Acute kidney injury (AKI) is a common and strong problem in the diagnosis of which based on measurement of BUN and serum creatinine. These traditional methods are not sensitive and specific for the diagnosis of AKI. AKI is associated with increased morbidity and mortality in critically ill patients and a quick detection is impossible with BUN and serum creatinine. A number of serum and urinary proteins have been identified that may messenger AKI prior to a rise in BUN and serum creatinine. New biomarkers of AKI, including NGAL, KIM-1, cystatin-C, IL-18, and L-FABP, are more favourable tests than creatinine which have been identified and studied in several experimental and clinical training. This paper will discuss some of these new biomarkers and their potential as useful signs of AKI. We searched the literature using PubMed and MEDLINE with acute kidney injury, urine, and serum new biomarkers and the articles were selected only from publication types in English. Acute kidney injury (AKI) remains a common and significant problem in the last decade . BetweenAKI has been defined conceptually as a rapid decline in glomerular filtration rate (GFR) that occurs over hours and days. It propels to a clinical syndrome characterized by a rapid decrease in renal excretory function, with the accumulation of products of nitrogen metabolism such as creatinine and urea clinically unmeasured waste products.The described notions have led to a consensus definitions of AKI by the Acute Dialysis Quality Initiative. These RIFLE  criteria have been broadly supported with minor modifications by the acute kidney injury network (AKIN) , 6, and These numerous problems with creatinine limit both clinical practice and the development of new therapeutics in AKI. Clinicians need tools that are not influenced by other clinical parameters or patient characteristics and that can identify losses in GFR soon after occurence. The ideal biomarker of AKI would be a substance that the kidney releases immediately in response to injury and that can be detected in the blood or urine without significant metabolism. This biomarker would be highly sensitive and specific for injury to the kidney. Extensive research efforts over this past decade have been directed at the discovery and validation of novel AKI biomarkers to detect injury prior to changes in kidney function and potentially to aid in the differential diagnosis of AKI.The purpose of this paper is to review the relevant AKI biomarker literature ofwhich the search performed on MEDLINE/PubMed using the search terms “acute kidney injury, urine and serum new biomarkers” and articles were selected from all publication types in English.2- migroglobulin. Studies in cultured human proximal tubule cells subjected to in vitro hypoxic injury confirmed the origin of NGAL from tubule cells. NGAL was also detected in the urine of mice in the early stage of cisplatin-induced nephrotoxicity [Human NGAL is a 25 kDa protein firstly identified bound to gelatinase in specific granules of the neutrophil. NGAL is a critical component of innate immunity to bacterial infection and is expressed by immune cells, hepatocytes, and renal tubular cells in various disease states , 12. Itstoxicity . These aROC) of 0.99 and 1.0 at 2 and 4 h after cardiopulmonary bypass (CPB), respectively [ROC for early diagnosis of AKI by urinary NGAL has varied from 0.61 at 18 h after CPB [ROC of 0.54 within 6 h of CPB [NGAL is the most extensively studied biomarker in AKI. Urinary and serum NGAL were demonstrated to be sensitive, specific, and highly predictive early biomarkers of AKI in children after cardiac surgery . Seventyectively . Anotherectively –20. The ectively . The AUCectively –29. Howefter CPB  to 0.96 h of CPB . The addh of CPB .NGAL may also represent early sensitive biomarker of AKI after contrast administrations for coronary angiography . NGAL waNGAL is an early predictive biomarker of contrast-induced nephropathy (CIN) in children . They stUrine and plasma NGAL levels also represent early biomarkers of AKI in an intensive care unite (ICU) , 38. A mNGAL has been evaluated as a biomarker of delayed graft function (DGF) in a patient undergoing kidney transplantation. Hollmen and colleagues  demonstrNGAL is an early biomarker of AKI in children and adults in the following situations: postcardiopulmonary bypass, after contrast administration, nephropathy, in critically ill ICU patients, and delayed graft function in patients undergoing kidney transplantation. (KIM-1) is a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain [Kidney injury molecule-1n domain . KIM-1 mn domain –54. KIM-n domain . Urinaryn domain , 56.KIM-1 is also a tissue and urinary biomarker for nephrotoxicant-induced kidney injury. Tissue and urinary expressions were measured with different nephrotoxic doses of cisplatin, folic aside, cadmium, gentamycin, mercury, and chromium , 57–60. KIM-1 is a biomarker of AKI in humans. Urine samples were collected from 32 patients with various acute and chronic kidney diseases, as well as from eight normal controls. There was extensive expression of KIM-1 in proximal tubule cells in kidney biopsies from six patients with biopsy confirmed acute tubular necrosis (ATN). Urinary KIM-1 levels were significantly higher in patients with ischemic ATN compared to levels in patients with other forms of acute renal failure or chronic renal disease. Adjusted for age, gender, and length of time delay between the initial insult and sampling of the urine, a one-unit increase in normalized KIM-1 was associated with a greater than 12-fold  risk for the presence of ATN .α-GST were able to predict the future development of AKI [KIM-1 was also measured in 90 patients undergoing cardiac surgery. Thirty-six patients who developed AKI within 72 h after surgery. The AUCs for KIM-1 to predict AKI immediately and 3 h after operation were 0.68 and 0.65, 0.61 and 0.63 for NAG, and 0.59 and 0.65 for NGAL, respectively. Combining the three biomarkers enhanced the sensitivity of early detection of postoperative AKI compared with individual biomarkers: the AUCs for the three biomarkers combined were 0.75 and 0.78. This study demonstrated that combining multiple AKI biomarkers improved the overall predictive value . A similt of AKI . This stRenal KIM-1 expression is significantly increased in human kidney tissue among patients with a wide range of kidney diseases, including various types of glomerulonephritis, chronic allograft nephropathy, acute rejection, immunoglobulin A nephropathy, systemic lupus erythematosus, diabetic nephropathy, hypertension, and Wegener's granulomatosis . Both reCystatin C is a protein produced by all nucleated cells. It is a polypeptide chain with 120 amino acid residues. It is freely filtered by the glomerulus, completely reabsorbed by the proximal tubules and is not secreted by the renal tubules . In this2 was better than creatinine (areas under the ROC curve: 0.85 and 0.79 for cystatin C and 0.63 and 0.62 for creatinine). This study concluded that serum cystatin C was better than serum creatinine to detect AKI in critically ill children [Serum cystatin C was measured in 25 children in the ICU. The ability of serum cystatin C to identify a creatinine rate a Schwartz creatinine clearance rate under 80 mL/min/1.73 mchildren . Anotherchildren .Plasma and urine cystatin C were prospectively collected from 72 adults undergoing cardiac surgery. AKI was defined as a 25% or greater increase in plasma creatinine or renal replacement therapy within the first 72 hours following surgery. Plasma cystatin C and NGAL did not predict the development of AKI within the first 6 h following surgery. However, both urinary cystatin C and NGAL were increased in the 34 patients who later developed AKI. The urinary cystatin C at 6 h after ICU admission was the most useful for predicting AKI . A recenEarly determination of allograft function and prognosis could lead to the development of therapies for kidneys with significant ischemia-reperfusion injury (IRI) and more effective recipient management, thereby improving outcomes. A study analyzed urine cystatin C in 91 patients who received deceased-donor kidney transplants to determine its peritransplant excretion pattern, utility for predicting delayed graft function, and association with 3-month graft function. Urine cystatin C/urine creatinine was highest in DGF for all time points. The area under the curve for predicting DGF at 6 h was 0.69 for urine cystatin C and 0.74 for urine cystatin C/urine creatinine. The urine cystatin C/urine creatinine ratio on the postoperative day was associated with 3-month graft function .IL-18 is a proinflammatory cytokine and the prototype of the chemokine superfamily. It is synthesized as an inactive 23 kDa precursor by several tissues including monocytes, macrophages, and proximal tubular epithelial cells. Animal studies explored the role of IL-18 in ischemic AKI –90. CaspDGF due to tubule cell injury frequently complicates deceased donor kidney transplants. Parikh showed that urinary NGAL and IL-18 represent early biomarkers for DGF. In patients with DGF, peak postoperative serum creatinine requiring dialysis typically occurred 2–4 days after transplant. Urine NGAL and IL-18 were elevated in the first day after transplant in patients with DGF. The receiver-operating characteristic curve for prediction of DGF based on urine NGAL or IL-18 at day 0 showed an area under the curve of 0.9 for both biomarkers . The samIn a study of critically ill adult patients with acute respiratory distress syndrome, increased IL-18 was found to be an early marker of AKI and it was an independent predictor of death . A subseAKI is also common after cardiac surgery in adults and children. The study tested whether urinary IL-18 is a predictive biomarker for AKI in patients undergoing CPB. Serum creatinine was detected 48–72 h after CPB. In contrast, urine IL-18 increased at 4–6 h after CPB. These study results indicated that urinary IL-18 is an early, predictive biomarker of AKI after CPB . AKI occL-FABP is a family of carrier proteins for fatty acids and other lipophilic substances such as eicosanoids and retinoids. FABP facilitates the transfer of fatty acids between extracellular and intracellular membranes. It was correlated with the degree of tubulointerstitial damage in a folic acid induced nephropathy . FABP exUrine L-FABP was measured in 40 pediatric patients prior to and following cardiopulmonary bypass surgery. Urinary L-FABP levels at 4 h after surgery were an independent risk indicator with the area under the receiver-operating characteristic curve 0.810, sensitivity 0.714, and specificity 0.684 for a 24-fold increase in urinary L-FABP. This study demonstrated that urinary L-FABP levels represent a sensitive and predictive early biomarker of AKI after cardiac surgery . A recenL-FABP was measured in 80 critically ill patients. Urinary L-FABP levels in patients with septic shock were significantly higher than severe sepsis without shock. Serum L-FABP levels did not have significant differences between patients with septic shock, severe sepsis, and healthy . AnotherL-FABP was evaluated as a biomarker of renal ischemia in both human kidney transplant patients and a mouse model of AKI. In 12 living related kidney transplant patients after reperfusion of their transplanted organs, and intravital video analysis of peritubular capillary blood flow was performed. A significant direct correlation was found between urinary L-FABP level and peritubular capillary blood flow, ischemic time of the transplanted kidney as well as hospital stay . A recenThere are multiple promising serum and urinary biomarkers, NGAL, KIM-1, cystatin C, IL-18, and L-FABP, which detect AKI before the rise in serum creatinine. However, serum creatinine is still the major determinant of kidney function. Determination of biomarkers of AKI in patients with AKI due to different causes, sepsis, ischemia, nephrotoxins, and contrast is important to monitoring. Establishing the optimal biomarkers for a clinical situation must require prospective validation in large numbers of patients with AKI and needs to be performed in different critically ill populations. These new biomarkers must be worked together to develop better definitions of AKI, probably in conjunction with serum creatinine, GFR, and urine output.


