross-sectional research lacking the outcome of lower extremities in patients with high cystatin C. Therefore, further follow-up data is needed to clarify the predictive value of cystatin C on the LLI and foot diseases.The strength of this study is that GFR was directly measured by the In conclusion, apart from renal function, serum cystatin C levels had a very close connection with PAD in Chinese T2DM patients. The optimal cutpoint of cystatin C was higher than 1.2 mg/L for reflecting more than 20 times increased risk of LLI. The detection of cystatin C concentration is of great value for screening out the patients with the angiostenosis risk of lower limb to prevent foot ulceration and amputation. The discovery of the detailed mechanisms underlying cystatin C and vascular abnormalities may be helpful to explore the novel therapeutic strategy and evaluation of curative effect for diabetic LLI and other macrovascular complications.


In patients with idiopathic normal pressure hydrocephalus (iNPH) responding to shunt surgery, we have consistently found elevated intracranial pressure (ICP) wave amplitudes during diagnostic ICP monitoring prior to surgery. It remains unknown why ICP wave amplitudes are increased in these patients. Since iNPH is accompanied by a high incidence of vascular co-morbidity, a possible explanation is that there is reduced vascular compliance accompanied by elevated arterial blood pressure (ABP) wave amplitudes and even altered cardiac output (CO). To investigate this possibility, the present study was undertaken to continuously monitor CO to determine if it is correlated to ABP and ICP wave amplitudes and the outcome of shunting in iNPH patients. It was specifically addressed whether the increased ICP wave amplitudes seen in iNPH shunt responders were accompanied by elevated CO and/or ABP wave amplitude levels.Prospective iNPH patients (29) were clinically graded using an NPH grading scale. Continuous overnight minimally-invasive monitoring of CO and ABP was done simultaneously with ICP monitoring; the CO, ABP, and ICP parameters were parsed into 6-second time windows. Patients were assessed for shunt surgery on clinical grade, Evan's index, and ICP wave amplitude. Follow-up clinical grading was performed 12 months after surgery.ICP wave amplitudes but not CO or ABP wave amplitude, showed good correlation with the response to shunt treatment. The patients with high ICP wave amplitude did not have accompanying high levels of CO or ABP wave amplitude. Correlation analysis between CO and ICP wave amplitudes in individual patients showed different profiles [significantly positive in 10 (35%) and significantly negative in 16 (55%) of 29 recordings]. This depended on whether there was also a correlation between ABP and ICP wave amplitudes and on the average level of ICP wave amplitude.These results gave no evidence that the increased levels of ICP wave amplitudes seen in iNPH shunt responders prior to surgery were accompanied by elevated levels of ABP wave amplitudes or elevated CO. In the individual patients the correlation between CO and ICP wave amplitude was partly related to an association between ABP and ICP wave amplitudes which can be indicative of the state of cerebrovascular pressure regulation, and partly related to the ICP wave amplitude which can be indicative of the intracranial compliance. The clinical condition idiopathic normal pressure hydrocephalus (iNPH) consists of unsteady gait, urinary incontinence, dementia, and enlarged lateral ventricles . The preICP; ≥4 mmHg on average and ≥5 mmHg in 10% of recording time), but in only 1 of 10 patients with low ICP wave amplitudes [In a previous study of 130 shunted iNPH patients, we had significant clinical improvement in response to shunt treatment in 9 out of 10 patients with high ICP wave amplitudes  and by Rikshospitalet (07/5870). Written informed consent was obtained from the patients before the study inclusion.2O.The patients were referred with suspected iNPH from local neurological departments based on their clinical symptoms and findings  combined with radiological ventriculomegaly. Based on our findings at neurological examination, the severity of clinical iNPH was graded using a NPH grading scale ranging from a best score of 15 to a worst score of 3  was performed in our out-patient clinic 12 months after surgery. We defined an increase ≥2 in NPH score at 12 months as representative of clinical improvement; the surgically treated patients were categorized either as responders (change in NPH score ≥2) or non-responders (change in NPH score <2), respectively.The design of the study was to simultaneously monitor CO, ABP, and ICP overnight using a computerized recording system, as part of the diagnostic procedure (above). The patients were kept supine in bed during the entire recording.plus . This is a minimally invasive technique incorporating two methods: a continuous arterial waveform analysis system (PulseCO), coupled to a single-point lithium indicator dilution calibration system (LiDCO) [2), and systemic vascular resistance (SVR). ABP was measured continuously in the right radial artery using the Truwave PX-600F Pressure Monitoring Set . The ABP sensor was placed at the level of the heart. ICP was monitored continuously using a solid sensor , introduced 1-2 cm into the frontal brain parenchyma through a small burr hole and a minimal opening in the dura, as previously described [Continuous monitoring of CO was performed with the LiDCO™ (LiDCO) ,31. As pescribed .® Pressure Logger  and analyzed using Sensometrics® software (dPCom AS). The LiDCO™plus and Sensometrics® software's had identical time reference. An example of the simultaneous recordings is illustrated in Figure The continuous ABP and ICP waveforms were sampled at 200 Hz, digitized using the SensometricsICP) and group B with low ICP wave amplitudes ; (ii) between CO vs. ICP wave amplitude (CO/MWAICP correlation); and (iii) between ABP and ICP wave amplitude . Differences between management groups of continuous data were determined by one-way ANOVA. Significant correlations between parameters of individual recordings were determined using the Pearson correlation. Significance was accepted at the 0.05 level.Of the 29 patients in the study, 20 were in management group A, and 9 in management group B. Shunting was performed on 22 patients, 19/20 from group A and 3/9 from group B. Demographic, clinical, radiological and management data of the two groups are shown in Table ICP correlation was significantly more negative in group A than B. When considering all 29 recordings, there was no significant overall correlation between average values of CO and ICP wave amplitude .The continuous monitoring of cardiac and pressure data gave no complications or side-effects. Comparison of the cardiac and arterial pressure data for groups A and B revealed no significant differences between groups in levels of CO or ABP wave amplitude . Thus, with higher pre-operative ICP wave amplitude levels, better clinical improvement of iNPH symptoms was observed 12 months after shunting  related poorly to the CO Figure ; ns and g Figure .ICP and MWAABP/MWAICP correlation levels (Table ICP levels (group A) even in the presence of significant positive CO/MWAICP correlation or significant positive MWAABP/MWAICP correlation. Among the 7 shunted patients with significant positive CO/MWAICP correlation, all the 4 shunt responders had elevated MWAICP levels (group A) while the 3 shunt non-responders had low MWAICP levels (group B). Moreover, among the 14 shunted patients with significant positive MWAABP/MWAICP correlation, all the 10 shunt responders had elevated MWAICP levels (group A); while 3 of 4 shunt non-responders had low MWAICP levels (group B).While shunt response was related to the level of ICP wave amplitudes, the response to shunting was less dependent on the CO/MWAls Table . In partABP correlation was seen in 28 of 29 patients (97%), significant positive CO/MWAICP correlation was seen in only 10 of 29 patients .While a significant positive CO/MWAon Table . When coICP correlation  was seen in 16 patients, 13 (81%) in group A and 3 (19%) in group B.Moreover, as shown in Table This study for the first time reports an association between CO and intracranial pressure dynamics in hydrocephalus patients. One major observation was that the increased ICP wave amplitude levels seen in 20 of the 29 patients were not accompanied with increased levels of CO or ABP wave amplitude , ABP  or CPP (mean CPP) parameters Table . This stABP/MWAICP correlation as an indicator of the state of cerebrovascular pressure regulation. According to this concept, when the cerebrovascular pressure auto-regulation is disrupted, the correlation between ABP and ICP wave amplitudes becomes positive. The method of computing moving MWAABP/MWAICP correlations was first applied to patients with head injury [How the ABP waves transfer into the ICP waves depends on the state of cerebrovascular pressure regulation. Previous work on the transfer