With a combination of different sympathetic tests, we aimed to elucidate whether impairment of sympathetic function in Parkinson's disease (PD) is the consequence of a central or peripheral efferent dysfunction.–5; 10–6; 10–7; 10–8) and by cold through forehead cooling. We also used sympathetic multiunit microneurography : bursts per minute; burst incidence (BI): bursts per 100 heart beats) and evaluated the presence of phosphorylated α‐synuclein deposits in skin innervation in biopsies from the thighs by immunohistohemistry.Thirty‐five patients with early‐to‐intermediate PD  and 20 age‐ and sex‐matched healthy controls  were recruited. Autonomic testing was performed in two subgroups and included the assessment of resting cardiovascular parameters, postprandial hypotension (PPH), orthostatic hypotension (OH), and vasoconstriction induced by intradermal microdialysis with different concentrations of norepinephrine  and during OH . Vasoconstriction induced by NE microdialysis and cold was unchanged in PD patients. MSNA was lower in PD patients than in controls . Phosphorylated α‐synuclein deposits could be found only in PD patients.Diastolic blood pressure was higher in the PD group at rest (We did not find indications for peripheral sympathetic nerve fiber dysfunction or adrenoreceptor sensitivity changes. The decreased MSNA argues in favor of central sympathetic impairment. With a variety of autonomic tests, we aimed to further elucidate the pathophysiology of autonomic impairment in Parkinson's disease. Since MSNA is reduced, our data favor a central origin of autonomic disturbances. However, since peripheral impairment of, for example, QSART in PD is known, combined central and peripheral mechanisms seem likely. The patients were recruited from the outpatient clinics of the Neurological departments of the University Medical Center Mainz, Justus‐Liebig‐University Giessen and Philipps‐University, Marburg. The patients were divided into two groups and were investigated in two centers (Mainz and Giessen):n = 2; H&Y 2: n = 14; H&Y 3: n = 4; URPDS III: median 10.0 (IQR: 7.0–25.0); disease duration: median 4 years (IQR 2–7 years); 10 age‐ and sex‐matched healthy subjects ; 6 women) underwent the following investigations: (a) resting blood pressure and heart rate; (b) testing of postprandial hypotension; (c) analysis of vasoconstriction induced by intradermal microdialysis with norepinephrine, and (d) forehead cooling.Patient group 1:20 patients suffering from early‐to‐intermediate stage idiopathic PD (median age: 65.5 (IQR 54.75–70 years), 13 women; H&Y 1: n = 6; H&Y 2: n = 7 H&Y 3: n = 2; URPDS III: median: 7.0 (IQR: 3.8–16.0); disease duration: median 3 years (IQR: 2–5 years)); 10 age‐ and sex‐matched healthy controls (median age: 58 years (IQR 57–61.25 years); 6 women) underwent the following investigations: (a) resting blood pressure and heart rate; (b) testing of orthostatic hypotension; (c) skin biopsy; and (d) assessment of muscle sympathetic nerve activity (MSNA).Patient group 2:15 patients suffering from early‐to‐intermediate stage idiopathic PD (median age: 62 years (IQR: 57.0–65 years); 6 women; H&Y 1: There were no differences regarding the parameters assessed in the study: H & Y, heart rate and blood pressure. However, we cannot rule out that the two patient groups differed in other aspects of PD that we did not assess.2.2To assess cardiovascular parameters at rest, blood pressure , and heart rate  were measured with a digital sphygmomanometer (WEPA) after 15 min resting in the supine position.2.3baseline) and after 30, 60, and 90 min using the hexokinase method. The differences between PGbaseline and each of the time points were calculated .Postprandial hypotension is defined as a decrease in SBP of at least 20 mmHg within 1 hr after drinking 75 g of glucose  of plasma norepinephrine  and epinephrine concentrations  were drawn at baseline in a supine position and after standing up after completion of the PPH test.2.4–5; 10–6; 10–7; 10–8; flow rate: 4 µl/min). Insertion‐related vasodilatation (neurogenic inflammation) subsides within 60 min  were inserted intradermally to a length of 1.5 cm by a 25‐gauge cannula. The fibers were placed transversally to the axis of the limb at a distance of approximately 3 cm. Each fiber was perfused with one concentration of norepinephrine (NE) diluted in saline  was calculated for each pixel by means of intensity of the Doppler shift of the backscattered laser light (arbitrary perfusion units [PUs]). Intensity of the vasoconstriction was analyzed offline  separately for each microdialysis fiber. Vasoconstriction expressed in flux values was normalized to baseline .Superficial blood flow was quantified using a laser Doppler imager system . LDI scans  were recorded at baseline and at intervals of 5 min after NE perfusion commenced. The mean baseline flux value in perfusion units was calculated as the mean from the three acquired baseline pictures. The size of the scanned area was 144 cm2.5A coated ice pack was placed on the participant's forehead for 20 s. This procedure has been demonstrated to reliably cause peripheral vasoconstriction . Briefly, after lying in a supine position for 15 min, blood pressure and heart rate were measured using a digital sphygmomanometer. The subjects then stood up, and blood pressure and heart rate were recorded directly after getting up as well as after 1, 2, 3, and 5 min. The test was considered pathologic if the SBP decreased ≥ 20 mmHg or the DBP decreased ≥10 mmHg  in the left peroneal nerve posterior of the fibular head as described previously . Burst frequency , burst incidence , and burst amplitude (BA) were acquired. Burst frequency represents burst gating and is a useful measure of the degree of activity reaching the effector organs; burst incidence reflects central drive and burst amplitude represents burst strength  and “time.” For analysis of the OH and forehead cooling, rm‐ANOVA was applied using the factor “disease” . Levene's test was applied to check for homogeneity of variances. Greenhouse‐Geisser correction was applied. Spearman correlation tests were employed to analyze correlations between clinical measures and morphological skin changes. Kolmogorov–Smirnov tests of normality were run for all data sets and parametric or nonparametric statistics were used accordingly. All values are given as medians and interquartile range (IQR) in the case of a non‐normal distribution and as means ± standard error in the case of a normal distribution. Values were considered significant if p < .05.Data were analyzed using the SPSS Statistics  software package. For analysis of the degree of vasoconstriction, repeated‐measures analysis of variances (rm‐ANOVA) was applied using the factors “disease” , “concentration” (NE concentration: 1033.1p < .001) was higher in the PD patients while SBP  and HR  were unchanged.At rest, DBP .PPH (drop of SBP ≥ 20 mmHg) occurred in 1 out of 10 healthy volunteers but in 9 of 20 PD patients. The maximum drop in SBP (⊿SBP_max) was higher in PD patients compared to the control group .Plasma glucose (PG) concentrations did not differ between PD patients and controls . In the standing position, serum norepinephrine was higher in both groups compared to supine position  while epinephrine was higher only in PD patients .Serum norepinephrine and serum epinephrine were not different between patients and controls (norepinephrine rest: PD: 207.00 (IQR 146.50–324.00) ng/L; controls: 224.50 (IQR 91.50–392.75) ng/L; ns; norepinephrine standing: PD: 471.00 (IQR 200.25–719.00) ng/L; controls: 567.00 (IQR 414.50–891.50); epinephrine rest: PD: 26.00 (IQR 20.00–78.00) ng/L; controls: 20.00 (20.00–32.23); epinephrine standing (PD: 47.65 (IQR 23.90–118.50) ng/L; controls: 35.00 . The vasoconstriction response did not differ between PD and healthy controls for any of the NE concentrations  dose dependently induced vasoconstriction , but in none of the controls. Therefore, the degree of OH is not severe. A quantitative analysis revealed that in this group of PD patients, DBP was higher compared to the control group , directly after standing up (p = .013) and after one minute of active standing (p = .044) compared to the controls. The systolic blood pressure as well as the heart rate did not differ between PD patients and controls .Orthostatic hypotension was present in 4 of the 15 PD patients (SBP decreased ≥ 20mmHg: 3.6n = 4), erector pili muscles (n = 2) but also in dermal nerve bundles that were not attached to autonomic structures (n = 5). No differences in morphological parameters between PD patients with and without P‐α‐synuclein deposits could be detected . As a secondary finding, P‐α‐synuclein deposits were present in 7 out of 15 PD patients but in none of the healthy participants. These deposits were found in vasoconstrictors n = , erector3.7t test; p = .001).Burst frequency (BF) at rest was significantly lower in PD patients compared to healthy controls .Burst incidence (BI) at rest was significantly lower in PD patients compared to healthy controls  did not differ between PD and healthy controls .3.8r = −.668; p = .007; r = −.680; p = .005).H&Y scale and PD duration but not age correlated negatively with the number of PGP9.5 positive fibers innervating the sweat glands  and PD duration .The presence of P‐α‐synuclein correlated with PD stage . Since the biographical data of the patients of the two investigated groups did not differ, we feel that our assumptions are nevertheless justified. Another key limitation of our conclusion might represent the lower sensitivity of peripherally mediated functional vasoconstriction tests. We did not detect any denervation‐related hypersensitivity of peripheral adrenoreceptors on peripheral sympathetic fibers innervating skin blood vessels by norepinephrine microdialysis. There is no evidence for vasoconstriction axon reflex. However, our results showing the clear reduction of MSNA in PD patients pinpoints toward a dominant role of centrally altered autonomic drive. Unfortunately, the routine investigations MIBG scintigraphy and head tilt test were not performed in our study. However, since we use multiple other tests we feel that our results are still valid. Another major limitation is that the study was performed without withdrawing medication. This could have a major impact on our OH and PPH findings since dopaminergic medication could be associated with a drop in blood pressure (Calne, Brennan, Spiers, & Stern, 5We provide evidence for functional rather than structural efferent sympathetic changes in intermediate PD patients. Our data with reduced MSNA argue in favor of central sympathetic impairment while we found no indications for peripheral sympathetic nerve fiber degeneration or dysfunction. However, longitudinal studies including treatment naïve PD patients are needed to further elucidate the nature and progression of autonomic pathology in PD.The authors have no conflict of interest to report.