Erythropoiesis stimulating agent (ESA)-resistant anemia is common in chronic kidney disease (CKD).To evaluate the determinants of severity of ESA resistance in patients with CKD and primary ESA-resistance.Secondary analysis of a randomized controlled trial 53 adult patients with CKD stage 4 or 5 and primary ESA-resistant anemia .Iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation.Participants were divided into tertiles of ERI. Multinomial logistic regression was used to analyse the determinants of ERI tertiles.n = 18), medium (n = 18) and high (n = 17) ERI tertiles were 1.4 ± 0.3, 2.3 ± 0.2 and 3.5 ± 0.8 IU/kg/week/gHb, respectively (P < 0.001). There were no significant differences observed in age, gender, ethnicity, cause of kidney disease, diabetes, iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation between the ERI tertiles. The median [inter-quartile range] serum alkaline phosphatase concentrations in the low, medium and high ERI tertiles were 89 , 99  U/L, respectively (P = 0.054). There was a weak but statistically significant association between ERI and serum alkaline phosphatase . Using multinomial logistic regression, the risk of being in the high ERI tertile relative to the low ERI tertile increased with increasing serum alkaline phosphatase levels (P = 0.02). No other variables were significantly associated with ERI.All patients, except one, were receiving dialysis for end-stage kidney disease. The mean ± SD ERI values in the low  Increased serum alkaline phosphatase is associated with decreased responsiveness to erythropoiesis stimulating agents in patients with end-stage kidney disease.Serum alkaline phosphatase is associated with severity of resistance to erythropoiesis stimulating agents in patients with chronic kidney disease with no identifiable causes for resistance to erythropoiesis stimulating agents.primary resistance to ESA are unknown.Since the introduction of erythropoiesis stimulating agents (ESA), there have been substantial reductions in the blood transfusion requirements of patients suffering from chronic kidney disease (CKD) . UnfortuESA treatment targeting hemoglobin levels above 130 g/L in people with CKD is associated with deleterious  or neutrDetails of the HERO Study protocol and population are described elsewhere , 33. In 2) and ESA- resistant anemia on a stable dose of either erythropoietin or darbepoetin for at least 8 weeks. ESA-resistant anemia was defined as hemoglobin concentration ≤120 g/L and ERI ≥1.0 IU/kg/week per g/L for erythropoietin and ≥0.005 μg/kg/week per g/L for darbepoetin. ERI was calculated as weight-adjusted weekly dose of ESA divided by hemoglobin concentration, (expressed as IU/kg/week per g/L). ERI for darbepoetin-treated patients was converted to an erythropoietin-equivalent value using a dose conversion factor of 200:1.Between June 2009 and December 2011, the study enrolled 53 adult patients with stages 4 or 5 CKD  were excluded. Participants were randomized in a 1:1 ratio to receive pentoxifylline  400 mg daily orally or an identical matching placebo. The randomization was performed by an adaptive allocation algorithm designed to minimize imbalance in treatment groups across three variables: study site; CKD stage (4 or 5) and ESA class (erythropoietin or darbepoetin) using a password-protected web-based system. The follow up period was 4 months, unless a participant experienced a hemoglobin concentration <65 g/L or required a blood transfusion. The primary efficacy outcome was ERI. Secondary outcome variables were hemoglobin concentration, ESA dose, rate of blood transfusions, adverse events, quality of life and cost-effectiveness analysis. Of the 53 participants, plasma samples for four oxidative stress biomarkers  were available in 41 participants.χ2 test for categorical data; one-way analysis of variance for continuous variables if data were normally distributed and Kruskal–Wallis test for non-normally distributed data. Simple linear regression was used to analyze the association between ERI and other variables. Non-normally distributed variables were appropriately transformed to improve normality of distribution. Associations between ERI and the following variables were analysed in linear regression models: gender, ethnicity, diabetes mellitus, cause of kidney disease, smoking status, ischemic heart disease, congestive heart failure, and body mass index category, age, reticulocyte count, total white cell count, ferritin, transferrin saturation, albumin, alkaline phosphatase, gamma-glutamyltransferase, alanine transaminase, aspartate transaminase, lactate dehydrogenase, albumin-corrected calcium, phosphate, parathyroid hormone, C-reactive protein, total F2-isoprostanes, protein carbonyls, GPX and SOD activities. Predictors of high ERI tertile versus low and medium ERI tertiles were determined by univariate multinomial logistic regression models. The same above mentioned variables were used in these models. Analysis was conducted using Stata/SE .This post-hoc analysis included only the baseline data from the main HERO Study and oxidative stress substudy. Results were expressed as frequencies (percentages) for categorical variables, mean ± standard deviation for continuous normally distributed variables and median [interquartile range] for continuous non-normally distributed variables. Participants were divided into tertiles of ERI . Differences between groups of patients were analysed by P = 0.054, Table Baseline characteristics of the study population according to ERI tertiles are described in Table 2 = 0.06, P = 0.03) . No other variables were significantly associated with ERI on univariate analysis  Fig. . On mult Fig. . OThis secondary analysis of the HERO Study showed that serum alkaline phosphatase was associated with severity of ESA resistance in a selected group of patients with advanced CKD who did not have any identifiable cause of ESA-resistant anemia. No other factors were found to be associated with severity of ESA resistance.In a study involving 38,328 ESKD patients receiving hemodialysis, Kalantar-Zadeh and colleagues reported a positive association between serum alkaline phosphatase level and ESA hyporesponsiveness . ImportaApproximately 31–37 % of ESKD patients receiving dialysis have raised levels of serum alkaline phosphatase , 44. SerThe most likely reason for the observed association between alkaline phosphatase and severity of ESA resistance in the present study is increased bone turnover and marrow fibrosis, since the median serum PTH levels in the middle and high ERI tertiles were 33 and 32 pmol/L, respectively compared with 17 pmol/L in the low ERI tertile . In the A strength of the study was that it involved patients from multiple centers across two countries, enhancing the internal and external validity of the findings. On the other hand, the study was limited by a relatively small sample size, such that it is possible that some associations with severity of ESA resistance were not able to be ascertained due to a type 2 statistical error. Moreover, as multiple variables were evaluated in this study, the observed association between alkaline phosphatase and severity of ESA resistance could have been due to a type 1 statistical error. Bone-specific alkaline phosphatase, other markers of bone turnover and bone biopsies were not evaluated, thereby limiting more detailed exploration of the potential mechanisms underpinning the association between serum alkaline phosphatase and severity of ESA resistance. Since the HERO study included a highly selected group of patients with no identifiable cause of ESA-resistant anemia, the findings of this study may not be generalizable to patients with a known cause of ESA hyporesponsiveness. This finding is hypothesis generating and needs to be confirmed by other studies.Alkaline phosphatase was associated with severity of ESA resistance in patients with advanced CKD and no apparent secondary cause of ESA-resistance. Larger prospective studies are required to confirm this association.


Increased central venous pressure secondary to an increase in intraabdominal pressure has been reported during laparoscopic surgery. However, no study has yet determined the effect of pneumoperitoneum on cross-sectional area (CSA) of central veins by ultrasonography during laparoscopic cholecystectomy. Herein, we aimed to quantify changes in CSAs of internal jugular (IJV) and subclavian veins (SCV) by ultrasonography during this surgery.2 at 12 mmHg. The CSAs of right IJV and right SCV were measured using a 6 Mhz ultrasonography transducer in supine and neutral positions before anesthesia induction (T1), 5 min after connecting to mechanical ventilator (T2), 5 min after creation of pneumoperitoneum (T3), at the end of pneumoperitoneum (T4), and 5 min after desufflation and before extubation (T5) both at end-expiration and end-inspiration.This study included 60 ASA I-II patients scheduled for laparoscopic cholecystectomy surgery under general anesthesia. Pneumoperitoneum was performed with COp < 0.001). Similarly the expiratory measurements of IJV CSA demonstrated significant increase in T3 value compared to T2 value (p < 0.001). The comparison of inspiratory CSA measurements of SCV showed significantly increased in T3 (p = 0.009) than T2 value. In expiratory measurements there was a significant increase in T3 (p = 0.032) value compared to T2. All measurements of IJV and SCV SCAs both end-inspiration and end-expiration T5 values significantly decreased compared to T4 values (p < 0.001).The comparison of IJV CSA at inspiration showed significant increase in T3 value compared to T2 value .Date of registration 21/07/2016, ISRCTN Registry ( No: Central venous catheter placement is a widely practiced medical procedure . Central2 insufflation. Although central venous pressure has been reported to increase [2 insufflation during laparoscopic cholecystectomy operation.During laparoscopic cholecystectomy operation, CSAs of IJV and SCV may be expected to increase owing to increased intraabdominal pressure by COincrease , 11, no This study was approved by Baskent University, Institutional Review Board and Ethics Committee (Project No: 13/254 and Chairperson: Prof. Dr. Hakan Özkardeş) and supported by Baskent University Research Fund. All patients gave an informed consent before study participation. The study was conducted at a tertiary university hospital between February 2015 and September 2015. It included a total of 60 ASA (American Society of Anesthesiology) group I-II patients aged 25–70 years who were scheduled to undergo cholecystectomy surgery with laparoscopic method.2O, providing a tidal volume of 6–7 ml/kg, respiratory rate of 12/min, and %40/%60 O2/air mixture. ECG, peripheral oxygen saturation, and noninvasive blood pressure monitorization were performed during surgery. All patients were applied pneumoperitoneum in supine position via CO2 insufflation (flow rate 2–4 L/min) to achieve an intraabdominal pressure of 12 mmHg. Respiratory rate was adjusted to reach an end-tidal carbon dioxide level of 30–35 mmHg during surgery. CSAs and diameters of right SCV and right IJV were measured in supine position on operating table at both end-expiration and end-inspiration by an ultrasonography device  using a 6 MHz two-dimensional flat ultrasonography transducer  before anesthesia induction , 5 min after intubation and connection to mechanical ventilator (T2), 5 min after creating pneumoperitoneum (T3), at the end of pneumoperitoneum (T4), and after desufflation and before extubation (T5). Figure Patients with cardiovascular disease, severe COPD, chest wall deformity, and a history of use of any drug altering vascular tonus, or a history of neck, clavicle, lung, great vessel, or chest wall surgery were excluded. Age, height, weight, and body mass index of each patient was recorded. The patients fasted for 8 h before the operation and were hydrated with isotonic saline infusion at a rate of 2 ml/kg/h. All patients were administered oral alprazolam 0.5 mg the night before the operation. All patients were administered general anesthesia. Anesthesia induction was achieved by i.v. propofol 2 mg/kg, i.v. fentanyl 1 μgr/kg, and i.v. rocuronium 0.6 mg/kg, and endotracheal intubation was followed anesthesia induction. Anesthesia maintenance was achieved by sevoflurane 1–2 % and i.v. remifentanyl 0.1–0.5 