of ABP waves into ICP waves gave evidence that loss of vasomotor tone of precapillary vessels  changed the ABP-to-ICP transmission into a passive and linear pressure transmission -29. Suchd injury  and iNPHd injury .ICP correlation) depends on the state of cerebrovascular pressure regulation (indicated by the MWAABP/MWAICP correlation). During disrupted cerebrovascular pressure auto-regulation, CO would directly affect the ICP wave amplitude levels (causing the CO/MWAICP correlation to become positive and approach +1), as opposed to a situation of intact cerebrovascular pressure auto-regulation when CO would less likely affect the ICP wave amplitude levels (causing the CO/MWAICP correlation to become non-significant or negative approaching -1). In line with this, in patients with a significant positive CO/MWAICP correlation, the MWAABP/MWAICP correlation was also significantly positive  or no clinical response (low ICP wave amplitudes) [ABP/MWAICP correlation), the response to shunting is primarily determined by the improvement in intracranial compliance following CSF diversion.It should be noted that a clinically-significant shunt response was seen in patients with increased ICP wave amplitudes even though the recordings were accompanied by significant positive CO/MWAlitudes) . This auICP, a negative association between CO and MWAICP predominates. Based on some information in the literature, it is tempting to speculate that such a negative correlation between CO and ICP wave amplitudes have relevance for the pathophysiology of iNPH. Following induction of experimental hydrocephalus in dogs, the ICP wave amplitudes increased  and the CO became reduced, causing a negative correlation between CO and ICP wave amplitudes [In this cohort, a significant negative correlation between CO and ICP wave amplitude was seen in 16 of 29 patient recordings (55%); 13 of the 16 recordings were in group A (high ICP wave amplitudes) showing that in patients with high MWAplitudes . They alplitudes . They suplitudes -7. Thus,plitudes -51.While this overall dataset from iNPH patients gave no evidence of increased CO or ABP wave amplitude levels in patients with increased ICP wave amplitudes, analysis of recordings from individual patients provide evidence that an association between CO and ICP wave amplitudes is partly related to the association between ABP and ICP wave amplitudes (which can be indicative of the state of cerebrovascular pressure regulation), and partly related to the levels of ICP wave amplitude . In this cohort, shunt response was primarily related to level of ICP wave amplitudes. Further research is needed to clarify how CO associates with the intracranial pressure dynamics in hydrocephalus patients.2: oxygen consumption; ICP: Intracranial pressure; HR: Heart rate; ICC: Intracranial compliance; iNPH: Idiopathic normal pressure hydrocephalus; MWAABP: Mean arterial blood pressure wave amplitude; MWAICP: Mean ICP wave amplitude; SV: Stroke volume; SVR: systemic vascular resistance.ABP: Arterial blood pressure; CBF: Cerebral blood flow; CBV: Cerebral blood volume; CO: Cardiac output; CSF: Cerebrospinal fluid; DOThe software used for analysis of the ICP recordings (Sensometrics Software) is manufactured by a software company  wherein Per Kristian Eide MD PhD has a financial interest.PKE: sole author. The author has read and approved the final version of the manuscript.Table S1 The NPH Grading Scale used at the Department of Neurosurgery, Oslo University Hospital - RikshospitaletClick here for file


The aim of our study was to compare the accuracy of BP measurements obtained by Datex Ohmeda GE S/5  and Criticare 8100E nGenuity . The secondary outcome measure was to compare the time taken by these monitors to obtain BP measurement.Non-invasive blood pressure (NIBP) is an indirect method of measuring blood pressure (BP). NIBP mon2, patients in whom Korotkoff sounds could not be heard, and patients with history of hypertension and diabetes, and pregnant patientswere excluded.After obtaining institutional ethical committee approval and informed consent, patients of either sex of 18-60 years, presenting for pre-anaesthetic evaluation for elective surgery, were included. Age, sex, height, weight and body mass index (BMI) were recorded. Patients with arrhythmia, BMI >25 or <18.5 kg/mAfter a rest of 5 minutes, the following four sequential same-arm NIBP measurements  were obtained in supine position by tying the same size cuff to the upper arm. The first and second readings were obtained by two anaesthesiologists (blinded observers) using standard sphygmomanometer by auscultatory method. The third and fourth readings were obtained by Monitor-1 and Monitor-2, respectively. A minimum of 3 minutes gap was maintained between any two measurements.™ technology  to determine NIBP which detects volume displacements within the artery and senses pressure variations within the BP cuff during inflation. The maximum cuff inflation rate is 15 mmHg/sec, with inflation limits to 300 mmHg in adult, 300 mmHg in paediatric and 150 mmHg in neonatal modes. Cuff pressure is allowed to remain above 30 mmHg for a maximum of 2 minutes. The cuff then rapidly deflates. This device has been clinically tested as per the requirements of EN 1060 and AAMI SP-10.Criticare 1800E nGenuity uses ComfortCuffP value <0.05 was considered significant. Demographic data were normally distributed [P< 0.001) compared to both Observer-1 (88.6 ± 8.8) and Observer-2 (89.4 ± 7.5). The time taken (sec) for measurement by Monitor-2 (21.9 ± 2.3) was significantly lower (P< 0.001) compared to Monitor-1 (25.8 ± 2.3).A total of 160 BP recordings [four sets of measurements from each of the 40 patients (M/F = 24/16)] obtained were analyzed. BP values were compared using repeated measures analysis of variance (ANOVA) and a tributed . There wtributed . AlthougAccurate measurement of BP is essential to classify individuals, to ascertain blood pressure–related risk, and to guide management in various clinical settings. All NIBPOur study showed that although both the monitors work on the principle of oscillometry, significant difference exists between the measurements. Our study did not involve extremes of age or blood pressures where NIBP monitors are known to be less accurate.6 Althoug™ technology may be associated with better patient comfort because of the lesser time required to obtain a BP recording and the lower peak inflation pressure even though this aspect was not assessed in the present study.Criticare 8100E nGenuity required significantly less time to obtain BP measurement. This is because the recording is obtained upon inflation of the cuff, whereas time taken by monitors obtaining BP upon deflation includes rapid inflation followed by deflation of the cuff. The ComfortCuffCriticare 8100E nGenuity and Datex Ohmeda GE S/5 were equally accurate in measuring systolic and diastolic BP, while the former recorded significantly higher mean BP and was faster.


This study aimed to compare the cerebral effects of terlipressin (TERLI) with conventional prehospital fluid resuscitation with lactated Ringer's solution (LR) in a model of haemorrhagic shock (HS).n = 2), HS (n = 9), LR  or TERLI . HS induced to target MAP of 40 mmHg was maintained for 30 minutes. Brain tissue oxygen pressure (PbtO2), intracranial pressure (ICP), cerebral perfusion pressure (CPP), haemodynamics and blood gas analyses were assessed prior to HS (baseline) up to 120 minutes after treatment. Tissue markers of brain oedema (aquaporin-4 (AQP4) and Na-K-Cl cotransporter-1 (NKCC1)), apoptosis (pre-apoptotic protein (Bax)) and oxidative stress (thiobarbituric acid reactive substances (TBARS)) were also measured.Pigs (20 to 30 kg) were randomized into one of the groups: Sham (2 (from 23.6 to 26.6 mmHg), ICP (from 1 to 2 mmHg) and haemodynamics , and a significant increase in blood lactate (from 6.7 to 8.9 mmol/l) and cerebral AQP4 , NKCC1 (237 ± 47% of sham), Bax (167 ± 44% of sham) and TBARS. Fluid resuscitation was followed by an increase in ICP (from 7 to 9 mmHg) and a decrease in CPP (from 41 to 52 mmHg), with an increased expression of cerebral AQP4 (210 ± 56% of sham), NKCC1 (163 ± 32% of sham) and Bax (137 ± 24% of sham). Only TERLI restored baseline values of CPP (from 54 to 61 mmHg) and did not change the cerebral expression of AQP4 (100 ± 6% of sham), NKCC1 (100 ± 1% of sham), Bax (102 ± 6% of sham) and TBARS. Both TERLI and LR recovered baseline levels of PbtO2  and MAP . Blood lactate levels were not recovered in any group .Sham animals had no significant changes in the variables assessed. HS resulted in a significant decrease in CPP (mean varied from 36 to 39 mmHg), PbtOTERLI recovered cerebral perfusion and oxygenation with no significant changes in ICP and cerebral markers of oedema, apoptosis and oxidative stress. LR did not recover CPP probably due to a significant increase in ICP caused by brain oedema, which may have contributed to the cerebral apoptosis. None of the treatments caused cerebral oxidative stress.


