According to recent epidemiologic studies, patients with sleep apnea/hypopnea syndrome (SAHS) are at increased risk of cardiovascular diseases, including stroke. However, the mechanisms are not well defined. Nocturnal apneas can trigger acute cerebral ischemia in predisposed patients and impaired vasodilatation is present in SAHS, but few studies have explored vascular cerebral dysfunction and often gave inconclusive results. The aims of our study were to assess whether patients with SAHS have impairment of cerebral hemodynamics with respect to controls, and to investigate a possible relationship with clinical data. We studied two groups, one of 76 SAHS patients and another one of 76 non-SAHS subjects matched for age, sex and main cardiovascular risk factors. All participants underwent a daytime transcranial Doppler study of right middle cerebral artery to record cerebral blood flow velocity and cerebrovascular reactivity by means of breath-holding test (BHT). SAHS patients have a reduction in mean cerebral blood flow velocity (MFV)  and BHT  when compared to non-SAHS controls. Moreover, MFV correlated negatively with the presence of coronary disease, and BHT with female sex and arterial pressure. On the other hand, in the SAHS group, MFV correlated negatively with oxygen desaturation severity. Patients with SAHS have impaired MFV and cerebrovascular reactivity when compared to controls. Interestingly, poorly controlled or unknown hypertension and severe nocturnal hypoxemia caused additional cerebral hemodynamic disturbances to these patients. Stroke is a seriousand common disorder and a major cause of death worldwide. The pathogenesis of stroke is multifactorial and not fully understood. Although several triggering factors have been already identified, they do no account for all the cases of stroke and new risk factors have been proposed  ≥10/h in overnight full polysomnography were included. Non-SAHS controls were selected from the community and hospital staff; subjects with chronic or heavy snoring, witnessed nocturnal apneas or excessive daytime sleepiness [Epworth Sleepiness Scale (ESS) ≥10] were excluded, although subjects with occasional snoring (less than once a week) were accepted. Both groups were matched for age, sex, smoking status, arterial hypertension (HT), dyslipidemia, diabetes mellitus (DM), coronary disease (CD) and peripheral arteriopathy (PA).2 > 45 mmHg), stroke, arrythmia, cardiac failure or cervical or intracranial arterial stenosis were excluded from the study. Diagnosis of HT, dyslipidemia or DM was done by the primary physician. The Study Protocol was approved by the Hospital General Universitario Ethic Committee. All participants entered the study after giving written informed consent.Patients with previous respiratory disease, diurnal hypercapnia  16-channel polysomnograph. Sleep stages and EEG arousal detection were scored according to standard criteria. Apnea was defined as an airflow cessation of more than 10 s in both the thermistor and nasal cannula. Hypopnea was defined as a 50 % reduction in airflow amplitude of at least 10 s in one airflow signal, with a 4 % oxygen desaturation and/or EEG arousal. AHI was defined as the sum of apneas and hypopneas per hour during the total sleep time. The oxygen desaturation index (ODI) and arousal index (AI) were defined as the respective number of 4 % oxygen desaturations and EEG arousals per hour during the total sleep time. CTAll the subjects were studied in the morning, between 10 a.m. and 12 a.m., in a quiet, semi-dark room, resting in a supine position. SAHS patients were studied within a month of the sleep study. All the tests were performed by the same investigator, who was blind to the results of the sleep study. First, the participants were routinely examined with continuous color-coded duplex ultrasound . If a significant (>50 %) stenosis was found, the patient was excluded from the study. Second, intracranial arteries  were identified through the temporal  or suboccipital (BA) windows by transcranial Doppler (TCD) . The peak systolic velocity (PSV) and end diastolic velocity (EDV) were recorded for each artery. The mean blood flow velocity (MFV) was calculated automatically using the formula:A MFV measurement greater than 95th percentile of our normal laboratory values in any intracranial artery was indicative of cerebral artery stenosis and the subject was excluded from the study.CVR was assessed by the breath-holding test (BHT). We continuously recorded the right MCA MFV at a depth of 50–55 mm. Participants were asked to hold their breaths for 30 s after a normal inspiration. The CBFV increase was recorded as the percentage increase in post-apnea MFV compared to the baseline value after breath-holding (Ratnatunga and Adiseshiah Apnea maneuver can induce changes in blood pressure (BP) that could in turn modify cerebral hemodynamics. For that, systolic (SBP) and diastolic blood pressure (DBP) were measured before and immediately