μgr/kg/min infusion. Mechanical ventilation was provided in the volume-controlled mode with an airway pressure not exceeding 20 cmHIJV was evaluated by placing the ultrasonography transducer longitudinally on skin at the level of cricoid cartilage without applying pressure. SCV diameter was measured by placing the same transducer at the junction of the medial and middle third of the clavicle, corresponding to the percutaneous needle entry area for SCV catheterization. The venous measurements included vein diameter, circumference, and cross-sectional area. All measurements were performed while the patients were in supine and neutral positions. The amount of intraoperatively administered fluids and duration of operation were recorded.p < 0.05.As previous studies with a power analysis performed considered a 20 % increase in IJV CSA significant, we planned to enroll at least 58 patients to obtain a confidence level of 95 %, and we ultimately enrolled a total of 60 patients. Study data were analyzed using SPSS  for Windows 11.5 software package. Kolmogorov Smirnov test was used to test the normality of continuous numeric variables. Descriptive statistics included mean ± standard deviation for continuous numeric variables, and number and percentage (%) for nominal variables. Only, T2–T3 and T4–T5 measurements were compared with each other. Normally distributed measurements were compared by two-paired samples t-test and non-normal distributed measurements were compared by nonparametric two-related samples Wilcoxon test. The results were considered statistically significant when p < 0.001). The expiratory measurements of IJV CSAs demonstrated significant increase in T3 value compared to T2 value (p < 0.001) (64 % increase). The comparison of inspiratory CSA measurements of SCV showed significantly increased T3 value than T2 value (p = 0.009). In expiratory measurements on the other hand, there was a significant increase in T3 ( p = 0.032) compared to T2 (Table p < 0.001). These results were graphically depicted in Fig. Sixty patients were included in the study. The demographic properties of the study population were shown on Table This trial studied the effects of pneumoperitoneum on the CSA measurements of IJV and SCV. According to the results of the study, pneumoperitoneum applied with a pressure of 12 mmHg caused significant increases in CSA of IJV and SCV at both expiration and inspiration. After desufflation of intraabdominal gas IJV and SCV CSAs decreased significantly. Measurements at desufflation period showed greater IJV CSA than basal measurements and this probably resulted from an elevated intrathoracic pressure due to mechanical ventilation.The effect of manuvers increasing intraabdominal pressure has been previously studied. Hepatic compression  and incr2 controlled respiratory rate. Hemodynamic changes secondary to increased intraabdominal pressure by gas insufflation vary by several factors including intravascular volume, the magnitude of intraabdominal pressure, and patient position. In this study, we tried to standardize these variables by making measurements in supine position, administering i.v. fluids during the fasting period, performing a standard intraabdominal pressure application, and adjusting respiratory rate by EtCO2 control.Pneumoperitoneum affects cardiovascular system by two ways, namely by direct pressure effect and hypercarbia. However, alterations induced by hypercarbia are less pronounced compared to those induced by the mechanical effects of increased intraabdominal pressure . We prevSince no different pneumoperitoneum pressures were used in our study, their effect could not be assessed. However, prior studies have shown that different pressures have variable hemodynamic effects . Dexter Moreover, the effect of intubation and mechanical ventilation on intrathoracic pressure should not be overlooked. That is, combined effect of increased intraabdominal and intrathoracic pressures may have contributed to CSA increase. This may explain the lack of a biphasic central vein CSA change despite pneumoperitoneum’s biphasic effect on venous return.Central catheters are not routinely used for monitorization of patients with a low ASA category in laparoscopic cholecystectomy operations. However, they may be necessary in case of severe cardiovascular insufficiency or respiratory complications. Although USG is now widely utilized for central catheterization, the latter is performed blindly by using reference points at many centers. A knowledge of diameter change in central veins will reduce the rate of complications in laparoscopic surgeries. According to the results of our study, central venous intervention can be more easily performed after laparoscopic insufflation in such patients. Future studies may investigate if CSA increments will be more exaggerated when maneuvers producing CSA increments, such as PEEP or Trendelenburg position, are applied in conjunction with laparoscopy, or whether different CSA increments will be obtained when different intraabdominal pressure limits are used.2 insufflation and trocar’s placement at the first stage of laparoscopy procedure. Therefore, the study was so designed that the measurements could only be made at the first stage of laparoscopy and 5 min after placing patients again in supine position following the end of the procedure. A study that would be conducted on patients continuously remaining in neutral position may allow performing more frequent measurements that would facilitate the observation of possible changes in every stages of laparoscopy procedure. As a result, after we observed the effect of intraabdominal pressure increase on vein CSAs, we decided to investigate the correlation of CSA changes with pressure alterations in abdominal compartment syndrome in a future study.This study had some limitations. First of all, as the patients were undergoing cholecystectomy operation, they were placed in head up and left lateral tilt position after COIn conclusion, pneumoperitoneum applied with a pressure of 12 mmHg during laparoscopic cholecystectomy produced significant increases in the CSAs of IJV and SCV. More studies are needed to study the clinical effects of this result, such as those on catheter placement time and the incidence of side effects, in patients necessitating catheter placement.ASA, American society of anesthesiologists; CSA, cross-sectional area; IJV, internal jugular vein; PEEP, positive end expiratory pressure; SCV, subclavian vein.


In addition, an ancillary study was designed to explore protein biomarkers and characterize them in relation to severe allergic asthma and treatment effects by proteomic approach.We designed the PROXIMA study  a cross-sectional phase plans to enroll 600 patients with severe allergic asthma, in step 4 therapy as per GINA guidelines, aged ≥18 years, needing a step up in therapy, and 2) a longitudinal phase on patients who will start omalizumab add-on therapy per clinician’s judgment at baseline visit (approximately 180–240 patients). The primary variable of the cross-sectional phase is the proportion of patients with severe asthma presenting with perennial form of allergy (skin prick test or in vitro test). The primary variable of longitudinal phase is proportion of patients who achieve disease control (assessed by Asthma Control Questionnaire [ACQ]) with omalizumab at 6 months, and maintain it at 12 months. Secondary variables are patient compliance to omalizumab, patient-reported perception of cognitive and emotional impact of the illness, assessed by Brief Illness Perception Questionnaire (Brief IPQ) and the health related quality of life evaluated by the EuroQoL 5D-3 L (EQ-5D-3 L). Safety endpoints will be recorded during the course of the study. Patients participating in the longitudinal phase will be enrolled for ancillary study if they provide additional informed consent. Protein species in complex mixtures will be identified using innovative MudPIT  method.The results of this observational study will provide estimate of patient population allergic to perennial allergens in Italy and information on patient-reported outcomes with omalizumab therapy in a real-world setting. The exploratory proteomic analysis on asthma biomarkers could eventually provide new data to identify responder patients to anti IgE therapy. Asthma is a highly prevalent respiratory disorder characterized by chronic inflammation and hyper-responsiveness of airways, and variable airflow obstruction, often reversible . More thIn patients with allergic asthma, who are already sensitized to a specific environmental allergen, exposure to same allergen acts as powerful trigger for asthmatic response, which is mast-cell driven in the early phase and inflammatory-cell driven in late phase ,8. MarkeOmalizumab, a recombinant monoclonal antibody (IgE antibody), reduces free IgE levels by binding to the Fc domain of the circulating IgE and thereby inhibiting IgE binding to FcεRI receptors. In addition omalizumab also blocks the IgE-dependent uptake of allergens by mature myeloid dendritic cells, thereby affecting the chronic allergic response ,10. CurrMedical literature lacks information on the proportion of patients with severe asthma presenting with the perennial form of allergy in Italy. Moreover, data on the effectiveness of omalizumab as add-on therapy for patients with severe persistent allergic asthma in the Italian population is limited.® In the Management of Asthma) study was designed to estimate the prevalence of perennial allergy in adult patients with severe allergic asthma in the Italian population and to evaluate the proportion of patients in this demographics who achieve disease control at 6 months and maintain it at 12 months in a sample of patients treated with omalizumab.The PROXIMA . The study comprises of 2 phases, a cross-sectional and a longitudinal phase 12 months). Patients entered in the longitudinal phase will be treated with omalizumab as per “scheda tecnica” [ months. In the cross-sectional phase, about 600 patients aged ≥18 years, diagnosed with severe allergic asthma currently in Step 4  and need a step up in therapy will be enrolled. About 30%–40%  are estimated to enter the longitudinal phase, start therapy with omalizumab, followed up for 12 months. Omalizumab as treatment choice will be based on clinician’s judgment and local treatment guidelines. As the study will involve questionnaire based assessments, patient unable to complete the patient questionnaires will not be enrolled for the study. Patients participating in the longitudinal phase will have the option to participate to an ancillary study .This study was designed and shall be implemented and reported in accordance with the Guidelines for Good Pharmacoepidemiology Practices (GPP) of the International Society for Pharmacoepidemiology (ISPE 2008), the STROBE  guidelines, the ethical principles laid down in the Declaration of Helsinki, and the AIFA  guideline for the classification and management of observational studies on drugs -15.Eligible patients may be enrolled only after written informed consent. The study documents including protocol and informed consent forms were approved by the ethics committees and institutional review boards of all participating centers.The two primary variables of the study are the proportion of patients with severe allergic asthma having allergy to a perennial form of aeroallergens  and the proportion of patients with asthma control at Months 6 and 12  with omalizumab therapy. Secondary variables in the cross-sectional phase are the level of asthma control, patient disease perception at baseline in all patients (whole sample) and in patients with perennial allergy compared with seasonal allergy, quality of life and healthcare resource utilization. In the longitudinal phase secondary variables are, 1) proportion of patients with at least 1 episode of asthma exacerbation during the 12 months study period; 2) patient compliance to omalizumab at 6 and 12 months; 3) persistence with omalizumab treatment for 12 month; and 4) quality of life and healthcare resource utilization at months 6 and 12.Patients with perennial form of allergy will be identified by clinicians on the basis of the results of skin prick test or in vitro tests for the reactivity to a perennial aeroallergen. Asthma disease control will be assessed