Cerebral autoregulation (CA) maintains cerebral blood flow over a range of perfusion pressure. Continuous CA monitoring might define pressure targets minimising secondary brain injury, but application is limited by available monitoring modalities. Near-infrared spectroscopy (NIRS) is a noninvasive optical technique characterising aspects of CA. The NIRS-derived tissue oxygenation index (TOI) is correlated with blood pressure (BP) to produce an index of vascular reactivity (TOx) . The con2), transcranial Doppler and NIRS . ORx and Mx were derived from continuous correlation between BP and neuromonitoring [Thirteen brain-injured patients were studied. Ipsilateral 60-minute recordings included intracranial pressure, brain tissue oxygen , ORx  and Mx. TOx showed no significant correlation (r = 0.18) as individual recordings demonstrated TOI fluctuations paradoxical to other monitoring. The mean lag between BP and HHb (24 seconds) was shorter than PbrO2 (68 seconds).There was correlation between HHBx (HHb may provide a surrogate to inform cerebrovascular reactivity assessment. Complexity in the oxyhaemoglobin component of TOI may be introduced by vasopressor-related skin artefact or arterial volume changes  explaini


Results. At age 68, hypertension and high clinic blood pressure (CBP) did not predict ABPM level. Smoking and low ankle-brachial index (ABI) predicted higher ABPM variability and pulse pressure (PP), but not absolute ABPM values. At age 82, hypertension, high or increasing CBP, strongly positively correlated with all variables of ABPM. Carotid stenosis, low or declining ABI during followup, correlated with higher nocturnal ABPM and PP. Concluding. Hypertension and vascular risk factors in a cohort of 68-year-old men do not result in higher ABPM at age 82, possibly due to inflection point in their pressure development. Higher ABPM reflects instead an increasing CBP and aggravating atherosclerosis during the preceding decade in that part of the cohort with previously favorable risk factor status.To assess an impact of vascular risk factors on ambulatory blood pressure measurement (ABPM) in the elderly, we followed up a population-based cohort of men from 68 until 82 years, when 104 survivors underwent ABPM.  Blood pressure levels in the very elderly are more scattered than in younger elderly or middle-aged persons. After initial blood pressure increase, which occurred up to the seventh decade in both sexes, a blood pressure decline has been observed , 2. HighStudies describing ambulatory blood pressure (ABPM) are mainly focused on younger elderly or middle-aged persons, mainly with essential hypertension, and seldom comprising population-based samples –20. FreqThe aim of our study was to assess a profile of ABPM in a cohort of octogenarian men who were longitudinally followed since random inclusion from a population of city of Malmö, Sweden. Contrary to previous studies, we assessed an impact of vascular and life-style risk factors observed at age 68, and a time progress of atherosclerotic disease, on the ABPM profile when subjects reached the age of 82 years.A prospective population sample study, “Men born in 1914”, has been in progress since 1968. It includes all men born in the even months of 1914 in the city of Malmö, Sweden. A total of 809 men were invited to participate in the study, and 703 men took part in the first health examination. When they were 68 years old, 465 men in the cohort and additional 95 new residents were invited to attend a new examination. Five hundred of them agreed to participate . The mosStudy subjects and their spouses answered to a questionnaire focusing on life-style factors, prescribed medicines, and previous diseases. All underwent medical examination including Hachinski ischemic score. To evaluate the role of established vascular risk factors, we measured levels of blood glucose, cholesterol, and triglycerides during fasting conditions and body mass index (BMI) at age 68. The participants were also classified as nonsmokers, former smokers, and smokers. Tobacco consumption of the smokers was measured as g/day. Alcohol consumption was self-reported and calculated in g 100% ethanol per week. At the recent followup at age 81, the medical examination was repeated, and 185 men answered a questionnaire focusing on lifestyle and health markers. Possible dementia was classified according to the DSM-IV criteria, and one subject was diagnosed as being demented.Two established markers of vascular disease were examined: carotid stenosis, determined using carotid ultrasound at age 81, and low peripheral circulation in the lower extremities, estimated using the ankle-brachial pressure index (ABI) at ages 68 and 81. The clinic blood pressure (CBP) was measured sphygmomanometrically in the upper right arm, in the supine position after 15 min of rest at age 68 and at age 81, using a calibrated mercury manometer and rubber cuffs . Hypertension was defined as systolic and diastolic brachial BP ≥160 mmHg or ≥90 mmHg, respectively, or medication for hypertension. These hypertension criteria have been used previously and were valid until the World Health Organization drew up new ones in 1999 . All theAmbulatory blood pressure monitoring was performed using Micro AM Recorder, Model KI5600 (Kontron Instruments). Readings at 20-minute intervals during a day (from 06.20 AM to 09.40 PM) and at 60 min intervals at night (from 10.00 PM to 06.00 AM) were performed. Monitoring was performed in patient's private environment without specific advices regarding physical activity. The ambulatory BP-measurement was performed with auscultatory method, but in case of measurement failure the examination was immediately repeated using an oscillometric method. The accuracy of KI5600 was confirmed by a simultaneous measurement with a standard mercury sphygmomanometer and accepted if they were within 10 mmHg of standard method. The exclusion of patients was made according to the quality criteria: deficit in measurement time intervals at least 6 h accumulated during a daytime or more than 3 h accumulated at nighttime, or more than 3 h consecutively during a daytime or at least 2 h consecutively during a nighttime. For the individual data, the relative nocturnal BP fall was calculated using a formula: (daytime BP-nighttime BP) × 100/daytime BP, and expressed in %. Preawakening SBP was defined as a mean of measurements at 04.00, 05.00, and 06.00 AM. Postawakening SBP was a mean of measurements: 06.20, 06.40, 07.00, 07.20, 07.40, and 08.00. Morning SBP surge is defined as a difference between Postawakening SBP and Mean SBP nighttime.Ankle blood pressure was estimated, both at ages 68 and 81 years, by placing a cuff at the ankle level and using Doppler signal on tibial posterior artery or dorsal foot artery to detect peripheral blood flow in the supine position. Reference pressure in the arm was calculated using strain gauge recording system. Arithmetic average of duplicate recordings was used. For each leg, an ankle-brachial pressure index (ABI) was calculated by dividing the ankle systolic pressure with the highest upper arm systolic pressure value.The examination of carotid arteries was made at age 81, using computed sonography system  with a 7 MHz B-mode real-time linear scanner, including a 5 MHz-pulsed and color-coded Doppler. The color-coded Doppler was used to localize areas with high-flow velocities in the internal carotid artery, and the maximum-flow velocity (m/s) was measured with the pulsed Doppler.P value of less than 0.05 was considered statistically significant. Local ethical committee at Lund University accepted the study, and informed consent was obtained from all participants.Summary values are expressed as mean ± standard deviation. Correlation analyses were performed using Spearman correlation test. Differences in vascular risk factors/markers were calculated with Mann-Whitney rank sum test. All data analysis has been performed using SPSS  statistical package. A two-tailed Values of ABPM, that is, daytime and nighttime SBP, DBP, systolic and diastolic variability (mean SD-SBP and SD-DBP), nocturnal SBP fall, morning SBP surge, preawakening SBP, and postawakening SBP are presented in Compared to a sample of 70-year-old population of Uppsala, Sweden , subjectCompared to a sample (age 73 ± 6) from a population of Madrid, Spain  at daytiCompared to 15-year younger Japanese population-based sample of Ohasama study (mean age 66.7 y) , subjectCompared to Italian Pamela population study (mean age 69.0 y ± 2.3), subjects of this study had similar daytime values, higher nighttime SBP with 6 mmHg but not DBP , 26.Compared to the oldest sample of population-based study from Dublin, Ireland (age 50–79 y) , subjectCompared to Uruguayan population sample of men untreated for hypertension at age >70 y , subjectIn a population study from Denmark , severalHypertension, diagnosed or treated during the first followup at age 68, has been tested as possible predictor of ABPM 14 years later . ABPM could also adequately express the grade of atherosclerotic process at age 82 by higher nighttime and preawakening BP-levels, higher nighttime BP variability, and PP values, in those men who had higher grade of carotid stenosis, lower ABI, and extended ABI-decline during the 14-year followup.Possible explanation of the lower ABPM values in the very elderly, compared to the younger population samples, could be a selective mortality of those subjects from our cohort, who died before age 68, that is, before the first followup, due to early hypertension, metabolic syndrome, intensive smoking, and advanced atherosclerosis . AnotherCigarette smoking, as the strongest risk factor at age 68, did not predict absolute values of BP in octogenarians, but increasing SBP and DBP variability (SD) by ca 20%, both daytime and nighttime. Similarly, lower ABI level at age 68 predicted higher daytime SBP variability and PP, and not the absolute ABPM values.At age 81, subjects defined as hypertensive expressed higher nighttime and daytime SBP, post- and preawakening SBP, and above all, higher PP. The values of clinic BP at age 81 correlated with values of ABPM, mainly clinic DBP, high values which were reflected by higher daytime and nighttime SBP, DBP, SD-SBP, and pre- and postawakening SBP as well as daytime PP. Clinic SBP at age 81 was reflected only by nighttime SBP and PP. It suggests that in very elderly men clinic DBP seems to express overall 24-h BP profile in a more adequate way that clinic SBP, and that diurnal PP should be used as an important complement to both clinic and diurnal BP measurements.Nocturnal values of ABPM could be used as a risk factor or marker of vascular burden in the octogenarian men. Nighttime and preawakening SBP and daytime PP correlated best with a grade of carotid stenosis. Similar result were observed concerning ABI, where high nighttime SBP, SD-SBP, PP, and high preawakening SBP were observed in subjects with a diminished peripheral leg circulation. Daytime values did not express that risk. The largest progress in peripheral arterial disease, expressed as a decreasing ABI over 14 years, was observed not in these subjects who had high absolute ABPM values, but in those who expressed high PP and high SBP-variability both night- and daytime, and had larger pre- and postawakening SBP.In conclusion, in a population sample cohort of 82-year-old men, high daytime and nighttime ABPM measurements reflected increasing office-BP and aggravating atherosclerosis only in the last decade. Subjects with early developed hypertension, peripheral atherosclerosis and active smokers already in their 60 ties reached an inflection point in their blood pressure development and did not express increasing ABPM values in their eighties any longer.


The aim of this study was to investigate the incidence and trend of comorbid conditions of attention deficit developed among asthma patients during 5 years period.This study was based on continuous data from the Taiwanese National Health Insurance Research Database which contained 98% of registry files of all 22.60 million populations. Asthma was selected with code 493.xx of the International Classification of Disease, 9th Revision, and Clinical Modification. Asthma case was defined that the diagnosis occurred more than three times within 6 months. A total 139,629  patients newly diagnosed with asthma in 2003 were enrolled in this cohort and follow-up. Attention deficit was defined as patients with first diagnosis ICD-9 code of 314.xx.There were 0.3% of asthma patients suffering from attention deficit in year 2003 and increased to 1.0% in year 2008. The male asthma patients suffered from attention deficit increased from 0.46% to 1.69% in, which is more common than females . The male asthma patients had 4-fold risk than females to have this problem. Comparing to non-asthma populations, both genders asthma patients presented with almost equivalent risk, though statistical significantly, to have attention deficit (p<0.001).Asthma patients significantly increased to develop attention deficit, and male patients had increasing trend within 5 years follow-up period.