after the breath holding, and BP variations were considered in data analysis; mean arterial pressure (MAP) was defined as:The difference between post-apnea MAP and baseline MAP was defined as:2 test for categoric variables. The linear association between two quantitative variables was established using the Pearson linear correlation index or Spearman test. Multivariate analysis was performed by multiple linear regression models, including all the independent variables that showed an association with dependent variable with p < 0.2. All other independent variables relevant for the objectives of the study were also included. The inclusion was performed by the “forward” selection method. The strength of the association was measured by the square multiple correlation coefficient adjusted (R2). A value of p < 0.05 was considered statistically significant.The SPSS 22.0 package  was used for the analysis. All the data were tabulated as mean and standard deviation for quantitative variables and as absolute numbers and percentages in the case of qualitative variables. The Kolmogorov–Smirnov test was used to analyze variables distribution. When necessary, the variables were transformed. In the bivariate analysis, quantitative variables were analyzed using the comparison of means tests (Student’s t or Mann–Whitney’s) and χSeventy-eight SAHS patients and seventy-six non-SAHS subjects were referred for TCD study. Two SAHS patients were excluded because of significant (>50 %) internal carotid artery stenosis and temporal hyperostosis, respectively. The baseline characteristics of the participants are shown in Table On bivariate analysis, the TCD study showed a significant decrease in MFV  and BHT  in SAHS patients with respect to non-SAHS (Table 2) was 0.124. MFV correlated negatively with the presence of SAHS and coronary disease (Table 2) was 0.115. BHT correlated negatively with the presence of SAHS, female sex and baseline MAP (Table Multivariate linear regression analysis was performed. The variables included in the model explaining MFV were: case/control status, age, gender, BMI, coronary disease and baseline MAP. The regression coefficient (RThe main polysomnographic values of SAHS patients are shown in Table 90, and positively with mean nocturnal O2 saturation. BHT correlated negatively with baseline MAP. On the other hand, we found no significative correlation between BHT and main respiratory variables on polysomnography.On bivariate analysis Table , MFV corThe vascular risk factors predisposing to stroke in SAHS are not completely defined. In this study, we found that daytime cerebral hemodynamics is abnormal in patients affected by SAHS. Specifically, we observed a significant reduction in MFV and BHT in the SAHS group when compared to controls. These findings are consistent with changes in cerebral circulation, and could indicate a potential greater vulnerability of the cerebral vasculature to stroke injury (Silvestrini et al. Reduced MFV in SAHS has been scarcely reported in previous studies and little importance has been given to this finding in most of them (Urbano et al. We also found CVR impairment in SAHS patients as described in previous studies, most of them including a small number of severe patients. Placidi et al. (Placidi et al. In the present study, we also found that decrease in CVR was independently related to high baseline BP values, indicating either unknown or poorly controlled hypertension. Chronic hypertension causes endothelial dysfunction and vasodilatation impairment. Moreover, one recent well-designed study (Drager et al. Another important finding from our study is the association of impaired CVR with female sex. Even though female sex is not a risk factor per se, greater reduction in CVR has been found in post-menopausal women as compared to premenopausal women and men of all ages (Matteis et al. In our SAHS group, MFV reduction was related to oxygen desaturation severity, but not to AHI. Oxygen desaturation severity has also been correlated with the presence of early markers of carotid atherosclerosis (Baguet et al. 2, a more recent paper (Coverdale et al. Our study has some potential limitations. First of all, a limitation in the TCD methodology is the correlation of the CBFV with cerebral flow when the MCA diameter remains constant at the point of insonation. Although previous studies did not find any significant difference in the diameter of the artery during changes in end-tidal COIn summary, our study highlights the impairment of daytime cerebral hemodynamics in patients with severe SAHS. These findings point out to possible functional and structural changes in cerebral microcirculation and perhaps in large intracranial arteries too as a potential mechanism to help to explain the increased risk of stroke in these patients. Further studies will be needed to identify risk groups more accurately and to evaluate possible changes in cerebral hemodynamics after therapeutic intervention.