by the Asthma Control Questionnaire (ACQ) using a 7-point scale, where 0 indicates well-controlled and 6 signify extremely poorly controlled asthma . A patieBrief Illness Perception Questionnaire (Brief IPQ) and EuroQoL 5D-3 L (EQ-5D-3 L) scale will be used to assess patient disease perception and quality of life, respectively. Brief IPQ is a 9-item questionnaire designed to rapidly assess cognitive and emotional representations of illness . All of Patient compliance will be assessed as the ratio between the number of injections of omalizumab administered during the observational period (month 6 and 12) over the total number of planned injections. Omalizumab persistence during the 12 months will be assessed by Kaplan-Meier survival curve analysis, where the event of interest will be the treatment discontinuation.The consumption of healthcare resources will be assessed by using a dedicated questionnaire collecting information on the number of hospitalizations, number of emergency department visits, number of outpatient visits and number of laboratory and diagnostic tests.1) percent (at baseline) will be measured by using standard clinical and laboratory assessment methods [Asthma exacerbations, serum IgE levels and forced expiratory volume in 1 s  method . The MudThere was no formal statistical hypothesis was set for the study. Descriptive analyses will be performed. The list and frequency of all proteins identified in the total sample of patients will be provided at baseline, 6 and 12 months of omalizumab treatment. In order to assess whether asthma protein biomarkers are related to the achievement and maintenance of disease control, the frequency of all identified proteins will be stratified by responders and non-responders (as defined in the PROXIMA main study). Since a large number of possible proteins are expected to be observed, Bonferroni’s correction will be applied. The 95% confidence interval will be calculated for both objectives.The PROXIMA observational study is designed to provide estimates on the number of patients with asthma who are allergic to perennial allergens and to assess the effectiveness of omalizumab in patients with severe allergic asthma in the Italian population for the first time. In various clinical studies, omalizumab has been shown to improve asthma control and reduce exacerbations in patients with inadequately-controlled severe allergic asthma . Current


To evaluate the effects of a low-sodium and high-potassium salt-substitute on lowering blood pressure (BP) among Tibetans living at high altitude (4300 meters).The study was a patient-blinded randomized controlled trial conducted between February and May 2009 in Dangxiong County, Tibetan Autonomous Region, China. A total of 282 Tibetans aged 40 or older with known hypertension (systolic BP≥140 mmHg) were recruited and randomized to intervention  or control (100% sodium chloride) in a 1: 1 allocation ratio with three months’ supply. Primary outcome was defined as the change in BP levels measured from baseline to followed-up with an automated sphygmomanometer. Per protocol (PP) and intention to treat (ITT) analyses were conducted.After the three months’ intervention period, the net reduction in SBP/DBP in the intervention group in comparison to the control group was −8.2/−3.4 mmHg  in PP analysis, after adjusting for baseline BP and other variables. ITT analysis showed the net reduction in SBP/DBP at −7.6/−3.5 mmHg with multiple imputations . Furthermore, the whole distribution of blood pressure showed an overall decline in SBP/DBP and the proportion of patients with BP under control (SBP/DBP<140 mmHg) was significantly higher in salt-substitute group in comparison to the regular salt group .Low sodium high potassium salt-substitute is effective in lowering both systolic and diastolic blood pressure and offers a simple, low-cost approach for hypertension control among Tibetans in China.NCT01429246ClinicalTrials.gov  The WHO predicts that cardiovascular disease (CVD) will become the leading cause of Disability Adjust Life Years (DALYs) in 2020 The high prevalence of hypertension in Tibetans is attributable to a very high level of daily dietary salt intake Low sodium salt substitute, as a low cost strategy to reduce sodium intake, has previously demonstrated marked reductions in systolic blood pressure among Han Chinese patients with high cardiovascular risk in the China Salt Substitute Study (CSSS). The magnitude of the effect was significantly associated with the baseline blood pressure of the CSSS cohort Of particularly note, the high altitude as the special regional living condition could actually cause significant difficulties to the local healthcare system in implementing hypertension prevention and control program as well as other health programs, such as lack of health care workers, remote and low access to health care services and medications, etc. Thus, the prevalence, treatment and control of hypertension in Tibet are very low The trial was approved by the Ethics Committee of Peking University Health Science Center, Beijing, China (#IRB00001052-09003). All participants and the patriarchs of their families provided informed consent for the family. The protocol and CONSORT checklist are available as supporting information see A community based survey of hypertension was first conducted Local residents aged 40 years and above from two townships (Yangbajing and Gongtangxiang) in Dangxiong County in Tibet Autonomous Region, China, were first invited to a hypertension screening, then those having measured systolic blood pressure ≥140 mmHg would be invited to the trial within 3 months. If the invitee’s systolic blood pressure was confirmed ≥140 mmHg again, regardless use of anti-hypertension medications, he/she would be invited to participate in this study. Of 287 patients who met our inclusion criteria, 282 were recruited after excluding 5 patients who met the exclusion criteria, including 1 patient who was too old and weak to travel, 1 patient who withdrew after inform consent, and 3 patients dropped by research staff due to their living far and arduous journey for follow up. The townships are located 90 kilometers northwest of Lhasa, with an average altitude of 4300 meters above the sea level.The study was planned to enroll patients only in Yangbajing Township originally. However, there were not enough patients meeting our inclusion criteria and agreed to participate in the study there, so the recruitment had to be extended to the nearby township Gongtangxiang in order to achieve the recruitment target. But we reduced data to be collected at baseline in Gongtangxiang due to resource restriction. For details of differences in data collection between the two townships please refer to Stratified randomization by township, gender, and baseline systolic BP (<160 or ≥160 mmHg) was performed immediately after eligibility assessment, using a computer generated randomization list. A random number generator provides a treatment allocation identification number to each enrolled patient. This assignment was secured in a password protected encrypted digital registry. Treatment allocation was only blinded to participants through the use of indistinguishable containers; with only the study allocation number labeled. There was also no way to tell salt-substitute and regular salt by their physical appearance. The difference of taste between salt substitute and regular salt is minor. Our previous study among young adults indicated that about 70% −80% of testers were unable to identify the difference in taste in a triangle food taste test (Data unpublished). There was 1 patient from control group but no patient from intervention group in our study quoted “poor taste” as the reason for dropping out, indicating our blinding to patients were successful.The anticipated allocation ratio between the intervention arm and control arm was set to 1:1. The intervention arm received a three months’ supply of salt substitute  , between December 2008 and February 2009. Blood pressure was measured with three consecutive blood pressure measurements (with at least one minute’s rest between each measurement) from a seated subjects’ right arm in a quiet room. A previously validated electronic sphygmomanometer  was used Once the patients were confirmed eligible and the inform consent was obtained, the baseline measurements were conducted immediately. The screening, eligibility confirmation and baseline measurements were all conducted by trained research staffAfter three months, all patients were asked to return for the measurements of blood pressure according to the same protocol used at baseline. We also collect data on anti-hypertension medication use during the whole study period for all participants.The primary outcomes were the changes in systolic and diastolic blood pressure from baseline to post-intervention over the three-month’ study period. The mean of the three systolic blood pressure measurements were used for analysis. The secondary outcomes were the proportion with hypertension under control (both systolic <140 and diastolic <90 mmHg) at post-intervention.On the basis of our prior study, an estimated sample size of 230 total patients will provide 90% power, with a one-tail α = 0.05, and standard deviation of 13 mmHg to detect a 5.0 mmHg difference between two arms in change on systolic blood pressure at 3-month follow-up from baseline, with a 1:1 allocation of 115 to each treatment arm. We assumed a 20% of participants lost to follow up and thus a total of 287 participants should be recruited.Intention to treat (ITT) analyses was conducted and all eligible 282 subjects were included in the intention to treat analysis Figure 12. All these major baseline characteristics were comparable between the two randomized groups   Table 1.). After adjusting for baseline blood pressure, sex, age, township, baseline BMI and using blood pressure lowering agents, the net reduction was still significant, at −8.2/−3.4 mmHg (SBP/DBP) from PP analysis and at −7.6/−3.5 mmHg (SBP/DBP) from ITT analysis , (p<0.05). Although the peak remained around 160/95 mmHg (SBP/DBP), the overall blood pressure reduction in salt-substitute group was reflected by the dramatic shift of BP distribution to the left .At three months’ follow-up period, the proportion of patients taking antihypertensive medications in the past two weeks was lower in salt-substitute group than in the regular salt group (34.7% vs. 46.4%), however the difference was not significant (p = 0.081).Three people died during the study period, two in control arm and one in the intervention arm. Two of the three died from cerebral hemorrhage, one in each group, and the third death was due to liver cancer.Families located in the central of a group of families that participated in the study were selected by our staff on site for the convenience to distribute study salt, according to their geographic location. Our study staff delivered study salt to these families and then called for the study participants living nearby to come to pick up the study salt. This gave us the opportunity to measure the salt container at these families and ask the questions to help us estimate relatively accurate the amount of salt consumption in these families. For the selected household, we weighted the amount of study salt delivered to the household at baseline and the amount of remaining study salt at the follow-up to estimate average daily salt consumption per person. A total of 54 (27 in each group) families had complete and accurate salt consumption data and reported not using other salt . The estimated average daily sodium chloride intake was 20.0±5.4 grams in the salt substitute group versus 26.9±8.1 grams in the regular salt group (p = 0.025). The additional potassium chloride intake is estimated at about 7.7±2.1 grams in the intervention group. Comparison between participants who did and did not have salt consumption data showed no significant difference in age, gender, blood pressure, education, smoking and alcohol drinking except for those with no data of salt consumption had a significantly lower proportion in use of anti-hypertensive drugs .The present study demonstrated a significantly reduction in both SBP and DBP in salt-substitute group , which is expectedly even greater than what we found in China Salt Substitute Study (CSSS) conducted in rural Han Chinese, where a 5.4 mmHg reduction in SBP and no significant reduction in DBP were shown In addition, we also found that blood pressure lowering agents use was lower in intervention group than in control group, though not statistically significant. This suggests the effect of salt substitute in lowering blood pressure demonstrated in the study would not be attributable to differential use of anti-hypertension medications. We believe that our observed effect would have an even higher magnitude if the use of anti-hypertension medications had been the same in both groups. The salt consumption data showed that the intervention group consumed 7 grams less sodium chloride and 7.7 grams additional potassium chloride on average per day, which, we believe, drove the blood pressure reduction significantly more in intervention group.2) at baseline. Although the results from baseline observations carried forward approach showed a smaller net reduction in both SBP (−5.9 mmHg) and DBP (−2.7 mmHg) and could be significantly underestimated the real net reduction, our results of both approaches showing a significant net reduction in SBP/DBP argue strongly for the validity of our study conclusion.Due to the imbalanced lost to follow up between intervention and control in terms of quantity and quality, we choose multiple imputations rather than baseline observations carried forward approach to impute the missing values in our ITT analysis. In fact, our intervention group lost more patients than control group (42 vs. 27 patients). Comparison of those lost in intervention and control showed that patients lost in intervention group had higher blood pressure (180.9 vs. 170.3 mmHg in SBP), less use of blood pressure lowering agents (42% vs. 50%), less women (29.6% vs. 70.4%), younger age (64.0 vs. 65.3 years) and higher BMI  and developed countries.The present study was limited by restricted financial resources available and austere environmental conditions (remote and rugged terrain at an elevation of 4300 m with serious oxygen deficit); which lead to a single follow-up at three months post randomization and precluded the ability to collect and analyze urinary sample to measure changes in sodium and potassium excretion. However, the present study was a randomized controlled trial design, which would minimize the biases and provide reliable observed effects yielding strong internal validity. Also due to the resource constraints, we were only able to collect baseline data on age, sex, SBP, use of blood pressure lowering agents and BMI. The other variables such as education, occupation, smoking and alcohol drinking were only collected for part of study participants and thus not included in the analysis for adjustment. However, the high comparability between the Intervention and Control in terms of these variables indicates that not having these variables adjusted would not significantly affect the internal validity. Thirdly, the salt consumption data collected in this study does not include sodium from natural foods and is only from a small fraction of the total study population. It should only be used for a rough estimation of sodium intake for local Tibetans. If possible, future studies in Tibet should consider use of 24-hour urine or dietary recalls to get more reliable data. Fourthly, our definition of hypertension excluded those with isolated diastolic hypertension and thus it should be cautious to extend our findings to isolated diastolic hypertension patients. Lastly, mean blood pressure in control group also dropped significantly after intervention. It was due to either seasonal blood pressure change or regression to the mean. The ‘white coat hypertension’ effect, if exist, should have been included in the regression to the mean. CSSS study had shown the similar seasonal blood pressure change where mean blood pressure reached the peak at the coldest season and the low ebb at the hottest season. However, our randomized parallel-controlled design well protected the validity of the study conclusion from the seasonal change and regression to the mean. Despite these limitations, this study was the first randomized control trial providing clear beneficial effects of salt substitute on blood pressure reduction in Tibet and area at high altitude.In conclusion, this study confirmed the prior evidence of the blood pressure-lowering effects achieved with reduced sodium salt substitute in other trials. The excellent effect in lowering blood pressure achieved in this trial showed great potential of salt substitute in prevention and control of cardiovascular disease in this area and other similar settings in the world.Protocol S1English translation of original protocol. A study to develop simple interventions for control of hypertension in Tibet highland.(DOCX)Click here for additional data file.Protocol S2Original protocol in Chinese.(DOC)Click here for additional data file.Checklist S1CONSORT 2010 checklist of information to include when reporting a randomized trial.(DOC)Click here for additional data file.


Impaired autonomic control of postural homeostasis results in orthostatic intolerance. However, the role of neurohormones in orthostatic intolerance has not been explained.st (reference) with 4th quartile of 3 min and maximal ΔSBP/ΔHR (i.e. pronounced hypotension or tachycardia) vs. changes in neuroendocrine biomarkers, respectively.Six-hundred-and-seventy-one patients  with unexplained syncope underwent head-up tilt (HUT) with serial blood sampling. Systolic blood pressure (SBP) and heart rate (HR) supine, after 3min, and lowest BP/highest HR during HUT were recorded. Plasma levels of epinephrine, norepinephrine, renin, C-terminal-pro-arginine-vasopressin (CT-proAVP), C-terminal- endothelin-1 (CT-proET-1), and mid-regional-fragment of pro-atrial-natriuretic-peptide (MR-proANP) were determined at supine and 3min of HUT. Multivariate-adjusted logistic regression model was applied to compare 1Higher resting CT-proET-1 predicted BP fall at 3min (Odds ratio (OR) per 1 SD: 1.62, 95%CI 1.18–2.22; p = 0.003), and max BP fall during HUT . Higher resting CT-proAVP predicted BP fall at 3min , which was also associated with increase in CT-proAVP  and epinephrine  during HUT. Lower resting MR-proANP predicted tachycardia at 3min , and max tachycardia during HUT . Further, tachycardia during HUT was associated with increase in epinephrine , and norepinephrine .Resting CT-proET-1 and CT-proAVP are increased in orthostatic hypotension, while resting MR-proANP is decreased in postural tachycardia. Moreover, early BP fall during orthostasis evokes increase in CT-proAVP and epinephrine, while postural tachycardia is associated with increase in norepinephrine and epinephrine. On stanTwo main variants of orthostatic intolerance, orthostatic hypotension (OH) and postural tachycardia syndrome (POTS), distinctly differ from syncope due to classical vasovagal reflex. In clasSome studies have indicated that neuropeptides may play an important role in cardiovascular dysautonomia and syncope . We haveThe aim of this study was to explore how circulating levels of the most important neurohormones involved in cardiovascular homeostasis, both at rest prior to HUT and during its early phase relate to the well-documented hemodynamic responses to HUT. As most of cardiovascular neurohormones, in particular atrial natriuretic peptide, endothelin-1, and vasopressin, are characterized by a short half-life of a few minutes, we applied newly developed laboratory assays to detect their stable fragments, thus allowing better estimation of neurohormone biosynthesis–11. PatiBetween August 2008 and October 2013, a total of 836 patients with suspected syncope i.e. TLOC unexplained by initial evaluation , were inad libitum. Prior to examination the patients were asked to complete a questionnaire, which explored past medical history, duration, frequency and features of syncope-related symptoms, smoking status, and current pharmacological treatment.The patients participating in the study were asked to take their regular medication and fast for two hours before the test, although they were allowed to drink water The specially designed HUT protocol included peripheral vein cannulation, supine rest for 10 minutes, blood sampling both at supine rest and in the upright position 3 minutes after elevation of the table at an angle of 60–70°, and optional nitroglycerin provocation according to the Italian protocol . NitroglBeat-to-beat blood pressure (BP) and electrocardiogram (ECG) were continuously monitored using a noninvasive validated method  , and subThe predefined point for the second hemodynamic assessment and blood sampling assigned to 3min of HUT was selected to comply with the current definition of classical vs. delayed orthostatic hypotension , and wasThe third assessment of the hemodynamic parameters between 3 and 20min of HUT, corresponding to lowest SBP/highest HR prior to obvious activation of vasovagal reflex and/or syncope or end of the passive HUT, was intended to identify those with delayed hemodynamic instability i.e. delayed OH or progressive postural tachycardia. The onset of vasovagal reflex was identified by typical prodrome and/or an abrupt change in hemodynamic parameters such as bradycardia and/or pronounced hypotension. Accordingly, the timing of the third hemodynamic assessment was selected by visual analysis of SBP and HR curves, and by consensus between two study investigators (DN and AF). If the maximal BP fall occurred before 3min of HUT and led to syncope and/or test termination, the authors decided to assign the corresponding hemodynamic parameters to both the second (3min) and third measurement (lowest SBP).The Regional Ethical Review Board in Lund, Sweden accepted the study protocol (ref no 82/2008), and all study participants gave their written informed consent. Written consent on behalf of the minors/children was obtained by from parents.Blood samples during supine rest before HUT and after 3min of HUT Figs –5 were u3min (SBPsupine−SBPHUT 3min), ΔSBPmaximal , ΔHR3min (HRHUT 3min−HRsupine), and ΔHRmaximal . As the assumption of normal distribution was not satisfied, interquartile differences in neurohormone concentrations  were analyzed using Kruskal-Wallis tests, and corresponding neurohormone concentrations were reported as median + interquartile range. Next, multivariate-adjusted logistic regression models (incl. age and gender as covariates) were applied by entering 4th quartile  vs. 1st quartile  of the assessed hemodynamic parameter as the categorical dependent variable, and standardized plasma concentration of the analyzed neurohormone (presented as standard scores) in supine position or its change after 3min of HUT as the independent variable, respectively.The main characteristics of study population are presented as mean and standard deviation for continuous variables, and percentages for categorical variables. Study population was stratified by quartiles of four HUT-related hemodynamic parameters, ΔSBPp<0.05 was considered statistically significant.As concentrations of the analyzed neurohormones were significantly right-skewed, we performed log-transformation prior to analyses. This model was designed to analyze concentrations of neurohormones in the subset of patients with the most pronounced hemodynamic divergence from baseline (i.e. hypotension or tachycardia) irrespective of whether the formal diagnostic criteria of OH and POTS were met or not during HUT. Accordingly, the final HUT diagnosis was not the object of analysis as the focus of this study was the presyncopal and not syncopal phase of the test. All analyses were performed using IBM SPSS Statistics version 22 . All tests were two-sided, whereby th (highest) quartiles of ΔHR represented a subset of patients with exaggerated chronotropic response to passive orthostasis, while median values of ΔHR for the entire study population  were very similar to those observed in non-syncopal adults [Summary of biometric and hemodynamic parameters for the whole study population is presented in l adults .The following paragraph refers to logistic regression models comparing highest  with lowest quartiles of the assessed hemodynamic responses to HUT as a reference  but not at 3min of HUT Figs –7.Decrease in SBP at 3min  and exclusion of patients (n = 27) with