The objective of this trial was to compare the blood-pressure lowering efficacy of amlodipine/losartan combination with amlodipine monotherapy after 6 weeks of treatment in Korean patients with stage 2 hypertension.In this multi-center, double-blind, randomized study, adult patients (n = 148) with stage 2 hypertension were randomized to amlodipine 5 mg/losartan 50 mg or amlodipine 5 mg. After 2 weeks, patients with systolic blood pressure (SBP) > 140 mmHg were titrated to amlodipine 10 mg/losartan 50 mg or amlodipine 10 mg. After 4 weeks of titration, hydrochlorothiazide 12.5 mg could be optionally added to both groups. The change from baseline in SBP was assessed after 6 weeks. The responder rate (defined as achieving SBP < 140 mmHg or DBP < 90 mmHg) was also assessed at 2, 6 and 8 weeks as secondary endpoints. Safety and tolerability were assessed through adverse event monitoring and laboratory testing. Baseline demographics and clinical characteristics were generally similar between treatment groups. Least-square mean reduction in SBP at 6 weeks (primary endpoint) was significantly greater in the combination group . The responder rate in SBP (secondary endpoints) was significantly higher in the combination group at 2 weeks  but not at 6 weeks (p = 0.0550) or 8 weeks (p = 0.0592). There was no significant difference between groups in the incidence of adverse events.These results demonstrate that combination amlodipine/losartan therapy provides an effective and generally well-tolerated first line therapy for reducing blood pressure in stage 2 hypertensive patients.NCT01127217ClinicalTrials.gov:  Hypertension has been recognized as an important risk factor for cardiovascular disease and is a leading risk factor for mortality . Each yeCurrent US and European guidelines for the treatment of stage 2 hypertension recommend early initiation of combination treatment consisting of two anti-hypertensive drugs from different therapeutic classes since most hypertensive patients require two or more anti-hypertensive drugs to achieve their target blood pressure level ,6. CombiThis was an 8-week, double blind, randomized study conducted at 8 hospitals in Korea. The study protocol was approved by the Korean FDA and the local ethical review boards of each hospital . The study was conducted in accordance with the ethical principles of the current Declaration of Helsinki. Subjects signed informed consent prior to any relevant laboratory tests.th Report of the Joint National Committee on Prevention, Detection, evaluation, and Treatment of High Blood Pressure (JNC 7) Figure . The res6.5 mmHg At Week 2, 38/73 subjects (52.1%) in the amlodipine/losartan combination group compared with 25/75 subjects (33.3%) in the amlodipine monotherapy group achieved the target SBP < 140 mmHg, and this difference was significantly different , at Week 6  and at Week 8  was lower than that of the amlodipine monotherapy group . The rate of subjects with treatment of HCTZ 12.5 mg after 6 weeks of treatment in the amlodipine/losartan combination group  was also lower than that of the amlodipine monotherapy group .A total of 86 treatment emergent adverse events (TEAE) were reported in 47 subjects [44 in 23 subjects (31.5%) in the amlodipine/losartan combination group and 42 in 24 subjects (32.0%) in the amlodipine monotherapy group; Table The results of this study demonstrated that the amlodipine/losartan 5/50 mg combination was significantly more effective at reducing SBP than amlodipine monotherapy after 6 weeks of therapy in stage 2 hypertensive patients. Responder rates for SBP < 140 mmHg were significantly greater at Week 2 in the combination group, suggesting a more rapid onset of action, and were numerically greater in the combination group at Weeks 6 and 8, with p-values nearing statistical significance. Both treatments were generally well tolerated. These results support the recommendations of the JNC-7, the European Society of Hypertension, and the Taiwan Society of Cardiology Guidelines for the Management of Hypertension, which advocate early initiation of combination treatment consisting of two anti-hypertensive drugs with complimentary mechanisms of action for stage 2 hypertension patients ,6,10Losartan and amlodipine are frequently used as first-line therapy in hypertensive patients, ,11,12 anSeveral different combination therapies have been shown to effectively treat hypertension. In two separate studies, the combination CCB-ACE inhibitor benazepril/amlodipine was shown to be significantly more effective in reducing blood pressure, and more patients achieved blood pressure control compared with amlodipine monotherapy ,16. SimiSeveral studies combining amlodipine with an ARB have demonstrated superior efficacy over monotherapy and comparable tolerability in patients of different races/ethnic origin. The EX-STAND trial showed that the combination therapy of amlodipine and valsartan (5/160 mg to 10/320 mg) achieved greater reductions in blood pressure after 8 weeks of treatment and faster onset of action in black subjects with stage 2 hypertension compared with corresponding component amlodipine monotherapies  . In IndiAlthough reductions in blood pressure may be affected by ethnic/racial difference and baseline blood pressure levels, the data from this study and the results from previous clinical trials demonstrate the efficacy of ARB and amlodipine combination therapy in treating stage 2 hypertension and support the recommendation that in patients who do not achieve recommended blood pressure reductions with a low dose of an antihypertensive agent, a combination therapy may be more effective than increasing the dose of a single agent. However, a more cost-effective option may be to use combination therapy first-line to achieve blood pressure goals quickly. The ability to generalize these results to the population as a whole, and especially to older patients, is limited by the small number of patients included and by the lack of ethnic diversity. Larger studies are warranted in more diverse populations. The results of the secondary and exploratory endpoints should be interpreted with caution since no adjustments were made for multiplicity.In conclusion, the results of this trial support the use of early initiation of amlodipine/losartan combination followed by subsequent dose escalation in patients who have not achieved recommended blood pressure levels. Amlodipine/losartan was generally well-tolerated and provides a superior first-line therapeutic option for patients with stage 2 hypertension.The authors declare that they have no competing interests.All authors participated in acquisition and interpretation of data, critically reviewing and revising the manuscript for important intellectual content, and approved the final version for publication.


Little is known about the responses of natriuretic peptides to developing congestive heart failure in ‘anephric’ end-stage kidney disease.We present three consecutive cases of surgically-induced anephric patients in a critical care environment: a 28-year-old Caucasian woman (with congestive heart failure), a 42-year-old Caucasian woman (without congestive heart failure), and a 23-year-old Caucasian woman (without congestive heart failure). Our limited study data indicate that cut-off values advocated for B-type natriuretic peptide and its N-terminal fragment to ‘rule out’ congestive heart failure in two of our end-stage kidney disease patients (without congestive heart failure) are largely appropriate for anephric patients. However, our index (first) patient developed congestive heart failure accompanied by the phenomenon of massive and persistent elevation of these natriuretic levels.Our findings suggest that patients from the anephric subclass suffering from congestive heart failure will develop supramaximal elevation of B-type natriuretic peptide and its N-terminal fragment, implying the need for dramatically higher cut-off values with respective magnitudes of the order of 50-fold  to 100-fold  higher than current values used to ‘rule in’ congestive heart failure. Further research will be required to delineate those cut-off values. The role of our devised ‘Blood Volume – B-type natriuretic peptide feedback control system’ on ‘anatomical’ and ‘functional’ anephric patients led to significant mathematically-enriched arguments supporting our proposal that this model provides plausible explanations for the study findings, and the model lends support to the important hypothesis that these two groups of anephric patients inflicted with congestive heart failure should effectively have similar natriuretic response behavior. Congestive heart failure (CHF) and renal failure (RF) act synergistically to increase the levels of B-type natriuretic peptide (BNP) and its co-secreted biologically inactive N-terminal fragment (NT-proBNP). These two cardiac neurohormones are mainly secreted from the ventricles and, to a lesser extent, the atria. They have an established role as useful diagnostic tests for CHF in both the pediatric and adult population, including RF patients-3.RF and CHF represent two merging pathologies with a varying spectrum for speed of onset and severity. The intersection of cardiac and renal insufficiency is referred to as cardiorenal syndrome (Type 1 to 5), which iThe surgically-induced anephric (SIA) patients are a rarity. Despite this, health care providers such as general practitioners, emergency physicians, intensive care physicians and anesthetists will probably come across these anephric patients at some point in their working career. Little is known about the magnitude of natriuretic rise in response to developing CHF in this unique ‘anephric’ ESKD scenario.We describe three consecutive SIA patients <60 years of age requiring high acute care in an Intensive Care Unit (ICU) or High Dependency Unit (HDU) at some point in their life between May 2004 and December 2009. The patients were all Caucasian adult women from a regional catchment population of 200,000 people in New South Wales, Australia. Using all information pertaining to their presentation obtained over varying periods of time , including hospital records, results of diagnostic imaging and laboratory testing, we carefully studied each patient in both a prospective and retrospective manner specifically to determine the presence or absence of CHF.The three subject patients were all on established hemodialysis (HD) thrice weekly (Monday-Wednesday-Friday schedule) for at least 30 days: the first session (Monday) was the dialysis session after a 72-hour inter-dialytic period whereas the second and third sessions were after a 48-hour period. All three patients were under the care of multidisciplinary teams; in particular under renal physicians to comprehensively manage their HD or post-renal transplant