Cardiovascular disease (CVD) is the leading cause of death globally and in Canada. Diabetes and hypertension are major risk factors for CVD events. Despite the increasing availability of effective treatments, the majority of diabetic and hypertensive patients do not have adequate blood pressure and glycemic control. One of the major contributors is poor treatment adherence.This study aims to evaluate the impact of treatment adherence for patients with both diabetes and hypertension on acute severe CVD events and intermediate clinical outcomes in Canadian primary care settings.We will conduct a population-based retrospective cohort study of patients living with both diabetes and hypertension in Ontario, Canada, between January 1, 2008, and March 31, 2018. The Social Cognitive Theory will be used as a conceptual framework by which to frame the reciprocal relationship between treatment adherence, personal factors, and environmental determinants and how this interplay impacts CVD events and clinical outcomes. Data will be derived from the Diabetes Action Canada National Data Repository. A time-varying Cox proportional hazards model will be used to estimate the impacts of treatment adherence on CVD morbidity and mortality. Multivariable linear regression models and hierarchical regression models will be used to estimate the associations between treatment adherence of different medication categories and intermediate clinical outcomes. Our primary outcome is the association between treatment adherence and the risk of acute severe CVD events, including CVD mortality. The secondary outcome is the association between treatment adherence and intermediate clinical outcomes including diastolic and systolic blood pressures, glycated hemoglobin, low-density lipoprotein cholesterol, and total cholesterol. Owing to data limitation, we use medication prescriptions as a proxy to estimate treatment adherence. We assume that a patient adhered to medications if she or he had any prescription record in the 4 preceding quarters and 1 quarter after each quarter of interest. Acute severe CVD events are defined based on the World Health Organization’s Monitoring Trends and Determinants in Cardiovascular Disease Project, including acute coronary heart disease, stroke, and heart failure. As causes of death are not available, the number of CVD deaths will be computed using the most recent systolic blood pressure distributions and the population attributable risks related to systolic blood pressure level.The project was funded by Diabetes Action Canada (reference number: 503854) and approved by the University of Toronto Research Ethics Board (reference number: 36065). The project started in June 2018 and is expected to be finished by September 2019.The findings will be helpful in identifying the challenges of treatment adherence for diabetic and hypertensive patients in primary care settings. This will also help to develop intervention strategies to promote treatment adherence for patients with multi-morbidities.DERR1-10.2196/13571 Cardiovascular disease (CVD) is the leading cause of death in Canada, accounting for one-third of deaths nationally . DiabeteTreatment adherence can be measured using either subjective or objective methods. One of the most frequently used subjective measures is the Morisky Medication Adherence Scale , which iUp to now, there were limited studies investigating medication treatment adherence and its association with CVD events -35 and cTreatment adherence is largely viewed, and measured, as a behavior at the individual level . HoweverOther studies of adherence at the individual level have employed the Health Belief Model or Theory of Planned Behavior to understand how individuals may engage in adherence behavior; however, these frameworks are limited in application at the population level and do not adequately explicate environmental determinants of adherence behaviors -60. SimiOur study seeks to examine the ways in which medication prescription, as proxy for adherence, impacts on CVD events and clinical outcomes. As shown in our conceptual framework , the behObjective 1: The first objective was to assess the impacts of treatment adherence on acute severe CVD events in Ontario between January 1, 2008, and March 31, 2018 (10 years).Hypothesis 1: Patients with a lower adherence rate of one or more medications  are more likely to develop acute severe CVD events (including death from CVD), adjusting for potential confounding factors.Objective 2: The second objective was to assess the impacts of treatment adherence on intermediate clinical outcomes in Ontario between January 1, 2008, and March 31, 2018.1c), LDL-C, and total cholesterol (TC), adjusting for potential confounding factors.Hypothesis 2: Patients with a higher adherence rate are associated with significant improvements in clinical outcomes including diastolic blood pressure, systolic blood pressure, glycated hemoglobin  patients with a past history of any acute severe CVD event, (2) patients who developed CVD events during follow-up where no date of CVD event was present, and 3) patients whose follow-up period was below 6 quarters as we cannot estimate its treatment adherence. A total of 15,642 eligible participants are identified in the finial study population  and 3. patients1c, LDL-C, and TC outcomes. The follow-up period will be measured approximately in months and treated as an independent variable.We will retrospectively follow-up all eligible participants until March 31, 2018 (by months). Follow-up ends when a participant dies, has any acute severe CVD event, or by the end of the study . For hypotheses related with clinical outcome, follow-up ends with the participant’s latest diastolic blood pressure, systolic blood pressure, HbAWe will utilize the Diabetes Action Canadian National Diabetes Repository as the data source. The Repository contains deidentified data from over 100,000 patients living with diabetes, currently from 4 Canadian provinces . Data are extracted from primary care EMRs of consenting family physicians and nurse practitioners by regional Practice Based Research Networks who are members of the Canadian Primary Care Sentinel Surveillance Network (CPCSSN) and are managed using previously described processes developed through CPCSSN . The RepDeidentified patient data from contributing practices in the Diabetes Repository include the following: (1) patient demographic characteristics, (2) patient health conditions, (3) physical and laboratory examinations, (4) medication prescriptions, (5) risk factors, and (6) comorbidities. A data dictionary that provides information on data elements is available at the Diabetes Action Canada website.Medication adherence rate is considered the exposure of interest. Medications will be classified as (1) antidiabetic medications, including metformin, sulfonylurea, and insulin, inhibitors of dipeptidyl peptidase 4, meglitinide, sodium-glucose cotransporter-2 inhibitors, thiazolidinedione, and alpha-glucosidase enzymes, (2) antihypertensive medications, including angiotensin converting enzyme inhibitors, thiazide diuretics, beta-blockers, calcium channel blockers, and angiotensin II receptor blockers, (3) statins, and (4) aspirin. We will measure patient adherence to each type of prescription if prescribed. Theoretically, the adherence rate could be calculated based on the prescription date and refills. However, we cannot depend on the refills as this information varies highly among primary care physicians  . PreviouThe primary outcome is the risk of any acute severe CVD events including mortality to identify cohort members who developed acute severe CVD events or who died from acute severe CVD events during the follow-up. Acute severe CVD events are defined based on the World Health Organization’s Monitoring Trends and Determinants in Cardiovascular Disease Project, including acute coronary heart disease , stroke (ICD-9 code 430-438), and heart failure (ICD-9 code 428) ,65,66.i is the proportion of the systolic blood pressure category i, HRi is the hazard ratio of CVD deaths in the systolic blood pressure category i, and k is the total number of systolic blood pressure categories. To estimate hazard ratios for CVD mortality comparing each of the 8 systolic blood pressure categories, Bundy et al conducted a network meta-analysis of 42 antihypertensive clinical trials [We could not access the cause of mortality among patients in this cohort owing to data limitation. Thus, we estimate the cause of mortality based on previous research by Bundy et al who offer a method to estimate the association between systolic blood pressure and CVD mortality . We willl trials . We will1c, LDL-C, and TC.The secondary outcomes are the most recent clinical treatment outcomes, including diastolic blood pressure, systolic blood pressure, HbA1c, LDL-C, and TC). Environmental determinants contributing to treatment adherence include those related to primary care physicians and health systems: (1) physicians’ demographic characteristics  and (2) complexity of prescription . All covariates will be treated as baseline covariates except that we will measure the incidence of comorbidities and the time to follow-up.Based on data availability, we will include the following personal-related factors: (1) patients’ demographic and socioeconomic characteristics , (2) risk factors , (3) comorbidities and its duration by the end of the follow-up period , and (4) clinical outcomes at baseline .For hypothesis 1, a time-varying Cox proportional hazards model will be performed to evaluate the hazard ratio between treatment adherence and the incidence of acute severe CVD and mortality, adjusting for all potential covariates. In addition, the interactions of adherence to multiple medications will be included as a block  in the C1c, LDL-C, and TC.For hypothesis 2, 4 multivariable linear regression models will be used to test the association between treatment adherence and the most recent clinical outcomes after adjusting for all potential covariates (model 2-model 5). An adjusted risk ratio with 95% CI will be generated. We will build the hierarchical regression  into thePrevious evidence has also indicated that there is no single correct lag and lead for estimating time-dependent association . Lag andThe study was approved by the University of Toronto Research Ethics Board (reference number: 36065). Data were deidentified when analyzed.The project was funded in July 2017 under Diabetes Action Canada (reference number: 