prevalent left ventricle ejection fraction (LVEF) <55% did not substantially change our results, except for MR-proANP in prediction of max SBP decrease, which was non-significant after exclusion of LVEF<55% .This study provides data from a large series of patients with a history of syncope and elucidates the neuroendocrine pattern associated with dysautonomic responses to orthostasis. We have observed that resting CT-proET-1, CT-proAVP, MR-proANP, and renin are elevated in patients with orthostatic hypotension, of these, two latter in the delayed form only, while BP fall on standing is associated with a significant release of vasopressin and epinephrine. In contrast, in patients with postural tachycardia, resting MR-proANP is downregulated, whereas both epinephrine and norepinephrine significantly increase on standing.Previous studies have examined neurohormones during or after syncope, paying little or no attention to hemodynamic changes preceding syncope, which might explain the contradictory findings observed in small series. On the contrary, the present study investigated the pre-test neuroendocrine profile and its early changes during HUT in relation to hemodynamic responses (early and late during HUT) offering insights into the mechanisms of cardiovascular dysautonomia in syncope.Increased CT-proET-1 baseline levels are associated with orthostatic hypotension  but elevThis study demonstrated that higher resting levels of CT-proET-1 consistently predicted decrease in SBP during the entire HUT, which suggests that CT-proET-1 might be a promising predictor of orthostatic hypotension, possibly of both classical and delayed forms.Suppression of ANP production has been found to be associated with reflex syncope . Supine It is tempting to speculate that the lower supine levels of ANP seen in patients with orthostatic tachycardia may be due to the lower blood volume and thus absence of mechanical stretching of the atria whereas higher resting levels of ANP could predict decrease in blood pressure due to stimulation of ANP secretion by neurohormones such as for example ET-1 or even by BP-associated gene variants, or by supine hypertension, often seen in OH.Previous studies have reported significantly higher levels of AVP at baseline in those with VVS compared with non–responders . MoreoveThis study demonstrated that higher resting level of CT-proAVP and pronounced AVP release during HUT paralleled orthostatic BP fall. These results suggest a possible compensatory role for AVP in patients with both classic orthostatic hypotension and early vasodepressor VVS, where increase in AVP during HUT may act as an important rescue mechanism invoked by cerebral hypoperfusion and/or falling left ventricle/right atrial filling pressure detected by mechanoreceptors.A previous study has demonstrated that 25% of normal subjects who develop vasovagal syncope after upright tilt have reduced renin activity both in magnitude and duration compared with the normal response . AnotherOur data demonstrate that higher resting levels of renin predicts maximal decrease in SBP occurring first after the initial 3min of HUT, which suggests an elevated renin activity to predict delayed orthostatic hypotension.A pronounced elevation of plasma epinephrine has been reported in patients with vasovagal syncope, and has been thought to play a role by possible vasodilatation resulting in hypotension . A signiAs demonstrated in this study, decrease in SBP at 3min paralleled increase in epinephrine, suggesting that epinephrine could act as a trigger- or, alternatively, as a compensatory mechanism in the acute phase of orthostatic hypotension  but not after prolonged standing (i.e. delayed). Further, both 3min and maximal increase in HR during HUT were associated with increase in epinephrine suggesting an important role of this neurohormone in orthostatic tachycardia.Norepinephrine has been shown to rise with acute orthostatic BP fall . PatientThis study demonstrated that lower resting levels of norepinephrine predicted decrease in SBP at 3min HUT, and thus may predict early SBP fall as in classical orthostatic hypotension or, alternatively, in the sudden-onset vasodepressor reflex. Moreover, increase in norepinephrine after 3min of HUT paralleled both early and maximal increase in HR during HUT. As for epinephrine (see above), norepinephrine may have an important role in orthostatic tachycardia. Consequently, the possible involvement in POTS of both norepinephrine and epinephrine has to be further evaluated.ex iuvantibus, convincing data and international consensus on their efficacy are lacking. Therefore, targeting the main neuroendocrine systems involved in circulatory homeostasis, which demonstrate a distinct alteration in the main forms of orthostatic intolerance, seems to be a promising strategy. Pharmacological intervention on endothelin, vasopressin, and natriuretic peptide systems using, for instance, neuroendocrine analogues might be a new approach to the therapy of dysautonomic syndromes.An effective therapy against cardiovascular dysautonomic syndromes such as orthostatic hypotension and POTS is not available today. Although both heart rate control and vasoactive drugs have been tested and are still being used In spite of the fact that our material provides data from a large number of patients with a recent history of syncope, no control subjects were included, as the approval of Regional Ethical Review Board did not allow inclusion of asymptomatic controls. However, HUT-related hemodynamic responses in the reference (first) quartiles and median values were very similar to those observed in normal populations and among controls . FurtherThe assays used in our study detected more stable fragments of ANP, ET-1, and vasopressin with a relatively longer half-life. However, for the detection of catecholamines and renin, standard laboratory assays available at the study site were used instead.Resting CT-proET-1 and CT-proAVP are increased in orthostatic hypotension, while resting MR-proANP is decreased in postural tachycardia.Vasopressin and epinephrine are released by abrupt hypotension, whereas increase in both epinephrine and norepinephrine parallel postural tachycardia.These observations may permit better understanding of and therapy in orthostatic intolerance syndromes.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.


Slowly, but absolutely, herbal remedies are being entrenched into evidence-based medical practice. This is partly due to the supporting clinical trials and epidemiological studies. The rationale for this expanding interest and use of plant based treatments being that a significant proportion of hypertensive patients do not respond to Modern therapeutic medication. Other elements to this equation are the cost of medication, side-effects, accessibility, and availability of drugs. Therefore, we believe it is pertinent to review the literature on the beneficial effects of herbs and their isolated compounds as medication for treatment of hypertension, a prevalent risk factor for CVDs. Our search utilized the PubMed and ScienceDirect databases, and the criterion for inclusion was based on the following keywords and phrases: hypertension, high blood pressure, herbal medicine, complementary and alternative medicine (CAM), nitric oxide, vascular smooth muscle cell (VSMC) proliferation, hydrogen sulfide, nuclear factor kappa-B, oxidative stress, and epigenetics/epigenomics. Each of the aforementioned keywords was co-joined with herb in question, and where possible with its constituent molecule(s). In this first of a two-part review, we provide a brief introduction of hypertension, followed by a discussion of the molecular and cellular mechanisms. We then present and discuss the plants that are most commonly used in the treatment and management of hypertension.The use of herbal therapies for treatment and management of cardiovascular diseases (CVDs) is increasing. Plants contain a bounty of phytochemicals that have proven to be protective by reducing the risk of various ailments and diseases. Indeed, accumulating literature provides the scientific evidence and hence  Cardiovascular disease (CVD) remains the leading cause of debility and premature death WHO, , and henHypertension is defined as having a systolic blood pressure (SBP) of ≥140 mmHg and a diastolic blood pressure (DBP) of ≥90 mmHg  and secondary hypertension. Secondary hypertension, which affects 5–10% of hypertensive individuals, is due to identifiable causes, such as diabetes and renal damage, and thus has a relatively higher chance of being treated. On the other hand, essential hypertension is acquired by multiple factors such as diet, age, lifestyle, neurohumoral activity, and interactions , sympathoplegic agents , renin inhibitor (Aliskiren), angiotensin converting enzymes (ACE) inhibitors , angiotensin receptors blockers , calcium channel blockers , α-adrenergic blockers , β-adrenergic blockers  to vasodilators , are used to manage blood pressure levels in hypertensive patients Archer, . HoweverEphedra sinica), aspirin , lovastatin (from Monascus purpureus), reserpine (from Rauwolfia serpentina), and taxol , small resistance size arteries (150–400 μm), and the microcirculation (arterioles and capillaries). Increased arterial reactivity (sensitivity and potency) due to dysregulation in endothelial nitric oxide synthase (eNOS) and pro-oxidant enzymes, enhanced basal and activated calcium levels due to overactive transmembrane calcium permeability through calcium channels, and/or coexistence of vascular smooth muscle cell (VSMC) hyperplasia and hypertrophy (vascular remodeling) can all lead to increased vasoconstriction. These pathological events lead to an increased ratio of vessel wall thickness as compared to the dimensions of the arterial lumen Folkow, . It is tVSMCs participate in the pathogenesis of hypertension , cyclic guanosine monophosphate  play a major role by promoting an environment of oxidative stress, which is a primary cause in the pathogenesis of hypertension . Under physiological conditions, Nrf2 activity is inhibited by its endogenous inhibitor Kelch-like ECH-associated inhibitor 1  to the inactive dihydrobiopterin (BH2). Effectively, this yields more superoxide anion that eventually depletes BH4. Therefore, a shift in balance from NO to superoxide formation ensues; this is referred to as uncoupling of NOS  is often recognized as an important indicator of vascular health. It plays an important role in blood pressure regulation due to its vasodilating potency  is an important biological mediator produced in VSMCs and potentially endothelial cells via the catalysis of L-cysteine by the enzyme cystathionine γ-lyase -induced hypertension in WKY rats  receptor  system plays a pivotal role in regulating blood pressure  for a period of 10 days, the authors reported a significant reduction of 17 mmHg in SBP, but the DBP remained unchanged . In mechanistic support of the blood pressure measurements, the group exposed human umbilical vein endothelial cells (HUVECs) to a garlic extract, which caused an increase in the bioavailability of NO, a potent vasodilator, by 200%  and garlic compounds-mediated increase in H2S is correlated with an increase in vasorelaxant activities in rat aortic rings .The endogenous signaling gases, NO and HGarlic's ability to inhibit ACE activity has also been recognized  leading to a decrease in BP -gene knockout mice , hexanic and methanolic] of Apium graveolens reduce blood pressure in deoxycorticosterone acetate-induced hypertensive rats  Krebs' solution; this was suggested to result from blocking of Ca2+ influx via calcium channels  relaxed potassium chloride and noradrenaline pre-constricted rat aortas -epicatechin (EC), (−)-epicatechin-3-gallate (ECG), (−)-epigallocatechin (EGC), and (−)-epigallocatechin-3-gallate .Flavonoids are noted for their vasorelaxant responses, including flow-mediated  is not only used as a culinary ingredient  produced a dose-dependent fall in SBP, DBP, and mean arterial blood pressure (MABP) in normotensive Sprague-Dawley rats by 40.84 ± 6.34%  plants are shrubs that belong to a genus comprising almost 300 species  for 3 months induced a decrease in both SBP and DBP by around 13 and 8 mmHg, respectively  and oligomeric proanthocyanidins , a plant indigenous to Southwest Asia , Spain, Greece, and