status.The ‘zenith’ pre-dialysis, ‘nadir’ post-dialysis and ‘average’ inter-dialysis body fluid levels meant that their reflective blood samples were to be collected at (respectively) the start of a HD session, the end of a HD session and on a HD-free day. Whenever possible, hematological tests, biochemical tests, and specific hormone analysis for prolactin , BNP , and NT-proBNP  were performed simultaneously on the same blood sample. Relevant data such as pre-dialysis ‘wet’ weight (kg) and post-dialysis ‘dry’ weight (kg) are used to estimate the net ultrafiltration volume removed as represented by a change in weight. Respectively, heart rate and respiratory rate are given in beats/minute and breaths/minute. Blood pressure (BP) in mmHg is recorded as systolic BP (SBP)/diastolic BP (DBP) with mean arterial pressure (MAP) computed from invasive arterial pressure waveform. Those same BP parameters were computed via the MAP = DBP + ⅓ (SBP – DBP) formula during electronic non-invasive BP measurements. ‘Severe HT’ is defined as SBP ≥180mmHg or DBP ≥120mmHg. ‘Resistant HT’ is defined as BP that remains above goal in spite of concurrent use of three anti-HT agents of different classes. The goal BP is less than 140/90mmHg in average risk HT patients.2 = kg/m2: normal (<25), overweight (25.0–29.9), and obese (≥30). Chronic kidney disease (CKD) is based on the abbreviated Modification of Diet in Renal Disease equation[Body mass index (BMI) is defined as (weight) ÷ (height)equation to yieldA 28-year-old Caucasian woman  with von Hippel–Lindau (VHL) syndrome had normal renal function before she abruptly became a permanent SIA patient  resulting in severe HT causing acute CHF (Event X) necessitating ICU admission (Day 0). Thus, her renal function just prior to the SIA state was normal. Her CHF became permanent and irreversible with the associated development of ‘intolerance to ESKD’ persisting for 5 years until her death (Event Y).A 42-year-old Caucasian woman  with polycystic kidney disease (PKD) was admitted to HDU (Day 0) for post-operative care following subtotal parathyroidectomy for secondary hyperparathyroidism. She was already in ESKD state before she transitioned smoothly onto being a temporary SIA patient  1.5 years earlier. Thus, her renal function just prior to the SIA state was ESKD. The ESKD component from her SIA state was temporary for a period of just over 2 years before her subsequent successful renal transplant (with resulting CKD Stage 3).A 23-year-old Caucasian woman , the younger biological sister of Patient 1 and also inflicted with VHL syndrome, was admitted to HDU (Day 0) for post-operative care following a renal transplant. She abruptly went into ESKD after becoming a SIA patient. Thus, her renal function just prior to the SIA state was normal. She was in this temporary SIA state for 4.5 months until this successful renal transplant (with resulting CKD Stage 2).For the interested reader, the clinical records on demographic and clinical characteristics of our subject patients are more fully detailed in their individual case reports  – BNP feedback control system’ Figure  with fur2 or those on renal dialysis therapy excluded).For the interested reader, our intentional in-depth dissection on the study strengths, limitations and main findings  acting as: (1) an and/or the end target-organ for the relevant hormones; and/or (2) an and/or the organ contributing to metabolic clearance rate (MCR) for the relevant hormones. This ‘significant elimination’ holds true for the first interference (with the associated loss of the kidney compensatory pathway) but less so for the second interference because: (i) anephric patients are dependent on, usually, intermittent HD to keep them alive and thus providing them with an artificial means to intermittently and variably clear relevant hormones ; and (ii) there may be non-renal pathways (via other organs or tissues) variably contributing to MCR for these relevant hormones as well. This study should offer further research insights into the biological organization of the human body at the system level emphasizing adaptive and integrative mechanisms. This will advance our knowledge of physiology thus increasing our understanding of how our bodies function in health and disease.For the interested reader, elucidation of utilizing a branch of mathematics known as combinatorics and step-by-step mathematical deduction applied to the BV – BNP feedback control system  supramaximal elevations of BNP and NT-proBNP in only one (obtainable) anephric patient inflicted with CHF , we were of the opinion that this should serve as a basis for future research aimed at further delineating the cut-off values for those hormones to diagnose CHF in anephric patients utilizing chemical biomarkers, thus enhancing the management of their cardiac disease. All these should broaden the knowledge of clinicians treating these patients and publicize the potential deleterious effect of not interpreting BNP and NT-proBNP tests appropriately in this setting. Based on elegant mathematical deductions, the BV – BNP feedback control system provides plausible explanations for our study findings, and lends support to the important hypothesis that ‘anatomical’ and ‘functional’ anephric patients inflicted with CHF should effectively have similar natriuretic response behavior.Written informed consents were obtained from the patients for publication of this case report. Copies of the written consents are available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.JYCT designed the study, developed the analytic approach, worked on data collection, and wrote the first draft and subsequent writing of the paper. BAP contributed to the writing of the paper. All authors read and approved the final manuscript.Appendix 1. Case reports.Click here for fileAppendix 2. Blood Volume – BNP feedback control system.Click here for fileAppendix 3. Study strengths, limitations and main findings[findings,10-12.Click here for file


The Global Asthma Physician and Patient (GAPP) survey evaluated the perceptions of both physicians and patients on the management of asthma. Here we present the results from the United States (US) subpopulation of the GAPP survey.The GAPP Survey was a large, global study . In the US, 208 adults (aged ≥ 18 years) with asthma and 224 physicians were recruited. Respondents were questioned using self-administered online interviews with close-ended questionnaires.Physician and patient responses were found to differ in regard to perception of time spent on asthma education, awareness of disease symptoms and their severity, asthma medication side effects, and adherence to treatment and the consequence of nonadherence. Comparison of the US findings with the global GAPP survey results suggest the US physician-patient partnership compared reasonably well with the other countries in the survey. Both patients and physicians cited a need for new asthma medication.Similar to the global GAPP survey, the US-specific findings indicate that in general there is a lack of asthma control, poor adherence to therapy, and room for improvement in patient-physician communication and partnership in treating asthma. Asthma is a major public health problem that affects an estimated 20 million people in the United States (US), with the prevalence expected to continue to rise in the future -3. AsthmEffective medications are available to help control the persistent symptoms of asthma and appropriate intervention with these is an essential part of any asthma management program . Inhaledβ-agonists (LABAs) for mild persistent asthma for which the GINA and NHLBI guidelines recommend ICS monotherapy ), ICS monotherapy, and leukotriene receptor antagonists were reported as being the most commonly used , followed by LABAs (7%) and anticholinergics (5%) (Q5a). Of patients interviewed, 30% also reported receiving 'other' forms of medication (Q5a). For first-line treatment, most physicians reported prescribing short acting β-agonists for all asthma severities and an ICS plus LABA combination for moderate and severe persistent asthma . The majority of physicians reported prescribing multiple medications for all severities of asthma. Almost all the physicians "somewhat" or "strongly" believed that treating inflammation reduced the risk of bronchoconstriction (97%) and that ICS therapy was the "gold standard" therapy for asthma (95%) (Q2b).When patients were asked about which medications they were currently receiving for their asthma, combination therapy . Less than a third of the physicians tested for an allergic component via skin prick (18%) or assayed the patient's blood for specific allergen-IgE (32%) (Q4b). Most physicians (94%) reported that for patients with an allergic component to their asthma the physicians incorporate allergen avoidance into the asthma management plan, and 72% and 75% said they explained that the patient should remain on controller medication and referred the patient to an allergist or pulmonologist, respectively (Q5b). About half the patients in the survey with an allergic component to their asthma said that their doctor explained how to avoid allergic triggers (59%) and to use controller medication (50%) (Q8a). About a third of these same patients (34%) reported being referred to an allergist or other specialists (Q8a).Physicians and patients had differing views on the level and content of education regarding asthma and its treatments. Both patients and physicians responded that the treating physician is primarily responsible for patient education regarding asthma  (Q9a and Q6b). Almost all the physicians (90%) in the survey responded that they spend up to 50% of the office visit discussing correct inhaler technique, development and execution of an individual management plan, and recognizing and monitoring symptoms Figure ; Q7b. OnPhysician and patient perceptions of how frequently they discuss short-term and long-term side effects of asthma medication also differed. Both physicians and patients reported themselves as the person who initiated the discussion of side effects (85% for physicians and 62% for patients) (Q13a and Q9b). Furthermore, 90% and 77% of physicians reported sometimes or always discussing short-term and long-term side effects, respectively , which contrasted with physicians who answered that the majority of patients knew about potential side-effects Table ; Q12b. FPhysicians and patients differed in their perception of how well patients recognize ICS-related side effects. Only 1% of patients interviewed said that they had experienced adrenal (cortisol) suppression, 8% said they had experienced long-term side effects, and 36% reported having short-term side effects (Q18a). In contrast, 17% of physicians reported that their patients had decreased cortisol production, 