503854). The study was approved by the University of Toronto Research Ethics Board (reference number: 36065). The project was started in June 2018. The results are expected to be finished by September 2019.1c, lipids, blood pressure, and body mass index are also important confounding factors, which may have a direct impact on CVD risk and clinical treatment outcomes [1c, LDL-C, and TC. Owing to the data availability, the percentage of missing data at baseline is as follows: body mass index (25.25%), diastolic blood pressure (23.54%), systolic blood pressure (18.27%), HbA1c (28.09%), LDL-C (46.21%), and TC (45.92%). We will use multiple imputation and consequently carry out a sensitivity analysis with and without imputation of missing data on all covariates. Our study will be the first population-based cohort study that systematically investigates the impacts of treatment adherence for patients with both diabetes and hypertension on CVD morbidity and mortality, and clinical treatment outcomes using a longitudinal and large-scale primary care EMR data. Our findings will help to identify challenges in treatment adherence for patients with diabetes and hypertension in primary care settings. Through this study, we hope to provide valuable evidence for policy and practice to inform the design and implementation of primary care health services to support adherence among patients living with diabetes and hypertension.CVD events represent a heavy disease burden on individuals and their families, the health system, and society in general. Improving treatment adherence to antihypertensive and antidiabetic medication has been well documented as an effective strategy to prevent CVD events. Compared with previous research, our study has several strengths. First, we will contribute new knowledge on the association between treatment adherence, acute CVD events, and clinical outcomes among patients with both diabetes and hypertension in the primary care setting. Second, we will examine the combined benefits of adhering to multiple medications in preventing CVD events and mortality and clinical treatment outcomes. Finally, our study provides further knowledge by addressing the limitations of previous studies, such as inclusion of important potential confounders such as comorbidities, their duration, and follow-up. For example, previous research reported that mental health conditions  were important factors when analyzing treatment adherence and CVD events but lacked the ability to identify such mental conditions ,74. Manyoutcomes . HoweverSeveral limitations should be noted in our study. First, this study is a retrospective study. All data were recorded from routine EMRs with possible errors and omissions. Thus, CVD may not be captured in full. As recording the medical diagnosis of diabetes, hypertension, and CVD is the responsibility of primary care physicians, there may be delays in EMR input. Second, treatment adherence is measured using a proxy, not a real measure. Theoretically, patients with both diabetes and hypertension are regarded as having a high risk of CVD events and should take prescribed medications consistently. We assume that prescription patterns correspond to medication-taking behavior. Third, owing to data limitations, we estimate CVD mortality using systolic blood pressure distributions and the population attributable risks related to the systolic blood pressure level. Fourth, aspirin is an over-the-counter medication that patients can obtain from pharmacies without a prescription. Thus, we may underestimate the adherence rates for aspirin. Finally, we employed the Social Cognitive Theory to explore the reciprocal relationship between that treatment adherence and diabetes/hypertension management outcomes (such as CVD), in the context of personal factors and environmental determinants. However, there were many factors not recorded in our database. For example, there were no variables such as primary language, ethnicity, health literacy, employment status, and marital status, which are factors contributing to patient understanding of the treatment or related to their daily management. There were no process variables recorded such as patient’s level of involvement in the treatment decision-making process, understanding of their disease, and family and social support. In addition, there was a lack of reporting on physician-specific variables, such as the level of communication to patients on the benefits and adverse effects of a prescription nor did we have variables related to the health system such as access to primary care and primary care models . These l


Although the beach-chair position (BCP) is widely used during shoulder surgery, it has been reported to associate with a reduction in cerebral blood flow, oxygenation, and risk of brain ischaemia. We assessed cerebral haemodynamics using a multiparameter transcranial Doppler-derived approach in patients undergoing shoulder surgery. 23 anaesthetised patients (propofol (2 mg/kg)) without history of neurologic pathology undergoing elective shoulder surgery were included. Arterial blood pressure  and cerebral blood flow velocity  were recorded in supine and in BCP. All subjects underwent interscalene block ipsilateral to the side of FV measurement. We evaluated non-invasive intracranial pressure (nICP) and cerebral perfusion pressure (nCPP) calculated with a black-box mathematical model; critical closing pressure (CrCP); diastolic closing margin (DCM—pressure reserve available to avoid diastolic flow cessation); cerebral autoregulation index (Mxa); pulsatility index (PI). Significant changes occured for DCM [mean decrease of 6.43 mm Hg (p = 0.01)] and PI [mean increase of 0.11 (p = 0.05)]. ABP, FV, nICP, nCPP and CrCP showed a decreasing trend. Cerebral autoregulation was dysfunctional (Mxa > 0.3) and PI deviated from normal ranges (PI > 0.8) in both phases. ABP and nCPP values were low (< 60 mm Hg) in both phases. Changes between phases did not result in CrCP reaching diastolic ABP, therefore DCM did not reach critical values (≤ 0 mm Hg). BCP resulted in significant cerebral haemodynamic changes. If left untreated, reduction in cerebral blood flow may result in brain ischaemia and post-operative neurologic deficit. The beach chair position (BCP) offers several advantages in shoulder surgery, such as a better intra-articular visualization and less risk of neurovascular trauma in comparison to surgery performed in the lateral decubitus position . HoweverThere are published reports of rare, but devastating, neurologic injuries occurring in patients in the beach chair position. These include stroke, spinal cord ischaemia, and transient visual loss –11. The Because of arterial blood pressure (ABP) hypotension and the gravitational effects of positioning the head above the level of the heart, such neurologic complications reported after shoulder surgery in the beach chair position may be the result of cerebral autoregulation failure, inadequate cerebral perfusion, and cerebral ischaemia. By assessing cerebral haemodynamics in patients undergoing surgery in the beach chair position, we aim to clarify whether these issues occur in this scenario.Transcranial Doppler (TCD) ultrasonography allows continuous and non-invasive assessment of cerebral haemodynamics by monitoring cerebral blood flow velocity (FV). From TCD signal processing, several parameters have been developed and applied in neurocritical care settings, which include cerebral autoregulation indices (CA), critical closing pressure (CrCP) of the cerebral circulation, non-invasive estimations of intracranial pressure (nICP) and cerebral perfusion pressure (nCPP). There are few published reports on the use of TCD in beach chair position for the assessment of cerebral haemodynamics, but unfortunately, most simply use mean FV as the main measure , 13. We We hypothesised that BCP may incidentally cause subtle deterioration of cerebral haemodynamics; this can be monitored by transcranial Doppler parameters during shoulder surgery under general anaesthesia. Therefore, the objective of this study is to assess cerebral haemodynamics using a multiparameter TCD-derived approach in patients undergoing shoulder surgery who were positioned from supine to beach chair position.Thirty-three patients with no history of neurological disease having elective shoulder surgery in the beach chair position were enrolled in this study. Patients were admitted to the Department of Trauma and Orthopaedics at Addenbrooke’s Hospital, Cambridge, UK, between March 2016 to 2017. The experimental protocol and informed consent were approved by the Institutional Review Board (REC 16/LO/0350). Informed consent was obtained from all individual participants included in the study.2) of 4.6–5.5 kPa.On arrival to the surgical suite, standard monitoring was applied, including pulse-oximetry, electrocardiography, and non-invasive arterial blood pressure in the arm. The patients did not receive anxiolytic medication prior to induction of anaesthesia. After pre-oxygenation, general anaesthesia was induced with intravenous propofol (2 mg/kg). To facilitate endotracheal intubation, cisatracurium besilate (0.15 mg/kg) was administered intravenously, and then the lungs were ventilated with a mixture of oxygen/air and sevoflurane (MAC of 0.8–1.0) to maintain an end-tidal carbon dioxide  were injected around the superior and middle trunks of the brachial plexus, between the anterior and middle scalene muscles. The plexus regional technique was performed after general anaesthesia. A catheter was not placed for post-operative analgesia in any cases.For these patients, we administered crystalloids before and during anaesthesia induction or small boluses of metaraminol to improve mean ABP when it presented below 65 mm Hg. The dose and choice of the strategy to maintain an adequate blood pressure depended on many factors, including the patient’s signalment, physical condition, and the length and type of the procedure.Potential neurological complications were assessed through clinical neurological examination of the patient at the end of the procedure and post-operative period in the recovery room, including the assessment of focal or global deficit and pupil characteristics.ARM). Any clinical interventions to control ABP were performed considering measurements obtained with this method. Additionally, ABP was monitored over time non-invasively using a finger-cuff  calibrated at the auditory meatus level (ABPFINGER) strictly for research