Morocco, is a stemless herb whose medicinal values have been sought for over 4000 years  dose-dependently reduced the BP of male Sprague-Dawley rats, possibly by modulating peripheral vascular resistance , and two of its primary components [Crocin (200 mg/kg) and Safranal (1 mg/kg)], attenuated MABP in normotensive and desoxycorticosterone acetate (DOCA)-salt induced hypertensive male Wistar rats  by blocking CaSaffron's antioxidant ability has also been widely reported. It was shown to reduce oxidative stress  has been widely used in traditional medicine of Brazil, China, and Southern Asia  generated a dose-dependent vasorelaxation in phenylephrine pre-constricted aortic rings from male WKRs or SHRs  as well as regulating IP3- and caffeine-gated intracellular Ca2+ stores  are used for health purposes and as refreshing beverages, food items , or lotions.Table 6). Indeed, a drop of BP from 146.48/97.77–129.89/85.96 mmHg was noticed , has been used in the kitchens of Europe, the Middle East, Africa, and South and Southwest Asia for centuries  to mild hypertensive male patients recorded a dose-dependent fall in both SBP and DBP, in the two treated groups compared to placebo -cholesterol relative to pretreatment concentrations  leading to concomitant relaxation of rat aorta , P. quinquefolius (American ginseng), P. japonicas (Japanese ginseng) and P. notoginseng (Chinese ginseng) are the four most common species of ginseng  was administered to mild hypertensive patients and caused a significant decrease of 3.1 and 2.3 mmHg in SBP and DBP, respectively  is known to activate eNOS  pathway, and therefore inhibits PDGF-induced VSMCs proliferation  positive cells. In the SHR, expression of p16, and retinoblastoma protein (Rb) was elevated whereas that of cyclin D1 and cyclin-dependent kinase 4 (CDK4) was decreased  inhibits the release of TNF-α  was shown to lower blood pressure in SHRs  or intravenous (1.75–3.5 mg/kg) administration of two bioactive constituents of ginger, namely (6)-gingerol and (6)-shogoal, produced triphasic blood pressure profiles: initial rapid fall, intermediate rise, and finally a delayed decrease in BP  has also been reported to inhibit lipid peroxidation as well as ACE in rat hearts , and has been supported by sound scientific evidence such as one based on clinical trials with large population groups. It is important to note that there are herbs and plants that could actually raise blood pressure and thus should be avoided by hypertensive patients. There are also other limitations for herbal therapy of hypertension. These limitations would be discussed in the second part of this review.All authors contributed to the writing. AE conceived, designed and revised the manuscript.This publication was made possible by grant # NPRP 4-571-3-171 from the Qatar National Research Fund (a member of Qatar Foundation). The Statements made herein are solely the responsibility of the authors. This grant was awarded to AE.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To determine how many kidney function tests are done, on whom, how frequently they are performed and how they have changed over time.Retrospective study of all serum creatinine, urine albumin and urine creatinine tests.Primary and secondary care in Oxfordshire from 1993 to 2013.Unselected population of 1 220 447 people.The total number of creatinine and urinary protein tests ordered from primary and secondary care and the number of tests per year stratified by categories of estimated glomerular filtration rate (eGFR). The frequency of testing in patients having their kidney function monitored.2) constituted 59% of all kidney function tests in 1993 and accounted for 83% of all tests in 2013. Test corresponding to chronic kidney disease (CKD) stages 3–5 declined after 2007. Reduced kidney function, albuminuria, male gender, diabetes and age were independently associated with more frequent monitoring. For a female patient between 61 and 80 years and with stage 3a CKD, the average number of serum creatinine tests (95% CI) was 3.23/year (3.19 to 3.26) and for a similar woman with diabetes, the average number of tests was 5.50 (5.44 to 5.56) tests per year.Creatinine requests from primary care increased steadily from 1997 and exceeded 220 000 requests in 2013. Tests corresponding to normal kidney function (eGFR >60/mL/min/1.73 mThere has been a large increase in the number of kidney function tests over the past two decades. However, we found little evidence that this increase is detecting more CKD. Tests are becoming more frequent in people with and without evidence of renal impairment. Future work using a richer data source could help unravel the underlying reasons for the increased testing and determine how much is necessary and useful. This study uses 20 years of data from a single laboratory that serves a well-defined population, typical of the wider UK population.To our knowledge, no other study has looked specifically at changes in serum creatinine test ordering rates, over time, in the UK.We did not have access to data on patient history or prescriptions or reasons for test ordering and so cannot comment on whether they were ordered with appropriate frequency.Serum creatinine (SCr) is widely used to measure renal function in the detection, diagnosis and management of chronic kidney disease (CKD) and other renal disorders such as acute kidney injury (AKI). Urinary albumin and protein are markers of kidney damage but also indicate disease from anywhere within the urinary tract. As both reduced renal function and elevated urinary albumin or protein are independently associated with adverse kidney outcomes 6The Kidney Disease Outcomes and Quality Initiative (KDOQI) clinical practice guidelines in early 20029Motivated by a previous analysis of lipid testing in the same region,Data included all requests for SCr, ACR, protein to creatinine ratio (PCR) and glycated haemoglobin (HbA1c) measurements from the Oxford University Hospitals Trust Clinical Biochemistry laboratories for the entire periods covered by the database (May 1969 to November 2014). One of the co-authors (BS) is the custodian of the laboratory information system, and all data were anonymised prior to extraction and analysis. We used the National Health Service (NHS) number as the primary identifier. Before this was available, patients were linked to their hospital number if they were known. Where neither of these were available, specimens were not extracted. Numerators were based on all tests, whether linked or not.Recording of creatinine requests prior to 1993 was inconsistent and there were few records of ACR/PCR tests prior to 2006. In September 2009, the reference method for creatinine changed to isotope dilution mass spectrometry and all creatinine measurements have been adjusted to reflect this. For each test result, the sex and date of birth of the patient, and the date, location and name of the requesting physician were extracted from the database. A request was coded as coming from either primary care or other non-primary care (secondary or tertiary) care using an amended version of the in-house laboratory coding system. Locales that had requested less than 50 tests over the entire study period were not included in the analysis.2) and mildly impaired (60–89 mL/min/1.73 m2) kidney function and the remaining four represent moderate to severely impaired kidney function and correspond directly to CKD stages 3a (45–59 mL/min/1.73 m2), 3b (30–44 mL/min/1.73 m2), 4 (15–29 mL/min/1.73 m2) and 5 (<15 mL/min/1.73 m2) . The MDRD formula has an adjustment for ethnicity, which raises eGFR for non-white ethnicity. We were unable to obtain these data, so made no adjustment and hence our eGFR staging is biased slightly towards more severe renal impairment. HbA1c  units) was categorised into four levels: (1) not measured, (2) under the diagnostic thresholds for diabetes (<48 mmol/mol), (3) controlled glycaemia (48–58 mmol/mol) and (4) uncontrolled glycaemia (>58 mmol/mol). Albuminuria was categorised similarly using diagnostic thresholds as: (1) not measured, (2) measured but less than 3 mg/mol for ACR or less than 15 mg/mmol for PCR, (3) microalbuminuria (>3 mg/mol (ACR) and >15 mg/mmol (PCR)) and (4) macroalbuminuria (>30 mg/mmol (ACR) or >50 mg/mmol (PCR)).eGFR was calculated from SCr using the MDRD formula,The total number of SCr, ACR and PCR tests ordered from primary care and non-primary care locales was calculated separately for each year from 1993 to 2013. In an additional analysis, we calculated age-adjusted yearly totals of creatinine testing in primary and secondary care by standardising to the age distribution in 1999. For this, we calculated creatinine testing rates per 5-year age brackets using population pyramid data for England between 1971 and 2011We examined factors related to the frequency of monitoring in a subcohort of people having kidney function/damage monitored, defined as having at least two tests further to the first year's measurement and complete covariate data. Measurements within the first year of follow-up were excluded as they are likely to be for reasons other than monitoring. We used Poisson regression to model the frequency of monitoring adjusting for initial level of kidney function, HbA1c testing, evidence of albuminuria or proteinuria, gender and age. All analyses were carried out using R V.3.1.215Data were obtained on 1 220 447 people, 527 753 of which had only one entry and the remaining 692 694 had median (IQR) follow-up of 7.6 (3.7–12.5) years. The percentage of specimens that could not be linked to either a hospital or NHS number was 20% in 1993 and dropped steadily to less than 1% in 2013 (see online supplementary figure S1).supplementary figure S2). Adjusted creatinine totals were lower than unadjusted totals and suggest that for 2013, 11.9% of the tests in secondary care and 12.6% in primary care can be attributed to shifts in age demographics since 1999 (see online supplementary figure S3).The age distribution of people that have creatinine measured in Oxfordshire changed over the duration of the study. There were more people  being tested in age brackets 85 or older in 2013, compared with 1999, but fewer in the 70–80s age brackets (see online supplementary figure S4).There were 167 701 participants with at least two tests further to the first year's measurement and complete covariate data. 2), the average rate of monitoring is estimated as 3.23 tests per year with 95% CI (3.19 to 3.26) and for a similar woman with controlled glycaemia, the average number of tests rises to 5.50 tests per year on average with 95% CI (5.44 to 5.56).The average rate (95% CI) of monitoring in the reference group  was 1.09 (1.09 to 1.11) tests per year . Relative increases in the frequency of monitoring were found for older people, for people with microalbuminuria or macroalbuminuria, lower eGFR, those with any HbA1c tests and higher HbA1c. The frequency of monitoring was also shown to increase with time, independently of other associated factors. Female gender was associated with a small but statistically significant relative decrease in the frequency of monitoring. For a female patient aged between 61 and 80 with stage 3a CKD  increased. The number of tests with results in the normal range (>90 mL/min/1.73 m2) has risen fastest since 2006/2007.Older people, people with higher HbA1c and people with kidney disease were most frequently tested for SCr. Up until 2005, the increasing volume of testing in primary care was accompanied by increasing numbers with CKD among those tested. After 2005, the volume of creatinine testing continued to increase, but the number of tests with eGFR corresponding to CKD stages 3–5 stabilised or decreased while the number of eGFR tests with results in the normal or mildly impaired range . Since most of the recent increase in testing is driven by tests on patients with normal to mildly reduced eGFR and as there is little evidence of benefit from intervening in people with early stage CKD,The increase in the volume of kidney function tests in Oxfordshire, and in particular creatinine testing, is likely to be due to a number of factors. There is a net increase in number of people being tested year on year and people are being tested more frequently independent of changes in common risk factors for CKD. Given the uncertainty around the best methods and intervals for monitoring renal function, it is unclear whether more frequent monitoring may lead to a net benefit, but as eGFR has considerable biological variability,