Increased bioavailability of phenylephrine is reported when combined with paracetamol in over-the-counter formulations for the symptomatic treatment of the common cold and influenza. Such formulations could increase phenylephrine-related cardiovascular adverse events particularly in susceptible individuals. Quantification of the effect of phenylephrine concentration on blood pressure allows simulation of potential adverse combination therapy effects.MEDLINE and EMBASE databases were searched for papers discussing or describing any adverse effect, hypersensitivity or safety concerns related to phenylephrine alone or in combination with other drugs.The pharmacodynamic relationship between plasma phenylephrine concentration and mean arterial blood pressure was characterized using published observations of blood pressure changes after ophthalmic eye drops. The resulting pharmacokinetic and pharmacodynamic parameters were then used to predict mean arterial blood pressure (MAP) changes in that population if given an oral combination of phenylephrine and paracetamol.There were 1172 papers identified for examination. Forty-seven reports fulfilled the inclusion criteria. Increases in blood pressure and decreases in heart rate have been reported with doses over 15 mg. It has been estimated that a 20-mmHg increase in systolic blood pressure would occur with an oral dose of 45 mg phenylephrine in normotensive healthy people. Those taking monoamine oxidase inhibitors report increased systolic blood pressure of greater than 60 mmHg. Blood pressure and heart rate changes are potentiated in patients with underlying hypertension. Simulation showed a modest increase in MAP when phenylephrine 10 mg was co-administered with paracetamol 1 g (4.2 vs 12.3 mmHg).Combination paracetamol phenylephrine oral therapy has potential to increase blood pressure more than phenylephrine alone in those with cardiovascular compromise.The online version of this article (doi:10.1007/s00228-015-1876-1) contains supplementary material, which is available to authorized users. Phenylephrine is a selective alpha-1 adrenoceptor agonist with powerful vasoconstrictive properties. Historically, its use had been restricted to the perioperative period and intensive care medicine for preparation of the surgical field and control of haemorrhage during ear nose and throat procedures, pupillary dilation and maintenance of blood pressure. Phenylephrine is commonly used now as a nasal decongestant in many over-the-counter (OTC) cold and influenza preparations.When phenylephrine was combined with another commonly administered cold and flu medication, paracetamol, the plasma concentration of phenylephrine was, on average, twice that obtained when phenylephrine was given alone and the peak concentration approximately four times higher . It is sHere, we provide a systematic narrative review of cardiovascular adverse effects associated with phenylephrine. We quantify the effect of phenylephrine concentration on blood pressure using published data and simulate the potential impact paracetamol phenylephrine combination oral therapy may have on cardiovascular endpoints.A broad search  did not describe an adverse effect for phenylephrine; (2) related to children under 12 years of age; (3) were not written in English or a full-text version was not available for purchase; (4) was not a clinical trial [either prospective or retrospective], case report or series, or a meta-analysis; and (5) did not relate to the cardiovascular system. References of identified papers were reviewed for additional relevant reports.n = 10) and 10 % (n = 10) eye drops  are contained in Tables n = 20). Further pharmacokinetic (PK) data were available from healthy volunteers given oral phenylephrine 10 mg alone, with blood for concentration assay taken at 5, 15, 30, and 45 min and 1, 2, 3, and 6 h . Technical methods for population parameter estimates using nonlinear mixed effects models (NONMEM) can be found in the The relationship between plasma phenylephrine concentration and mean arterial blood pressure was characterized using those published data from Kumar and colleagues , who relA total of 1172 papers were identified for examination. Forty-seven reports fulfilled the inclusion criteria. The majority of literature concerning phenylephrine and cardiovascular effects related to its use as a hypertensive agent for the management of hypotension associated with shock and spinal anaesthesia. These effects are therapeutic in these scenarios, and as they are not adverse effects, they are not discussed. Case reports and studies that described unexpected or unwanted cardiovascular effects following the use of phenylephrine are listed in Table The standard OTC 10-mg dose of phenylephrine appears to be well tolerated by the majority of people; however, increases in blood pressure and decreases in heart rate are reported