purposes. Cerebral haemodynamic parameters were calculated using ABPFINGER. Cerebral blood flow velocity was assessed using transcranial Doppler  in the middle cerebral artery ipsilateral to the surgerical side. The monitoring sessions were performed by an experienced operator (DC) and the TCD probe was hand-held in place during the entire recording. The use of a headset for probe support was unfeasible due to technical difficulties to accommodate such a structure in the configuration of the surgical chair’s headrest. Only ABPFINGER and FV signals were recorded simultaneously.ABP was non-invasively measured for clinical purposes with a cuff via an oscillometric method from the arm ; and before commencement of surgery with the patient in beach chair position (phase B). Beach chair position was achieved by tilting the table at an automated smooth pace to an angle range of 45–90° adjusted for surgical exposure on an individual basis (around 30 s). The measurements during phase B started once the surgical team had the patient in an optimal and stable sitting position, and the onset time varied . ABPARM was collected retrospectively from the hospital’s electronic records during the study’s analysis phase. Pre-operative  and operative values  for ABPARM were collected.ABPhttp://www.neurosurg.cam.ac.uk/icmplus/). The recorded signals were subjected to manual artefact removal and analysed with ICM+®. All calculations were performed over a 10 s sliding window.All parameters were calculated and averaged for both phases. Raw signals were digitized using an analog–digital converter  sampled at a frequency of 100 Hz and recorded with ICM+®  . Delta differences between parameters are presented as mean and percentage change. The statistical significance level for all tests was set at A sample size calculation for this study was performed using power analysis based on the proportional power calculation for a binomial distribution , in which a power of 80%, significance level of 5%, and medium Cohen’s “d” effect size (d = 0.5) were considered. This analysis yielded a sample size of 32 individuals for detecting the specified effect. Based on the number of cases in the area admitted to our Department of Trauma and Orthopaedics between March 2016 and 2017, we could recruit 33 eligible patients during the study period.The study was completed in 23 patients: 4 patients could not be included due to absence of an insonation window for TCD; 6 patients due to poor recordings of either ABP or FV. The mean age was 50.83 years . The mean monitoring time was 5.40 ± 1.60  min for phase A and 5.30 ± 1.50  minutes for phase B. Table ARM . Between supine and BCP, significant differences occurred in DCM (mean decrease of 6.43 mm Hg (− 34%) (p = 0.009)) and PI (mean increase of 0.11 (+ 11%) (p = 0.05)). ABPFINGER exhibited a decreasing trend from phase A to B, as well as nICP, nCPP, and CrCP. End tidal CO2 did not change significantly between the two phases.There was a significant difference between pre-operative and operative ABPWhen compared to TCD parameters in a healthy population , patientFINGER than nICP .nCPP values were lower than previously reported in healthy volunteers (< 60 mm Hg ), and deFINGER from phase A to B; consequently, DCM did not reach critical values (≤ 0 mm Hg), remaining above a mean of 12 mm Hg during BCP. Changes in CrCP were strongly correlated with changes in diastolic ABP . Nevertheless, considering individual cases, two patients during phase B  and one patient during phase A presented relatively low values for DCM below 5 mm Hg. Generally, changes in DCM and diastolic FV were correlated [∆R = 0.40 (p = 0.05)].Mxa showed lower levels indicating dysfunctional cerebral autoregulation (Mxa > 0.3) in phases A and B. CrCP did not approach diastolic ABPFINGER, FV, PI, nICP, and nCPP; Fig. No patient presented symptoms or signs suggestive of neurological damage after shoulder surgery in our cohort. Individual and mean changes across phases from supine (A) to beach chair position (B) are shown in Fig. Our study demonstrates that changing from the supine to beach chair position adversely affects cerebral haemodynamics with significant decrease in DCM and increase in pulsatility index, and an impairment in all cerebral haemodynamics parameters.In previous studies reporting catastrophic perioperative brain infarction associated with shoulder surgery in the sitting position, the patients did not present any risk factors for perioperative stroke, and the authors attributed these complications to intraoperative cerebral hypoperfusion .p = 0.49). Therefore, in this case, PI could be better described as an indicator of increased cerebrovascular resistance.Cerebral hypoperfusion can be represented by the low cerebral blood flow velocity pattern observed in our study, which was even lower than previous findings in a study assessing normative values in healthy volunteers . This ma2)] indicated that these patients were more likely to have impaired autoregulation and lower rSCO2 in comparison to patients undergoing surgery in the lateral decubitus position. Moreover, in a study from Hayashi et al. . By monitoring CrCP, DCM can be trended and may represent an important clinical threshold in patients with arterial hypotension [Although the decrease in ABPotension , as it cGiven the association of these modelled parameters with the vasomotor tone of blood vessels, CrCP and DCM logically relate to changes in previously available TCD parameters, such as the mean or diastolic flow velocity values. However, mathematical models may improve our comprehension of cerebral haemodynamics over the existing TCD parameters in a variety of conditions affecting the brain, provided that they are able to outline the main relationships among several physiological parameters in quantitative terms . In critWe could not identify any cases in which DCM decreased to 0 mm Hg, although it decreased significantly between phases Fig. . NeverthFor instance, in a study of Hanouz et al. , the autGiven our findings, continuous multiparameter TCD monitoring could provide a more comprehensive interpretation of the haemodynamic changes and guide individualised management of ABP and cerebral haemodynamics in the BCP operative setting. A special scenario would be combining ABP and multiparameter TCD monitoring for cases at imminent risk of cerebrovascular derangements, such as in patients with idiopathic intracranial hypertension, hydrocephalus, diabetes, arterial hypertension, and history of stroke. In these cases, special attention should be given to manage ABP within normal ranges with vasopressors or fluids before and throughout beach chair position. In this context, recent studies have even suggested the use of invasive arterial lines to improve the monitoring of ABP and consequently cerebral blood flow in the BCP operative setting , 47. MorFurthermore, from a surgical point of view, given the observed arterial hypotension leading to dysfunctional cerebral autoregulation and other potential cerebrovascular risks, a possibility to be considered is performing the procedure with only a regional block instead of general anaesthesia. Under these conditions, the normal functioning of cardiovascular reflex responses could prevent events of arterial hypotension in the beach chair position.ARM and ABPFINGER could not be compared effectively in any stages of the experimental protocol since simultaneous recordings of these parameters were unfeasible. We have presented both variables for the sake of a qualitative comparison only, to trace a parallel between changes in ABP observed clinically (ABPARM) and experimentally (ABPFINGER). We also acknowledge the heterogeneity among patients as to individual changes in ABP and FV, however, we can only speculate its causes. For instance, the effects of anaesthesia with consequent absence of the cardiovascular reflex responses could have influenced ABP and FV across the wide age span of the patients recruited.This study has potential limitations. First, is the small number of patients included in the study analysis, which was inferior to the calculated sample size. Nevertheless, given the limited study period and the absence of potential eligible patients during this time, we could not accomplish the established sample size. However, we could obtain consistent results even with the reduced number of patients included in the study. Baseline FV and ABP were not monitored before anaesthesia induction. We hypothesized that supine position after induction should be the baseline phase, as the effects of anaesthesia on cerebral haemodynamics should be considered. Moreover, due to surgical configurations, we could not extend monitoring of the parameters throughout surgery. However, according to Hanouz et al. , signifiShort periods of FV and ABP monitoring makes the autoregulation index calculation potentially less reliable. Thirty minutes is considered as a standard, but shorter periods were also used in the past (1-min epochs over time) . IncreasAnother potential limitation is the absence of the gold standard invasive technique for ICP monitoring, which would have allowed the determination of the degree of accuracy of TCD in estimating ICP and CPP. However, invasive monitoring of ICP cannot be considered in a cohort of patients without any indications of brain injury. In TBI patients, the nICP estimation method used in this work showed a 95% confidence interval for ICP prediction of 9.94 mm Hg. Although the accuracy of the method is not ideal at the current stage of development, it has shown good prediction ability for detection of ICP increases associated with changes in cerebral blood volume (ROC area under the curve of 0.82), as well as good correlation with standard invasive methods to track changes of ICP in time non-invasively (R = 0.80) . HoweverIn conclusion, our study suggests altered cerebral haemodynamics in patients undergoing shoulder surgery in the beach chair position. The driving force for such a  pattern was an arterial blood pressure staying out of the assumed cerebral autoregulatory range for both supine and beach chair positions. Nevertheless, the gravitational effects to which patients were subjected during BCP caused a further worsening of the cerebral hemodynamic parameters. These findings may have particular significance in patients with clinically overt or covert cerebrovascular disease, especially in an older population or patients with the latter condition in whom the outcome may be more catastrophic.