To identify potential electrocardiographic predictors of peripartum cardiomyopathy (PPCM).This was a case–control study carried out in three hospitals in Kano, Nigeria. Logistic regression models and a risk score were developed to determine electrocardiographic predictors of PPCM.p = 0.001), while the presence of ST–T-wave changes increased the odds of PPCM 12.06-fold (p < 0.001). In the patients, QRS duration modestly correlated  with left ventricular dimensions and end-systolic volume index, and was responsible for 19.9% of the variability of the latter . A risk score of ≥ 2, developed by scoring 1 for each of the three ECG disturbances , had a sensitivity of 85.2%, specificity of 64.9%, negative predictive value of 86.2% and area under the curve of 83.8% (p < 0.0001) for potentially predicting PPCM.A total of 54 PPCM and 77 controls were consecutively recruited after satisfying the inclusion criteria. After controlling for confounding variables, a rise in heart rate of one beat/minute increased the risk of PPCM by 6.4% (In postpartum women, using the risk score could help to streamline the diagnosis of PPCM with significant accuracy, prior to confirmatory investigations Although peripartum cardiomyopathy (PPCM) was first described in 1880, much remains unknown about it.The aim of this study was to determine potential ECG variables that predict the diagnosis of PPCM. If proved, such variables could help to streamline the diagnosis of PPCM prior to confirmatory investigations, particularly in limited-resource settings.This was a case–control study carried out in the Murtala Mohammed Specialist Hospital (MMSH), Aminu Kano Teaching Hospital (AKTH), and a private cardiology clinic in Kano, Nigeria. The research protocol was approved by the ethics committees of each of the study centres, and the study conformed to the ethics guidelines of the Declaration of Helsinki, on the principles for medical research involving human subjects.4The inclusion criteria for the patients were: (1) confirmed diagnosis of PPCM; (2) onset of symptoms towards the end of pregnancy or within the puerperium, and presentation to hospital within nine months postpartum; (3) age of at least 18 years; and (4) written informed consent. Patients were excluded if: (1) their symptoms could be explained by diagnoses other than PPCM; (2) their symptoms started in early pregnancy or after the first five months postpartum; (3) they were younger than 18 or older than 45 years; (4) they denied consent to participate.To be included, the controls had to satisfy the following criteria: (1) be apparently healthy; (2) no past history of any cardiac disease or systemic hypertension (except pregnancyinduced hypertension); (3) normal ECG ;6T-wave inversion with or without ST-segment depression were considered abnormal in all leads except aVR, V1 and V2.5 In addition, flat T waves in leads III or aVF were also considered non-specific.5Controls were excluded if: (1) they presented their children for immunisation after five months postpartum; (2) they presented to the hospital as patients; (3) they were younger than 18 or older than 45 years; (4) they were known or found clinically to have any cardiac disease; (5) they denied consent. The sample size for the controls was estimated at 1.5 × the total number of patients (± five patients).PPCM was defined according to the recommendations of the Heart Failure Association of the European Society of Cardiology working group on PPCM, and left ventricular (LV) systolic dysfunction was defined as LV ejection fraction < 50%.7At the study centres, physicians in the Internal Medicine, and Obstetrics and Gynaecology Departments were approached and requested to refer all patients with suspected PPCM to the principal investigator (PI) for further evaluation. Patients were then interviewed, clinically evaluated and recruited consecutively. Hospital in-patients with PPCM were clinically assessed and underwent investigations within the first 48 hours of admission.Demographic data, relevant aspects of the history and physical signs, results of investigations, co-morbid conditions, and complications were included in a detailed questionnaire. Baseline levels of serum urea, electrolytes and creatinine were carried out in the laboratories of AKTH, while 12-lead ECGs at rest, and transthoracic echocardiograms (for PPCM patients only) were all carried out by the PI at the study sites, according to standard recommendations.9All ECG recordings were studied and interpreted by the investigators in the standard fashion, and ECG intervals/ durations were measured using manual callipers.t- and Mann–Whitney U-tests were used to compare categorical and continuous variables as appropriate. Binary logistic regression models were used to determine predictors of PPCM among the ECG variables, and values were expressed as odds ratios (OR) and 95% confidence intervals (CI). Pearson’s correlation coefficient and linear regression models were used to further assess relationships between variables of interest.Frequencies, mean, median and inter-quartile ranges were used to describe patients’ characteristics. Chi-square, Fisher’s exact probability, Student’s p-value < 0.05 was considered statistically significant. The statistical analysis was carried out using SPSS version 16.0 software.A simple score assigning 1 to each identified independent ECG predictor was composed and its accuracy in predicting PPCM was determined using the area under the receiver operating characteristics (ROC) curve (AUC), and AUC > 0.75 was considered satisfactory. A A total of 54 PPCM and 77 controls satisfied all the inclusion criteria and were consecutively recruited. PPCM patients were recruited at the time of confirmation of diagnosis, when specific heart failure treatment was also commenced.p > 0.05). However, mean serum level of creatinine was higher (p = 0.045), and mean serum sodium and potassium levels were significantly lower (p = 0.009 and < 0.001 respectively) in patients compared to controls.The baseline characteristics of the subjects are presented in p > 0.05) between the two groups. However, patients had significantly faster heart rates, broader QRS durations, prolonged QTc intervals, and more frequent tachycardia and ST–T-wave abnormalities  than the controls .ECG findings are presented in p ≤ 0.003). In addition, heart rate < 100 beats/min reduced the risk of having PPCM by 89.7% (p < 0.001). The presence of ST–T-wave abnormalities increased the odds of PPCM almost 12-fold (p < 0.001), while QRS duration > 110 ms and QTc duration > 460 ms increased the odds 5.2-fold (p < 0.001) and 9.5-fold (p < 0.001), respectively.The results of the logistic regression models are presented in p < 0.001 each), while the latter two lost their prediction of PPCM (p > 0.05 for each). The addition of serum sodium or potassium levels to the models with heart rate and ST–T-wave abnormalities did not influence the results, as the two ECG variables maintained their predictive value (p < 0.001), although serum potassium exerted greater influence than sodium levels. Therefore after controlling for confounding variables, including serum sodium and potassium levels, a rise in heart rate of one beat/min increased the risk of PPCM 6.4% (p = 0.001), while the presence of ST–T-wave changes increased the odds of PPCM 12.06-fold (p < 0.001).Stepwise multivariate regression analyses were then carried out to control for confounding factors. In the initial model, including heart rate, ST–T-wave abnormalities, QRS duration and QTc interval, the former two maintained their statistical significance . R2 = 0.199; p = 0.003).The patients were evaluated echocardiographically. Mean end-diastolic and end-systolic dimensions , LV end-systolic volume index (LVESVI) and LV ejection fraction (LVEF) were 61.4 ± 8.8 mm, 51.0 ± 9.1 mm, 85.1 ± 33.1 ml/m2 and 34.4 ± 9.9%, respectively. The relationship between these echocardiographic and ECG variables are presented in p < 0.0001)  see  for predThis study describes, perhaps for the first time, the use of postpartum ECG variables in a simple risk score that seems to predict PPCM diagnosis among women at risk for the disease. PPCM patients and controls had similar age, systolic and diastolic blood pressures and body mass index. Therefore, the findings could not have been influenced by these possible confounders.Our findings show that the presence of heart rate less than 100 beats/min reduced the risk of diagnosing PPCM to 89.7%, while the presence of ST–T-wave abnormalities, QRS duration more than 110 ms and QTc duration longer than 460 ms increased the odds of PPCM 12.0-, 5.2- and 9.5-fold, respectively. In the initial multiple regression model, heart rate and ST–T-wave abnormalities maintained their high statistical significance in predicting PPCM but not QRS duration and QTc interval. This finding was not influenced by serum sodium or potassium levels.None of our patients had malignant arrhythmia, and ectopic beats were equally uncommon in both groups. These results are supported by previous reports in women with PPCM as well as in healthy pregnant women.12Serum sodium and potassium levels were significantly lower in the patients than the controls, possibly because of water retention caused by heart failure syndrome.For the first time, we have developed a simple scoring system using three ECG variables that could potentially predict PPCM with an accuracy of 83.8%. A risk score of ≥ 2 had a sensitivity of 85.2%, specificity of 64.9% and NPV of 86.2%. The score’s satisfactory accuracy in predicting the diagnosis of PPCM makes it appealing for routine use, particularly in areas where the disease is prevalent and more expensive diagnostic facilities are limited.Our results have shown that in the patients, ECG measurements were related to cardiac structure and function, suggesting diffuse pathological changes. QRS duration modestly correlated with LVEDD, LVESD and LVESVI, explaining 19.9% of the variability of the latter, but had only a trend towards a relationship with LVEF. Furthermore, QRS duration of > 110 ms significantly increased the odds of PPCM 5.2-fold, in spite of the faster heart rate in patients compared to controls.These results are supported by a previous study, which showed an association between QRS duration and mortality among predominantly male (98%), elderly Caucasians with moderate to severe LV systolic dysfunction caused by a variety of diseases (LVEF < 40%).et al. in dilated cardiomyopathy patients, with a lower prevalence in idiopathic (68.8%) compared to those with familial disease (87.5%), but there was no association between such electric disturbance and survival.T-wave abnormalities were identified in 68.5% of our patients. Similar findings were reported by Ntusi In our series, QRS duration was the only ECG variable that correlated with LV dimensions and end-systolic volume index, while heart rate and ST–T-wave abnormalities had higher sensitivity in predicting PPCM. Longitudinal follow-up studies would determine the prognostic impact of ECG variables in the setting of PPCM.Heart rate and ST–T-wave changes seemed to independently predict the diagnosis of PPCM. In addition, a simple score of ≥ 2, counting 1 for each of three ECG abnormalities  had 83.8% accuracy for predicting PPCM in women at risk. These findings could help to filter out patients requiring additional investigations in areas with limited resources.This study has some limitations. Firstly, serum levels of calcium and magnesium were neither assessed nor controlled for, but deficiencies of these electrolytes have not been reported to be common in PPCM patients.This study shows, for the first time, that in women presenting within the first nine months after delivery with symptoms of heart failure, heart rate and ST–T-wave abnormalities were potential predictors of a diagnosis of PPCM. QRS duration modestly correlated with LV dimensions and LVESVI. A simple ECG-based score could potentially predict the diagnosis of PPCM, a finding that could help to streamline the diagnosis of PPCM prior to confirmatory investigations, particularly in limited-resource settings, where the disease is common.