48% said their patients had long-term side effects, and 92% said their patients experienced short-term side effects (Q16b). Patients stated that side effects resulting from asthma medication caused them to consider switching (29%) or to switch medication (24%), consider skipping (26%) or skip doses (19%), or consider stopping (21%) or stop taking the medication entirely (22%), or change dosage (26%) (Q19a).Perceptions of compliance differed between patients and physicians. When queried regarding the percentage of time they took their asthma medication according to their doctor or healthcare professional instructions, 35% of patients said they were fully compliant, 32% said they were compliant more than 50% of the time, and only 8% of patients said they were never compliant (Q20a). However, none of the physicians reported that their patients were fully compliant, 54% said that their patients were at least 50% compliant, and 5% said their patients were never compliant (Q17b). There are multiple reasons patients reported for being noncompliant; the most frequent responses were that symptoms went away, they felt they didn't need the medication that often, or they forgot to take the medication  and physicians (79%) thought that there was the need for a new treatment option in the US (Q23a and Q21b). When describing the required attributes for a new ICS, patients and physicians cited a lower potential for long-term side effects, efficacy equivalent to that of currently available ICS treatments and reduced propensity for oropharyngeal side effects (Q24a and Q22b). In addition, physicians thought the ability of the medication to be delivered without a spacer and that it have high lung deposition would be important treatment characteristics of a new ICS.The GAPP survey was designed to identify differences in perspectives between physicians and patients on the treatment of asthma . OverallThe GINA  and NHLBSimilar to the global results, US-speciGlobal  and US pThe global  and US fDespite defining the reasons for poor compliance, patients and physicians surveyed both globally  and in tβ-agonists). In both groups of physicians LABA/ICS combination is the most common treatment (> 90%) for moderate-to-severe asthma as recommended by the guidelines [Both the global  and US-sidelines ,8. AlthoThere are several aspects of this study that should be considered when interpreting the results. The range of asthma severity of the patients interviewed in this survey is not known. Asthma severity is known to influence the perceptions and behaviors of patients with regard to therapy, disease knowledge, and adherence ,19. The Overall the US-specific findings of the GAPP survey are similar to those of the global  and of tThe US findings may suggest a need for improved patient-physician partnership in the US and may support a change in the US from a more physician-led, technology-based, acute disease centered model of care to a more patient-centered medical home model. The patient-centered medical home model uses evidenced-based guidelines in treatment decisions and ensures adequate patient communication with healthcare professionals to help patients meet the challenges of a chronic disease such as asthma ,28,29. AConflicts of Interest: Dr M. S. Blaiss: Dr Blaiss had received honoraria and been a consultant for the following companies: ALTANA Pharma, GlaxoSmithKline, Merck & Co, AstraZeneca and Schering Plough, Alcon, Teva, Novartis/Genentech, sanofi-aventis, and UCB; Dr M. A. Kaliner: Dr Kaliner has been involved in advisory boards and consultancy positions for the following companies: Alcon Laboratories, Glaxo-SmithKline, AstraZeneca, Greer Laboratories, Medimmune, MedPointe/Meda, Novartis-Genentech, Sanofi-Aventis, Schering Plough, Strategic Pharmaceutical Advisors and Teva Specialty Products/Ivax Laboratories. In addition to this, he has been involved in the speaker's bureaus for the following companies: Abbott Laboratories, Alcon Laboratories, Glaxo-SmithKline, MedPointe/Meda, Novartis-Genentech, Sanofi-Aventis, Schering Plough and Teva Specialty Products/Ivax Laboratories. Dr Kaliner has also received research grants from all asthma and allergy companies; Dr C. E. Baena-Cagnani: Dr Baena-Cagnani has been involved in the speaker's bureau for GlaxoSmithKline and sanofi aventis and has received speaker's honoraria from ALTANA, sanofi-aventis, UCD, AstraZeneca, FAES, Novartis, Schering-Plough, Lofarma , ALK-Abello and BioAllergy . Dr Baena-Cagnani has received clinical research support from Schering-Plough, sanofi-aventis, MSD, GSK, and Novartis.; Dr R. Dahl: Dr Dahl has been in advisory boards, participated in scientific clinical trials and been a speaker at meetings supported by ALK, Astra Zeneca, Boerhinger-Ingelheim Pfizer, GSK, UCB, Nycomed, MSD, Stallergen, TEVA, ONO, Dainippon, and Airsonett; Dr E. J. Valovirta: Dr Valovirta has been an advisory board member at ALK-Abello and MSD Finland, and has received honoraria and has been a consultant for the following companies: Altana Pharma, GSK, Merk & Co., Astra-Zeneca, Schering Plough, and ALK-Abello; Prof G. W. Canonica: Prof. Giorgio Walter Canonica has been: a scientific consultant as a single scientist or in national/international boards; a researcher in scientific trials in his university or in collaboration with other research institutions; and a speaker in scientific meetings, seminars and educational activities devoted to specialists, general practitioners and other healthcare professionals. These activities were totally or partially supported by the following commercial companies: A. Menarini, Alk-Abellò, Almirall, Altana-Nycomed, Anallergo, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Gentili, GSK, Lofarma, Merck Sharp & Dome, Novartis, Pfizer, Schering Plough, SigmaTau, Stallergenes, UCB Pharma, Uriach, and Valeas.Supplemental digital content is available for this article. Direct URL citations appear in the text, and links to the digital files are provided in this article.


Patients with chronic heart failure (CHF) experience a number of debilitating symptoms, which impact on activities of daily living and result in poor quality of life. Prospective memory, which is defined as memory to carry out future intentions, has not been investigated in this group. However, emerging evidence suggests CHF patients have difficulties with cognitive processes related to prospective memory. Self-care, which partly relies on prospective memory, is essential in symptom management and preventing acute clinical deterioration. This study aims to measure prospective memory in CHF patients, and examine the relationship between prospective memory and CHF self-care.A comprehensive neuropsychological assessment will be conducted to assess a range of cognitive functions and psychopathology. The primary focus will be an assessment of prospective memory using a well-established behavioral measure; Virtual Week. Thirty CHF patients attending a nurse-led management program will be recruited from three hospital sites in Melbourne, Australia and their self-care behaviors will be assessed using the Self-care Chronic Heart Failure Index (SCHFI), a validated self-report tool. An additional 30 healthy controls, matched on age, gender, and IQ will be recruited from the general community.This is a group comparison study that will provide an evaluation of the prospective memory abilities of CHF patients. The findings of this research will provide insight into whether prospective memory may be hindering patients’ ability to perform adequate self-care. Patients with chronic heart failure (CHF) represent a rapidly increasing and vulnerable group of individuals with a dismal prognosis . DespiteA key strategy within CHF management programs is to promote and engage patients to perform specific self-care behaviors . CHF selCognitive dysfunction has been observed in as many as 75% of patients in select CHF populations ,15 and iProspective memory (PM) is defined as memory to carry out future intentions . It invoA key distinction between different prospective memory tasks is that some are event-based and others are time-based. Event-based tasks are triggered by an event cue and require monitoring of the environment for that cue . For exaFailures in prospective memory are often exhibited by individuals with neurological disorders that impact on functional independence ,26. FurtThe aims of this study are to determine if: 1) prospective memory ability of CHF patients is impaired compared with an age-matched group, 2) CHF patients exhibit more prospective memory failures in event-based or time-based tasks than matched controls, 3) prospective memory deficits in CHF patients are globalized, or specific to a particular type of prospective memory task, 4) prospective memory ability correlates with self-care maintenance behaviors, management skills, and confidence, and 5) prospective memory ability correlates to functioning as assessed by the Heart Failure Screening Tool (Heart-FaST). Findings from this study will contribute to our understanding of the factors that predict adequate engagement in CHF self-care and provide avenues for developing appropriate interventions.This study will use a group comparison design to examine the prospective memory abilities of patients with CHF. Groups will be matched on age, gender, years of education, and premorbid intelligence estimated/indexed by the National Adult Reading Test (NART) .Participants will include adults 18 years and over, although due to the prevalence of CHF in the elderly, the majority of the sample will be above 50 years. The CHF group will have a confirmed diagnosis of CHF based on national guidelines . All parInformation relating to a range of participant variables will be collected in order to characterize the sample. These variables include demographic details, number and quality of social supports, education level, occupation status and history, history and current treatment of depression and/or anxiety, and comorbid illness burden (measured using the Charlson Comorbidity Index). Cardiac related history will also be obtained, including cardiovascular risk factors, length of time living with chronic heart failure, type of chronic heart failure diagnosis, chronic heart failure etiology, prior treatments for chronic heart failure , observations of clinical features, and self-care behaviors   and abilThe SCHFI is a comprehensive self-report instrument of self-care practices pertinent to the management of CHF. The SCHFI comprises 15 items rated on a 4-point response scale. It has three subscales: maintenance, management and confidence . Self-caThe Heart-FaST was developed to assist clinicians in applying educational and support strategies based on self-care capacity . Unlike Addenbrooke’s Cognitive Examination–Revised is a short, sensitive