Cerebrovascular regulation, referring to cerebral autoregulation, cerebrovascular reactivity, and neurovascular coupling, is intrinsic control mechanism of cerebral blood flow and is considered critical for the maintenance of adequate cerebral perfusion. Much previous work has related cerebrovascular regulation to the occurrence and prognosis of a range of neurological disorders, including cerebrovascular diseases, trauma, stroke, cognitive impairment, and neuropsychiatric disorders. Though many studies have identified these links, clinical exploitation of cerebrovascular regulation remains poorly developed. In addition, optimal methods for evaluation and data analysis in clinical studies need to be further discussed. In this special issue, we have brought together several papers that investigate cerebrovascular regulation in neurological disorders. We hope that this issue can encourage further studies on a number of important aspects of cerebrovascular regulation.The study by J. M. D. van den Brule et al. entitled “Influence of Induced Blood Pressure Variability on the Assessment of Cerebral Autoregulation in Patients after Cardiac Arrest” addresses the influence of increased blood pressure variability on cerebral autoregulation assessment. Cerebral autoregulation measurements are performed in comatose patients after cardiac arrest both at rest and during intervention (tilting of bed). The review of J. M. D. van den Brule et al. entitled “Cerebral Perfusion and Cerebral Autoregulation after Cardiac Arrest” focuses on the alteration of cerebral perfusion and cerebral autoregulation after cardiac arrest, both of which are important in the development of secondary brain damage. The temporal course of cerebral blood flow after the return of spontaneous circulation, as well as cerebral autoregulation after cardiac arrest, is described in this review article.X. Nie et al.'s review entitled “Futile Recanalization after Endovascular Therapy in Acute Ischemic Stroke” summarizes the predictors of futile recanalization and provides support for clinicians to make informed decisions about vascular recanalization therapy. Futile recanalization is one of the main causes of endovascular treatment failure and poor outcome. Impairment of cerebral blood flow regulation, bad collateral circulation, subacute reocclusion, large hypoperfusion volumes, and microvascular compromise were shown to be involved in this complicated process. The paper of Y. Ma et al. entitled “Pinocembrin Protects Blood-Brain Barrier Function and Expands the Therapeutic Time Window for Tissue-Type Plasminogen Activator Treatment in a Rat Thromboembolic Stroke Model” presents a study of the protective effects of pinocembrin on t-PA administration-induced blood-brain barrier damage in a rat thromboembolic stroke model. The potential mechanisms with which blood-brain barrier damage contributes to hemorrhagic transform after t-PA treatment are still unclear. The disruption of cerebrovascular regulation may play an important role in it.M. L. Bøthun's study entitled “Time Course of Cerebrovascular Reactivity in Patients Treated for Unruptured Intracranial Aneurysms: A One-Year Transcranial Doppler and Acetazolamide Follow-Up Study” addresses the time course of cerebrovascular reactivity (CVR) in patients treated for unruptured intracranial aneurysms, by comparing CVR within the first week after aneurysm treatment with CVR one year later. Factors that influence stability of CVR over time are also proposed in this study. The study of S. Lv et al. entitled “Compromised Dynamic Cerebral Autoregulation in Patients with Epilepsy” investigates cerebral autoregulation capability in patients with epilepsy during the interictal period and explores factors related to cerebral autoregulation parameters. The possible mechanisms of compromised cerebral autoregulation are discussed. N.-F. Chi et al. present a study entitled “Comparing Different Recording Lengths of Dynamic Cerebral Autoregulation: 5 versus 10 Minutes”, in which dynamic cerebral autoregulation indices between 5- and 10-minute recordings in patients with ischemic stroke and healthy controls are compared. The study indicates that, to minimize the influences of time-dependent autoregulation variables, recording length should be unified in a single study or between studies.The papers of this special issue provide new insights into cerebrovascular regulation in neurological disorders through its mechanisms, assessments, and clinical importance. Nevertheless, further studies are needed to help us to unlock the mystery of cerebrovascular regulation and its underlying mechanisms in neurological disorders, address technical challenges, and move on to providing the much-expected benefit to our patients.


However, these targeted algorithms do not exist during critical care, as the physiological determinants of rSO2 during critical illness remain poorly understood.To maintain adequate oxygen delivery to tissue, resuscitation of critically ill patients is guided by assessing surrogate markers of perfusion. As there is no direct indicator of cerebral perfusion used in routine critical care, identifying an accurate strategy to monitor brain perfusion is paramount. Near-infrared spectroscopy (NIRS) is a non-invasive technique to quantify regional cerebral oxygenation (rSONCT02344043) who received high-fidelity vital sign monitoring. Adult patients (≥ 18 years) admitted < 24 h to a medical/surgical intensive care unit were eligible if they had shock and/or required mechanical ventilation. Patients underwent rSO2 monitoring with the FORESIGHT oximeter for 24 h, vital signs were concurrently recorded, and clinically ordered arterial blood gas samples and hemoglobin concentration were also documented. Simultaneous multiple linear regression was performed using all available predictors, followed by model selection using the corrected Akaike information criterion (AICc).This prospective observational study was an exploratory analysis of a nested cohort of patients within the CONFOCAL study (2), and hemoglobin concentration. This model accounted for a significant proportion of variance in rSO2  and was significantly associated with PaCO2 (p < 0.05) and hemoglobin concentration (p < 0.01). Our selected regression model using AICc accounted for a significant proportion of variance in rSO2  and was significantly related to age (p < 0.05), PaCO2 (p < 0.01), hemoglobin (p < 0.01), and heart rate (p < 0.05).Our simultaneous multivariate model included age, heart rate, arterial oxygen saturation, mean arterial pressure, pH, partial pressure of oxygen, partial pressure of carbon dioxide , retrospectively registered January 8, 2015.This trial is registered on clinicaltrials.gov (Identifier: The online version of this article (10.1186/s40635-019-0247-0) contains supplementary material, which is available to authorized users. The resuscitation phase  of critical illness is directed at maintaining adequate oxygen delivery to tissues to end-organ injury. Several organ systems have objective surrogate markers that can be serially monitored to ensure optimal end-organ perfusion. For example, renal perfusion is monitored by serially measuring urine output and serum creatinine levels . In cont2). An adhesive sensor and light source are placed on the forehead, which emit varying wavelengths of infrared light  that pass through the skin and bone with minimal absorption to an approximate depth of 2–3 cm of cerebral tissue .2 signal is a viable neuromonitoring modality to assess cerebral oxygenation during critical illness, as this signal was predicted by known and reliable clinical determinants of oxygen delivery during the first 24 h of critical illness. Further elucidation of the determinants of the rSO2 signal may be useful in developing resuscitation algorithms designed to optimize cerebral oxygenation, an important therapeutic target among critically ill patients. However, clinically relevant covariates will need to be modeled in future analyses.Our analysis provides evidence that the NIRS-derived rSOAdditional file 1:Figure S1. Repeated measures Bland Altman plot indicating that the pooled data across the center and right sensors display a high level of agreement. Note. The red dotted lines indicate the 95% limits of agreement . The black line represents the mean  of recordings across sensors. Black dots represent pooled recordings of regional cerebral oxygenation across 10 intensive care unit patients. As an illustrative example, the Bland Altman analysis indicated that the mean difference  between the sensors was − 0.31, which indicates that the right sensor on average records 0.31% higher than the center sensor. Furthermore, the lower and upper limits of agreement  were minor, indicating that the sensors display high agreement. (JPEG 2129 kb)Additional file 2:Figure S2. Histograms of high-frequency hemodynamic variable recordings used to remove anomalous data before conducting regression analysis. Diastolic BP = diastolic blood pressure; MAP = mean arterial pressure; systolic BP = systolic blood pressure; rSO2 = regional cerebral oxygenation; SpO2 = arterial oxygen saturation. (PDF 37 kb)Additional file 3:Figure S3. Matrix of the pooled correlation analysis of all predictors of regional cerebral oxygenation included in the simultaneous regression model. This plot provides visual representation of the associations between various hemodynamic/physiological parameters. The direction of the association is represented by the color , and the strength is indicated by shading . Each colored square has corresponding text, which represents the p value for the correlation analysis between the column and row parameter. The asterisks indicate significant Pearson correlations coefficients (p < 0.05). (JPG 7206 kb)Additional file 4:Figure S4. Bar graph illustrating that amount of missing values per high-frequency vital sign recording. Diastolic BP = diastolic blood pressure; MAP = mean arterial pressure; systolic BP = systolic blood pressure; rSO2 = regional cerebral oxygenation; SpO2 = arterial oxygen saturation. (PDF 22 kb)