cognitive screening test that measures five cognitive domains; attention/orientation, memory, verbal fluency, language and visuospatial abilities. Lower scores suggest poorer cognitive performance [The formance . The ACEformance  and willVirtual Week; a computerized board game that stimulates a week of everyday activities  where the participant is required to make choices about the tasks relevant to the event . At some of these events, participants have to remember to perform a prospective memory task. For example, at the beginning of the game, participants might be asked to remember to ‘drop in the dry cleaning’ (PM task) when ‘shopping’  [The e (HADS)  is a 14 e (HADS) . The HADe (HADS) .Four measures will be used to assess participants’ executive functioning. Executive functions are higher order thinking processes.Trail Making Test (TMT) [The st (TMT)  assessesst (TMT) , and thest (TMT) .Hayling Sentence Completion Test[The tion Test assessestion Test.Digit Span, a subtest of the Wechsler Adult Intelligence Scale-IV (WAIS-IV) [The WAIS-IV)  is a meaWAIS-IV) .verbal fluency[The final measure of executive functioning is an adaptation of the Controlled Oral Word Association task, which is a measure of l fluency. Two typl fluency,47.Rey Auditory Verbal Learning Test (RAVLT) [The  (RAVLT)  will be  (RAVLT) . The RAV (RAVLT) .A research assistant, in collaboration with the CHF nurses, will screen and recruit participants for the CHF group. A detailed history will be collated based on patient self-report information and review of medical records. Around three months later, participants will be tested in a single session, lasting between two to three hours. The delay of three months will be built in to ensure that participants are medically stable when they complete the neuropsychological assessment. The ACE-R will be administered first to assess each participant’s cognitive functioning. Virtual Week will be administered next, followed by the remaining measures. Participants will be offered at least one break throughout the session and will be encouraged to take additional breaks as needed. The study protocol is illustrated in Figure p-value of <0.05. As participants will be required to perform different prospective memory tasks , analyses will also examine whether prospective memory lapses are specific to a particular task, or pervasive across tasks. Comparisons based on normative samples will also be reported for the cognitive screen (ACE-R), measure of premorbid intelligence (NART), three measures of executive function , and verbal memory .A descriptive analysis of all variables will be performed. A mixed factorial ANOVA will be used to examine main effects and interactions of prospective memory tasks, across CHF patients and healthy controls. Statistical significance will be considered at a Sample size estimations are based on a previous study using Virtual Week with a clinical sample involving multiple sclerosis (MS) patients . Almost Exploratory correlation analyses will be conducted to examine the relationship between different prospective memory types  and the three domains of self-care: self-care maintenance behaviors; management skills; and confidence. Further exploratory correlations will investigate the relationship between the three clinical factors  assessed by the Heart-FaST, and self-care ability. Preliminary correlations will also be conducted to examine the association between Heart-FaST and the behavioral measure of prospective memory, Virtual Week.This study has been approved by the Eastern Health Research and Ethics Committee (LR39/1112), and the Human Research Ethics Committee of the Australian Catholic University . Informed consent will be obtained from all the participants in the study.The results of this study will be the first to provide insights into the prospective memory difficulties experienced by patients with CHF. The study will test the hypothesis that prospective memory abilities are impaired, compared to healthy controls. Prospective memory failures experienced by CHF patients could affect self-care, for example by forgetting to pick up prescription medications from the pharmacist, forgetting to attend doctor appointments, forgetting to take daily medications and performing daily weighing, and failing to respond to >2kg changes in weight, all of which are considered crucial for the management of their condition . TherefoA fundamental approach to improving adverse CHF patient outcomes and associated healthcare costs lies in applying individualized education and support strategies . ImproviA number of practical considerations in undertaking this study have been considered and addressed. Given that CHF patients are typically older adults, a touch screen will be made available for participants who are either unwilling or unable to use a computer and mouse for testing. Using a simulated touch screen with participants pointing on screen and experimenters operating mouse overcame previous reluctance or difficulties of adults using a computer when playing Virtual Week . We acknACE-R: Addenbrooke’s Cognitive Examination-Revised; CHF: Chronic heart failure; HADS: Hospital Anxiety and Depression Scale; Heart-FaST: Heart-Failure Screening Tool; MS: Multiple sclerosis; NART: National Adult Reading Test; PM: Prospective memory; RAVLT: Rey Auditory Verbal Learning Test; SCHFI: Self-care Chronic Heart Failure Index; TMT: Trail Making Test; WAIS-IV: Wechsler Adult Intelligence Scale-IV.The authors declare that they have no competing interests.Principal responsibility for study design and conduct is assumed by JC and PGR. TH is involved in the data collection and overall project management; all other authors are responsible for the supervision of the project and its ethical approval and conduct. TH, JC, and SNM drafted the manuscript. All authors provided critical review for important intellectual content and approved the final manuscript.1TH is a registered psychologist who is currently undertaking her Doctor of Philosophy and Masters of Clinical Psychology. 2JC is a Senior Research Fellow (Cardiovascular Research Centre) with a program of research aimed at developing screening methods and informing clinical practice in the application of individualized patient education and management strategies directed at improving health outcomes among patients diagnosed with heart failure. 1SNM is a lecturer in the School of Psychology, and she has previously worked as a practicing psychologist and research psychologist. 2CFS is an Associate Professor of Research in the Cardiovascular Research Centre where she co-heads the psychosocial program of research. 2DRT is a Professor of Nursing in the Cardiovascular Research Centre where he heads the psychosocial program of research. 1PGR is a Professor in the School of Psychology. He is currently leading the Cognition and Emotion Research Lab that conducts experimental psychology research in the field of cognitive psychology and neuropsychology.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/13/63/prepub


Bariatric surgery is able to improve glucose and lipid metabolism, and cardiovascular function in morbid obesity. Aim of this study was to compare the long-term effects of malabsorptive , and restrictive  procedures on metabolic and cardiovascular parameters, as well as on metabolic syndrome in morbidly obese patients.170 patients studied between 1989 and 2001 were called back after a mean period of 65 months. 138 patients undergoing BPD (n = 23) or LAGB (n = 78), and control patients  were analysed for body mass index (BMI), blood glucose, cholesterol, and triglycerides, blood pressure, heart rate, and ECG indexes .After a mean 65 months period, surgery was more effective than diet on all items under evaluation; diabetes, hypertension, and metabolic syndrome disappeared more in surgery than in control patients, and new cases appeared only in controls. BPD was more effective than LAGB on BMI, on almost all cardiovascular parameters, and on cholesterol, not on triglyceride and blood glucose. Disappearance of diabetes, hypertension, and metabolic syndrome was similar with BPD and with LAGB, and no new cases were observed.These data indicate that BPD, likely due to a greater BMI decrease, is more effective than LAGB in improving cardiovascular parameters, and similar to LAGB on metabolic parameters, in obese patients. The greater effect on cholesterol levels is probably due to the different mechanism of action. Obesity is often accompanied by diabetes, hyperlipidemia, arterial hypertension ; all areBariatric surgery improves glucose and lipid metabolism ,15 and aBariatric surgery has been reported to reduce LVM indices in a number of studies, and has beneficial effects on virtually all sections of electrocardiogram (ECG). It is pThe amount of weight loss is greater with malabsorptive than with restrictive bariatric procedures ,15,25. OLaparoscopic gastric banding (LAGB) and biliary pancreatic diversion (BPD) are routinely performed at participating Institutions, following the indications and guidelines of NIH ; proceduThe protocol of this study, i.e. ad-hoc call-back of patients for selected determinations, was specifically approved by local ethics committees, and all participating patients gave written informed consent. Patients undergoing surgery between 1989 and 2001 were considered in this study; all patients agreeing to come back to Institutions were considered; they were interviewed about current therapies, and underwent anthropometric evaluation, ECG recording, and heart rate and blood pressure measurement, fasting blood sampling for glucose and lipid determination. Patients who refused surgery and agreed to be followed-up (controls), were also considered. They were treated with diet . Patient-2) was calculated, and was used as an index of myocardial oxygen consumption and hence of work load of the heart [Arterial hypertension was diagnosed when systolic/diastolic blood pressure was ≥ 140/90 mmHg, or when subjects were under antihypertensive treatment. Diabetes mellitus was diagnosed when fasting blood glucose levels were > 126 mg/dl, or when subjects were under antihyperglycemic treatment (metformin). Rate pressure product . QT intervals were measured manually from the onset of the interval between Q and S waves of the electrocardiogram to the end of the T wave on the isoelectric baseline, and corrected according to Bazett's formula (QTc = QT/√RR) . When a 2 test. Pairwise correlations were computed between changes of clinical conditions (independent variables) and change of Cornell voltage-duration product, and of RPP (dependent variables). Next, a multivariate regression analysis was carried out to assess the role of independent variables significant at univariate analysis (plus age and sex) in change of clinical conditions