The level of sNGAL  was not higher in hypertensive patients than in the age-sex-matched control group. Additionally, the sNGAL level was found to be directly and positively correlated in patients with positive ACA IgG . These results demonstrate that autoimmunity may be one of the pathogenetic factors of hypertension and aPL antibodies might be a potential marker of renal involvement.Antiphospholipid syndrome (APS) is a multifactorial, autoantibody-mediated disease. Antiphospholipid antibodies (aPL) directed against negatively charged phospholipids or various combinations of phospholipid-binding proteins seem to be an independent pathogenic factor that plays a critical role in APS. Unfortunately, their role in hypertension is not fully elucidated. The aim of our study was to determine aPL titers in hypertension patients and investigate the association of aPL with renal impairment parameters. Forty-seven patients with arterial hypertension , aged 41–85 years old (mean 65.9 ± 10.1 years), and 21 age-sex-matched subjects without severe hypertension as control group , mean age 61 ± 11.3 years, were enrolled in this study. Patients with other risk factors like Rheumatoid Arthritis and Systematic Lupus Erythematosus (SLE), both viral and bacterial acute infections, and cancer were excluded from the study. The aPL (anticardiolipin (ACA) and anti-b2GPI antibodies, IgG and IgM) were measured by ELISA  with a cutoff of 15 GPL/MPL for ACA and 15 U/mL for b2GPI. Serum Neutrophil gelatinase-associated lipocalin (sNGAL) was measured by ELISA kits . Biochemical analysis such as serum creatinine (Cr), were measured by automated analyzer and finally estimated glomerular filtration rate (e-GFR) was calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). Fifteen patients were positive for ACA IgG (31.9%), two for anti-b2GPI IgM (4.2%), and three for anti-b2GPI IgG (6.3%). Furthermore, three persons from control group were positive in anti-b2GPI IgG (14.27%). The serum level of anti-b2GPI IgG was significantly higher in patients compared to healthy controls ( The term antiphospholipid syndrome (APS) was coined by Hughes in the early 1980s to describe a unique form of autoantibody induced thrombophilia, hallmarks of which are recurrent thrombosis and pregnancy complications . RecentlAntiphospholipid syndrome may be presented with many other clinical symptoms that are not included in the classification criteria . Less co2. The different stages of CKD form a continuum. The stages of CKD are classified as follows:2)Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m2)Stage 2: Mild reduction in GFR (60–89 mL/min/1.73 m2)Stage 3a: Moderate reduction in GFR (45–59 mL/min/1.73 m2)Stage 3b: Moderate reduction in GFR (30–44 mL/min/1.73 m2)Stage 4: Severe reduction in GFR Stage 5: Kidney failure  equations. According to The Kidney Disease: Improving Global Outcomes (KDIGO) 2012 , ChronicPatients in stages 1–3 are usually asymptomatic. Thus, there is a great need for novel biomarkers aimed at early and accurate diagnosis of diminished kidney function to prevent rapid deterioration and progressive renal injury.One of the most studied and promising biomarkers is NGAL, a small molecule released in blood or urine. Potential situations leading to elevated GFR are Acute Kidney Injury (AKI), tubular cell injury, or inflammation. Researchers have confirmed that a low stable secretion maintains serum levels of around 20 ng/mL. Different diseases such as neoplasia, sepsis, CKD, pancreatitis etc. may be the trigger for epithelial impairment and subsequent augmented production . Serum cThe aim of our study was to evaluate aPL in a group of hypertensive patients with severe essential hypertension and estimate the renal function compared to a control group. Renal dysfunction, as measured by reduced GFR and/or increased urinary albumin excretion, revealed possible association with hypertension. The novel serum marker NGAL was also used to highlight renal dysfunction.This case-control study included 47 patients with hypertension from outpatient clinics, not selected by sex or ethnicity. Hypertension was diagnosed following the recommendation of the World Health Organization/International Society of Hypertension . It is generally accepted that the presence of aPL is associated with acute bacterial and viral infection, neoplasms, ESRD, and acute cardiovascular diseases such as myocardial infarction. This may lead to transient and asymptomatic increase of aPL antibodies or may be an important step during antiphospholipid syndrome. The exclusion criteria were as follows: (1) recent acute myocardial infarction; (2) acute ischemic stroke; (3) neoplasms (current or past); (4) acute viral or bacterial infection; (5) autoimmune disorders such as SLE; (6) ESRD. Moreover, no patient had a history of pregnancy-morbidity such as unexplained fetus death. Twenty-one age and sex-matched non-hypertensive subjects were studied as controls.Clinical and demographic data were obtained from an interview with patients, considering the following information: (1) age, sex, race/ethnicity; (2) history of high blood pressure; (3) current cigarette smoking; (4) Diabetes Mellitus (DM), according to clinical history and current treatment with oral antidiabetic drugs and/or insulin; (5) history of hypercholesterolemia. All data are shown in Systolic and diastolic blood pressures  were measured while the patients were at rest in a sitting position by an aneroid sphygmomanometer. The hypertensive condition was confirmed when SBP rose to 140 mmHg or more, or DBP elevated to 90 mmHg or more.Serum samples were centrifuged and frozen within 2 h of collection and subsequently stored at −70 °C until testing by different assays. The aPL, both IgG and IgM types (ACA and anti-b2GPI), were measured by ELISA  with dilution of 1:100 and concentration above 15 GPL/MPL for all isotypes constituting a positive result. Positivity of tests was considered based on proposed values from the manufacturer, due to its agreement with the 99th percentile analysis of 30 blood donors.To estimate the renal function sCr was measured using an automated biochemical analyzer, and the estimated glomerular filtration rate (e-GFR) was calculated using CKD EPI formula. Finally, sNGAL levels were also measured by ELISA commercial kits .The study was approved by the Bioethics Committee of the University General Hospital of Alexandroupolis, Greece (Ethics Committee identification code: 941).χ2) test were performed. A value of p < 0.05 was considered as statistically significant. The correlation between two quantitative variables was determined with the Pearson’s correlation tests.Data are expressed as mean ± standard deviation and percentages were analyzed. Nonparametric tests  and the chi-square , aged 41–85 years old (mean 65.9 ± 10.1 years). Of these patients 14 (29.8%) were diabetic, 9 (19.1%) had a history of Acute Coronary Syndrome (ACS), and 70.2% had dyslipidemia. Body mass index (BMI) was 29.7 ± 6.4 kg/m2 . Group B2 (2 .p = 0.68). The mean serum level of anti-b2GPI IgG was significantly higher in patients in comparison to healthy controls . The mean levels of ACA (IgG and IgM) and anti b2GPI IgM were not different between controls and patients , according to the manufacturer’s guidelines. Among these, 15 were positive for ACA IgG (31.9%), two for anti-b2GPI IgM (4.2%) and three for anti-b2GPI IgG (6.3%). Furthermore, three persons from control group were positive for anti-b2GPI IgG (14.27%), but the mean serum level of anti-b2GPI IgG was not different between patients and controls  was not statistically significant. Moreover, sNGAL was found to be directly and positively correlated in patients with positive ACA IgG     . No corr 0.0001) . Further = 0.21) , as well = 0.34) .We report the clinical and laboratory findings of a cohort of 47 patients with hypertension who had positive tests for aPL. The diagnosis of APS is based on both clinical and laboratory criteria. Unfortunately, the criteria and the laboratory tests show wide variability within assays, making diagnosis quite difficult. It is well established that hypertension is a frequent clinical feature of APS which indicates a renal implication. The other clinical features include: renal artery stenosis (RAS), thrombotic microangiopathy (TMA), and other histological manifestations of the APS nephropathy (APSN). In the series of patients with hypertension that we studied, no patients developed any thrombotic manifestation of APS. Cacoub et al. described five patients with APS complicated by hypertensive crises, where all had normal magnetic resonance angiograms of the renal vessels. Three of their patients, according to contrast angiography, developed distal microangiopathy, but no stenosis or thrombosis of the main renal arteries . FurtherRollino et al. report in their study the frequency of aPL positivity at 8% . Other sThe international consensus classification (ICS) for diagnosis of APS  necessitTo estimate the renal function in our study we used different biomarkers such us sCr, e-GFR, and sNGAL. Importantly, the present study depicted that NGAL was found to be directly and positively correlated in patients with positive aPL. To our knowledge, there are no reports that analyze potential synergistic role of sNGAL and ACA as a diagnostic marker regarding the presence of early renal impairment in arterial hypertension.Taken together, our results indicate that antiphospholipid antibodies may play an important role in hypertension and indicate renal involvement in APS. The early identification and appropriate therapeutic interventions in APS patients with kidney involvement may have important prognostic implications in preventing the determination of renal failure. We also suggest that it may be advisable for hypertensive patients suspected of APS to be tested for aPL antibodies, aiming for early and accurate diagnosis.Finally, the lack of association between sNGAL levels with any measure of blood pressure limits the potential role of sNGAL as a predictive marker.Potential limitations of our study were that we had a small sample size of patients. Moreover, we excluded patients with thrombotic events, which may be a clinical manifestation of APS. Moreover, in this study we do not measure other autoantibodies such as anti-Angiotensin II, anti-atrial natriuretic peptide or gene polymorphisms which may play role in the pathogenesis of hypertension ,26.Having considered all the above, and in agreement with recent literature ,25, it s


An association of rs139401390 located to a region 58.8 kb upstream of renalase (RNLS) with eGFR was detected in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study . Direct genotyping of rs139401390A > G suggested increased eGFR by 12.0 ml/min/1.73 m2 per A allele (p = 0.000004). Genome-wide replication of rs139401390A > G in the Coronary Artery Disease and Renal Failure (CAD-REF) registry with a mean eGFR of 47.8 ml/min/1.73 m2  was only nominally significant. Comparison of rs139401390 genotypes for risk of reduced kidney function in the overall LURIC study revealed higher adjusted odds ratios (OR) for eGFR <60 ml/min/1.73 m2 for CAD patients  compared to patients with/without CAD . No significant risk elevation was detected in patients without CAD . rs139401390 may affect kidney function in CAD patients with mild reduction in eGFR.Chronic kidney disease (CKD) is an independent risk factor for onset and progression of coronary artery disease (CAD). Discovery of predisposing loci for kidney function in CAD patients was performed using a genome-wide association approach. Inclusion criteria were CAD with ≥50% stenosis (≥1 coronary artery) and a creatinine-based estimated glomerular filtration rate (eGFR) of 30–75 ml/min/1.73 m Most recently, CKD has been established as a new non-traditional and independent risk factor for onset and progression of cardiovascular disease (CVD)6. Impaired kidney function can be diagnosed by the estimation of glomerular filtration rate (eGFR) and the risk of CVD events increases with decreasing GFR8. This observation translates into clinical consequences as most CKD patients die of CVD before reaching end-stage renal disease9. While the deleterious impact of end-stage renal disease and, more recently, the harmful effects of CKD on CVD have been reported, the clinical course of mild-to-moderate renal impairment remains poorly understood10 and interdependent pathophysiological mechanisms of CKD and CVD are largely unknown.Chronic kidney disease (CKD) is a worldwide emerging health problem which affects more than 1 out of 10 adults in the general population of developed countries12. Moreover, a recent bidirectional cross-trait single nucleotide polymorphism (SNP) analysis13 testing the hypothesis that genetic variants replicatively associated with renal function might increase the risk of vascular disease and vice versa reported minimal overlap of risk variants. Out of 19 analyzed SNPs associated with kidney function and 64 validated vascular SNPs, only one vascular locus (SH2B3) was significantly associated with eGFR while no association of kidney variants with vascular traits was observed13.The identification of candidate genes involved in impaired kidney function in the presence of CVD could offer insight into the pathogenesis of this reno-cardiac disease entity and would reveal potential therapeutic targets. However, genome-wide association studies (GWAS) of renal function traits have so far been performed with a focus on the general populationThus, we examined genetic associations in a selected group of patients with a comorbidity of coronary artery disease (CAD) and impaired kidney function.2 and angiographically documented ≥50% stenosis of at least one coronary artery. The discovery study sample derived from 3,316 participants of the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) whose characteristics have been described in detail elsewhere14. In brief, LURIC is a German cohort study designed to investigate biochemical and genetic cardiovascular risk factors. Patients referred to coronary angiography had been consecutively recruited at the Ludwigshafen Heart Center between July 1997 and January 2000. The LURIC study was approved by the ‘Landesärztekammer’ Ethics Committee of Rheinland-Pfalz, Germany (reference 837.255.97). All patients gave written informed consent for participation. For the current analysis, 499 CAD patients with a mild reduction in kidney function were selected for a genome-wide association study (GWAS) on eGFR (discovery cohort). The mean creatinine-based eGFR of the LURIC discovery study sample was 60.7 ml/min/1.73 m2.The study was designed as a cross-sectional analysis of eGFR as continuous trait in patients with CAD recruited in a clinical setting. Inclusion criteria for the primary analysis were a creatinine-based mild impairment of kidney function with an eGFR of 30–75 ml/min/1.73 m15. The CAD-REF registry is a prospective observational German multicenter study. Patients had been enrolled at 32 qualified German centers between January 2008 and May 2011, coordinated at the University Hospital of Muenster. All investigations in CAD-REF were performed after approval of local ethics committee of the medical association Westfalen-Lippe and the Westphalian Wilhelms-University of Muenster, Germany (reference 2007-315-f-S). Genome-wide data was available for 574 randomly selected CAD-REF study participants of CKD stage 3 (creatinine-based eGFR 30–59 ml/min/1.73 m2). The mean creatinine-based eGFR of the CAD-REF study sample was 47.8 ml/min/1.73 m2. All experiments were performed in accordance with relevant guidelines and regulations.The independent replication study sample derived from 3,352 patients of the Coronary Artery Disease and Renal Failure registry (CAD-REF) whose characteristics have been described in detail elsewhere15.Both studies enrolled subjects of European ancestry and determined patients’ eGFR using the creatinine-based “Modification of Diet in Renal Disease” (MDRD) equation. Creatinine was determined from a single serum measurement at the first clinical visit. In LURIC, creatinine was determined by liquid chromatography/mass spectrometry (LC/MS). In CAD-REF, creatinine was determined using the enzymatic peroxidase-antiperoxidase (PAP) method. CAD was defined as angiographically documented >50% stenosis of at least one coronary artery at the first clinical visit. Essential hypertension was defined as systolic blood pressure >140 mm Hg, diastolic blood pressure >90 mm Hg, or the use of antihypertensive drugs. Hyperlipidemia was defined as a total plasma cholesterol level >200 mg/dl, or use of lipid-lowering drugs. Diabetes mellitus was defined as increased fasting (≥126 mg/dl) and/or post-challenge (2 h after the 75 g glucose load > 200 mg/dl) glucose and/or elevated glycated haemoglobin (>6.5%) and/ or history of diabetes/ use of antidiabetic drugs−6 and minor allele frequency < 0.01. PLINK was used to test samples for relatedness. In the case of a PI-HAT > 0.3 the sample with the lower call rate was excluded. Both datasets were imputed to the 1000 G EUR reference panel  using MACH16. The analysis included >10 million SNPs and small InDels of high quality (r2 > 0.3). Chromosomal positions are based on GRCh37.3. For further statistical analyses using SPSS, the best-guess genotypes for rs139401390 were imported into the database containing the clinical data. Best-guess genotypes could only be determined with high confidence for 489 samples. Thus, for the remaining 10 samples, rs139401390 genotypes were set to ‘missing’. Direct genotyping of the lead SNP rs139401390 was performed using TaqMan SNP genotyping assay on a real-time PCR System ABI7900  in a 384 well format according to manufactures instructions.In both cohorts, genomic DNA was prepared from patients’ peripheral blood. LURIC data were generated using the Affymetrix Human SNP Array 6.0. For the CAD-REF study, the Illumina Omni 2.5-Quad Chip was used. SNPs were excluded in case of a low genotyping call rate (<0.95), Hardy-Weinberg-Equilibrium p < 10n (percent) of subjects in each group. Continuous data are presented as means ± SD. SPSS version 19.0  statistical software package was used. The genome-wide