such as diabetes mellitus, arterial hypertension, and metabolic syndrome, and changes of Cornell voltage-duration product, and of RPP; we reported significance of the whole model, plus F and p of variables statistically significant at multivariate regression analysis. p levels < 0.05 were considered statistically significant.Inter-group comparisons were performed by one way analysis of variance (ANOVA) followed by Scheffè's multiple comparison test. Intra-group comparisons were performed by two-tailed Student's t test for paired samples. Since a normal distribution of data was not assured, non-parametric tests (Mann-Whitney and Wilcoxon test) were also used. Absolute frequencies and changes of comorbidities were compared by χFigure In surgery patients, decrease of systolic and diastolic blood pressure, of Cornell voltage-duration product, of RPP correlated with decrease of BMI. The decrease of cholesterol was greater with BPD than with LAGB, independent of initial BMI, and of the amount of weight loss (not shown), and therefore seems due to the kind of surgery rather than to the amount of weight loss.At multiple regression analysis disappearance of diabetes mellitus was significantly associated with presence of diabetes at the beginning ; disappearance of arterial hypertension was associated  with presence of hypertension at the beginning  and change of BMI ; disappearance of metabolic syndrome was associated  with presence of metabolic syndrome at the beginning  and with change of BMI . Table BPD is known to induce a greater weight loss than LAGB, independently of initial BMI; this information comes from a meta-analysis  and fromSome cardiovascular parameters were more influenced by BPD than by LAGB, such as diastolic and systolic blood pressure, Cornell voltage-duration product and RPP. It seems that this was generally due to a greater effect on BMI, although a direct role of BMI in multiple regression analysis was not evident.Bariatric surgery is known to improve all sections of ECG ; ECG hasHR and QTc are assumed as an index of sympathetic overactivity ; their dThese data indicate that BPD, likely due to a greater BMI decrease, is more effective than LAGB in improving cardiovascular parameters, and similar to LAGB on metabolic parameters, in obese patients. The greater effect on cholesterol levels is probably due to the different mechanism of action.ANOVA: analysis of variance; ATP III: adult treatment panel III; BMI: body mass index; BP: blood pressure; BPD: biliopancreatic diversion; CHF: congestive heart failure; CV: cardiovascular; ECG: electrocardiography; FXR: farnesoid X-receptor; HR: heart rate; LAGB: laparoscopic adjustable gastric banding; LVH: left ventricular hypertrophy; LVM: left ventricular mass; LXR: liver X-receptor; PPAR: peroxisome proliferator activated receptor; QTc: corrected QT interval; RPP: rate pressure product.The authors declare that they have no competing interests.AEP, FF, GM, GA, and NS designed the study protocol. GM, AV, ML, FF were in charge of evaluating patients, organizing databases, performing statistical analysis. GM, GA, and NS were the surgeons performing all surgical procedures. All authors substantially contributed to writing the manuscript. All authors read and approved the final manuscript.


The renin-angiotensin-aldosterone system (RAAS) plays a dominant role in the pathophysiology of hypertension, diabetes mellitus, chronic kidney disease and chronic heart failure. Therefore, drugs that block key components of the RAAS such as ACE inhibitors (ACEI) and angiotensin receptor blockers (ARBs) have gained wide clinical use for these indications. Despite progress, the morbidity and mortality of patients treated with ACEI or ARBs remain high. Aliskiren  is the first orally active inhibitor of renin approved for clinical use as an antihypertensive agent. The development program has established that at the licensed doses of 150 mg and 300 mg. Aliskiren is effective either as monotherapy or in combination with drugs from the other major classes. In this review we analyze and review the information already gained with Aliskiren, raises questions regarding the advantages of DRIs as monotherapy compared to marketed ACEIs and ARBs, their potential added value in combination with other RAAS modulators and other still unproven benefits in relation to prorenin and renin receptor biology. Hypertension is one of the most important risk factors for, and causes of, cardiovascular disease. The difficulty in achieving a normal blood pressure range in some patients makes the rate of cardiovascular disease high ,2,3. ForAliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. It acts at the point of activation of the renin-angiotensin-aldosterone system, or renin system, inhibiting the conversion of angiotensinogen to angiotensin I by renin and thereby reducing the formation of angiotensin II by angiotensin-converting enzyme (ACE) and ACE-independent pathways. Aliskiren is a highly potent inhibitor of human renin in vitro  ,5,6,7,8.Aliskiren inhibits plasma renin activity (PRA) by up to 80% following both single and multiple oral-dose administration. Similar reductions in PRA are observed when aliskiren is administered in combination with agents that alone increase PRA, including diuretics , ACE inhibitors (ramipril) and angiotensin receptor blockers , despite greater increases in the plasma renin concentration ,10,11. MHypertension and type 2 diabetes are common comorbidities, thus many patients receiving antihypertensive medication require concomitant therapy with hypoglycaemic or lipid-lowering drugs. Co-administration of aliskiren with metformin, pioglitazone or fenofibrate had no significant effect on the pharmacokinetics of these drugs in healthy volunteers. These findings indicate that aliskiren can be co-administered with metformin, pioglitazone or fenofibrate without the need for dose adjustment ,13,16.Aliskiren is the first renin inhibitor to be licensed for use as an antihypertensive drug in both the United States and Europe. Opinions vary considerably concerning the future of aliskiren and renin inhibition. Some experts argue that renin inhibitors should only be prescribed when less expensive blockers of the renin-angiotensin system (RAS), with established effects on morbidity and mortality, are not tolerated or have failed to reduce blood pressure effectively. Others propose that because renin is a highly specific catalyst for the rate-limiting step of the RAS, renin inhibitors have the potential to supersede angiotensin-converting enzyme inhibitors and angiotensin receptor blockers as the preferred inhibitors of the cascade in patients with particular pathologies and/or genotypes . It has The evidence supporting the use of renin inhibitors to control hypertension, but limiting this use in patients with kidney disease progression even if ACE and ARB decrease cardiovascular risk in patients with chronic kidney disease. Renin-angiotensin-aldosterone system inhibition exerts a renoprotective effect independent of blood pressure reduction. Many studies using an end-point of proteinuria compared the effects of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker monotherapy with combination ACE/ARB therapy. Despite methodological limitations, most studies suggest that combination therapy provides a greater antiproteinuric effect than monotherapy, perhaps because of more prolonged and complete RAAS inhibition. COOPERATE and ONTARGET used more robust end-points to study renoprotective effects. In COOPERATE Study; combination therapy resulted in significantly longer times to doubling serum creatinine or developing end-stage renal disease than Trandolapril or losartan monotherapy. However, a secondary ONTARGET finding was that combination therapy significantly increased the risk for renal dysfunction compared with ramipril or telmisartan alone ,16,17,18versus existing RAAS antagonists in treating hypertension and target organ damage are under investigation. The antihypertensive efficacy of aliskiren monotherapy has been compared with that of other RAAS antagonists and combinations of aliskiren with these agents. Many studies have shown that aliskiren is equally effective as angiotensin receptor blockers and may be slightly more effective than angiotensin converting enzyme inhibitors in lowering blood pressure. In contrast to the other RAAS antagonists, aliskiren shuts down the entire downstream RAAS cascade. This results in greatly increased plasma renin concentration due to removal of angiotensin II-mediated feedback inhibition of renin release, which has raised concerns about whether direct renin inhibition adds anything to inhibition of downstream components of the RAAS cascade [24].The potential advantages and disadvantages of aliskiren therapy et al., that compared DRI to ramipril 10 mg conclude that aliskiren-based therapy produced sustained blood pressure (BP) and PRA reductions over 26 weeks; ramipril-based therapy lowered BP and increased PRA. PRA reductions persisted four weeks after stopping aliskiren, suggesting an inhibitory effect beyond the elimination half-life of the drug. Palatini et al. reported that aliskiren 300 mg provided a sustained BP-lowering effect beyond the 24-h dosing interval, with a significantly smaller loss of BP-lowering effect in the 24-48 h period after dose than irbesartan 300 mg or ramipril 10 mg .Till now aliskiren was added to valsartan in stage 2 hypertension in a recent report. This combination therapy provided significantly greater BP reductions over aliskiren or valsartan monotherapy. Also aliskiren was combined with losartan, with similar results. Finally, Freiberger Aliskiren has the potential to become the first orally active renin inhibitor that provides a true alternative to ACE-inhibitors and Ang II receptor antagonists in therapy for hypertension and other cardiovascular and renal diseases. As monotherapy, aliskiren now is reserved for use as an alternative to ACE-Is or ARBs, where these are ineffective or poorly tolerated. Till now a large, formal, and prospective randomized study with major endpoints with aliskiren has not been completed Without such data, especially when alternative therapeies have such data, it is difficult to make a firm recommendation. Aliskiren is well on its way but falls short of this criterion until the navigator study is complete. In our opinion in the future it is possible that aliskiren could supplant ACE inhibitors and ARBs, because it was demonstrated more effective than ACE and ARB to reduce BP and to reduce PRA. Combination therapy with the direct renin inhibitor, aliskiren, and the angiotensin receptor blocker or ACE inhibitor has been shown to produce greater BP reductions than either agent alone in some double-blind study and it will represent the next future.