analysis was performed using the software ProbABEL17 with the additive genetic model and adjustment with adjustments for age and sex. Adjustment for the first three principle components was used to adjust for population substructure. The genomic inflation factor lambda in LURIC was 1.037. No transformation for eGFR distribution was performed. QQ and Manhattan plots were drawn for the analysis of the results using the R-package “qqman”. Regional plots were drawn using Locuszoom18. The P value for genome-wide significance was set to p < 5 × 10−8, which corresponds to an α of 0.05 with a Bonferroni correction for one million tests. Suggestive significant SNPs with a p value < 1 × 10−6 in the discovery analysis were selected for replication. SNPs with a P value < 0.0055 (Bonferroni correction for nine SNPs) in the replication cohort were regarded to mark suggestive significant loci.Hardy-Weinberg equilibrium was examined using chi-square test. Categorical data are presented as 2 and in the replication study sample (CAD-REF = 574) 47.8 ml/min/1.73 m2 . Additional suggestive regions of association were located to chromosomes 2q14.2 , 11p11.2 , 3q22.1  and 3q27.1 .The condensed clinical characteristics of the LURIC discovery sample and the independent CAD-REF registry replication sample are summarized in Table 2 eGFR per major A (p = 0.000004). SNP rs139401390 was selected for independent replication in the CAD-REF study. The replication analysis suggested that rs139401390 was significantly associated with eGRF . The correlation between imputed genotype and genotype determined by direct genotyping was 99.2%. A subsequent recalculation suggested an effect of rs139401390 on eGFR by +12.0 ml/min/1.73 m2 in all LURIC patients with CAD  by rs139401390 genotype using imputed genomic data. The analysis revealed that the risk-allele combination (rs139401390_G/A) was associated with eGFR < 60 ml/min/1.73 m2 also in an adjusted  analysis    was comparably low   for eGFR < 60 ml/min/1.73 mRNLS was significantly associated with eGFR on the genome-wide level. Independent replication in patients of the CAD-REF study missed a significant association of the identified locus with eGFR. However, further analyses of rs139401390 associations within LURIC for patients with and without a comorbidity of impaired kidney function and CAD suggested a potential impact of rs139401390 on eGFR in this disease entity.We report on a GWAS of eGFR in CAD patients of European ancestry with impaired kidney function. In the LURIC discovery sample, SNP rs139401390 located 58.8 kb upstream of RNLS was significantly associated with eGFR. Since association studies have demonstrated the affected genes are often located up to several megabases from the phenotype-associated variant, expression of the most proximal gene is not necessarily altered and rs139401390 might thus not mark RNLS. In addition, the RNLS locus has not yet been identified as a genetic risk locus for eGFR (or CKD) using genome-wide analyses. However, the coded protein renalase has frequently been discussed in CKD and CVD. Renalase was identified as a candidate involved in the regulation of cardiac function and blood pressure in 2005 by a cDNA library screen19. The initial study focused on the endocrine function of the kidney and reported on a novel flavin adenine dinucleotide–dependent amine oxidase termed renalase19. The data suggested that human renalase  to be secreted into the blood by the kidney and identified significant renalase-depending breakdown of catecholamines in vitro, including dopamine, epinephrine and norepinephrine19. Addressing the link between the kidney and the cardiovascular system, subsequent studies used Sprague-Dawley rats injected with recombinant renalase, leading to a significant decrease in systolic, diastolic and mean arterial pressure as well as left-ventricular end-systolic and end-diastolic pressure, maximum left ventricular pressure, the rate of ventricular pressure change and heart rate19. In a follow-up study, it was reported that renalase knockout worsened kidney injury in animals20. It has also been proposed that renalase could modulate the intra-renal dopamine system, affecting sodium and phosphate excretion21.Our initial analysis suggested that rs139401390 located 58.8 kb upstream of in vivo are incompletely understood22. Renalase synthesis has been reported to be impaired in a renal artery stenosis rat model and the authors suggested that renal blood flow is a major determinant of renalase synthesis23. Notably, plasma renalase has been reported to be inactive while urinary renalase exerts amine oxidase activity under basal conditions24. Rapid activation of renalase by catecholamines within 30 sec has been observed16, which has led to the assumption that renalase may circulate as a proenzyme that requires specific signals for activation22. Recombinant renalase exerted protective effects in mouse models of acute kidney injury25 also independent of its ability to metabolize catecholamines20. Administration of renalase had also an intense and prolonged antihypertensive effect in an animal model of salt-sensitive hypertension26 and renalase perfusion exerted heart-protective effects on a cardiac ischemia mouse model27. More recently, and independent of its enzymatic properties, renalase has been suggested to exert cytokine functions that provide cell protection by activating a receptor‐mediated pro-survival signaling cascade28. While reduced renalase plasma levels have been reported in studies using animal models of CKD29, the correlation in humans is less definite. Initial studies suggested that CKD in humans is associated with renalase deficiency19 but recent reports including kidney30 and heart31 transplant patients as well as dialysis patients33 have led to controversial discussions35. Of note, discrepant findings have also been suggested to depend on the methods used to determine renalase levels34. Since the current study focused on the identification of disease-associated variants, we did not analyze if rs139401390 affects renalase levels.The molecular mechanisms that mediate the acute activation of renalase 12, which consists of 20 predominantly population-based European studies. Notably, this analysis did not suggest an association of rs139401390 with eGFR in a population-based setting (data not shown), pointing to an important role for rs139401390 in CAD. Since separate analysis of rs139401390 risk alleles in the entire LURIC cohort revealed an elevated OR for eGFR < 60 ml/min/1.73 m2 in the presence of CAD, also dependent on the initial eGFR, rs139401390 might identify CAD patients that could benefit from more intensive clinical monitoring to prevent further reduction of kidney function.While we detected a significant effect of rs139401390 genotypes on eGFR in the LURIC discovery cohort, no association was seen in the CAD-REF study. This observation might highlight an impact of rs139401390 risk alleles on eGFR in CAD patients with mildly reduced kidney function but not in CAD patients with moderately reduced kidney function and accompanying risk factors . We investigated whether the identified rs139401390 genotype affected kidney function in the general population and conducted a separate association analysis of rs139401390 in 108,165 participants of the CKDGen consortiumRNLS in linkage disequilibrium with rs139401390. The transcription factor Gli2 has been reported to be an essential hedgehog signaling component involved in cardiogenesis38. The SLC35C1-CRY2 locus on chromosome 11 may be involved in the development of hypertension39 and circadian gene expression involving cryptochrome-2 (CRY2) has been reported to be of importance in the vasculature and the heart40. Moreover, a synergistic effect of renalase and CKD on endothelin-1 in CAD patients has been suggested41.Some limitations exist for the current analysis. Our study exclusively included participants of European ancestry and different results may be observed in other ancestral groups. We used an indirect measure of GFR, estimated by the MDRD equation, as direct determination of kidney function is not suitable on a population scale. The studies involved a one-point measurement of creatinine and the phenotypes of CKD initiation or progression have not been studied. No transformation procedure was used to adjust the eGFR distribution which could have affected the analysis. Observed low minor allele frequencies may have affected the presented findings and the calculation of the per-allele effect on eGFR. A major limitation is the missing replication of the suggested association of rs139401390 in an independent cohort, which may be based on study sample size and heterogeneity. Thus, future studies are warranted to validate our findings. While our discussion focuses on the potential impact of the identified variant on renalase expression, other genes might also be affected with a relevant impact on kidney function and we cannot exclude that the observed association was caused by other functional polymorphisms in genes other than RNLS may be associated with eGFR in CAD patients with a mild reduction of kidney function. Our study requires independent replication and may represent a potential basis for future studies on rs139401390, the enzyme renalase and the RNLS locus and their impact for the impairment of kidney function in CAD.In conclusion, we suggest that rs139401390 located to a region 58.8 kb upstream of