with doses over 15 mg , 7. It hUnwanted cardiovascular effects are commonly reported when phenylephrine is administered intravenously for its hypertensive effects and appear to be dose dependent –19. The Cerebrovascular events have also been reported. Tark et al. report the case of an otherwise healthy 50-year-old woman who suffered intracerebral haemorrhage after oral administration of standard doses of cold medicines containing phenylephrine and paracetamol for 4 days before hospitalization . Other sThe pharmacokinetic/pharmacodynamic (PKPD) analysis was based on 49 subjects (with 387 observations) who received phenylephrine ophthalmic eye drops where plasma concentrations were available for analysis. Patients had a mean age 34.3 SD 8.2 years and a mean weight 74.4 SD 3.4 kg. Pharmacokinetic and pharmacodynamic parameter estimates are reported in Table Pharmacodynamic parameter estimates estimated from the phenylephrine ophthalmic study  were comPhenylephrine has now replaced pseudoephedrine in most over-the-counter (OTC) cold and influenza medications. There are few data reporting adverse events associated with oral phenylephrine use. What little information available must be gleaned from other routes of administration where more formal studies have been conducted: phenylephrine interacts with monoamine oxidase inhibitors and possibly other drugs to potentiate its hypertensive effect; cardiovascular changes may be more pronounced in people with underlying cardiovascular disease and may lead to decreased myocardial oxygenation, cardiac arrhythmias, decreased cerebral oxygenation and exaggerated vasoconstriction and stroke.That few adverse events following oral administration of phenylephrine are reported is not surprising, though not necessarily reflective of the actual incidence of adverse effects. Relative oral bioavailability remains poorly documented but may be as little as 0.003 . AbsorptThe simulation study assumes that the administration of phenylephrine with paracetamol more than doubles the bioavailability of phenylephrine and reduces the absorption half-time by 50 % resulting in a doubling of phenylephrine plasma concentration and an approximate fourfold increase in Cmax, with large between-subject variability , 1. Of cAn important consideration is the substantial variability in Cmax : a subgrWhen medications are administered OTC, the burden of safety should be high—with only 40 % of consumers reading the packet label when they take a medicine for the first time and only 7 % reading safety information and warnings , and chaIn 2007, the FDA determined that there was insufficient data to support increasing the dose to the higher 25 mg whilst maintaining a similar safety profile to the 10-mg dose . At the ESM 1(DOCX 26 kb)


Assessment of the association of blood pressure measurements in supine and standing position after a postural change, as a proxy for blood pressure regulation, with standing balance in a clinically relevant cohort of elderly, is of special interest as blood pressure may be important to identify patients at risk of having impaired standing balance in routine geriatric assessment.In a cross-sectional cohort study, 197 community-dwelling elderly referred to a geriatric outpatient clinic of a middle-sized teaching hospital were included. Blood pressure was measured intermittently (n = 197) and continuously  before and after a controlled postural change from supine to standing position. The ability to maintain standing balance was assessed during ten seconds of side-by-side, semi-tandem and tandem stance, with both eyes open and eyes closed. Self-reported impaired standing balance and history of falls were recorded by questionnaires. Logistic regression analyses were used to examine the association between blood pressure and 1) the ability to maintain standing balance; 2) self-reported impaired standing balance; and 3) history of falls, adjusted for age and sex.Blood pressure decrease after postural change, measured continuously, was associated with reduced ability to maintain standing balance in semi-tandem stance with eyes closed and with increased self-reported impaired standing balance and falls. Presence of orthostatic hypotension was associated with reduced ability to maintain standing balance in semi-tandem stance with eyes closed for both intermittent and continuous measurements and with increased self-reported impaired standing balance for continuous measurements.Continuous blood pressure measurements are of additional value to identify patients at risk of having impaired standing balance and may therefore be useful in routine geriatric care. Five to 30 percent and 53 to 78 percent of elderly aged above 65 years suffer from orthostatic hypotension (OH) Few studies investigated the relation between blood pressure regulation and standing balance In clinical practice, comparison of blood pressure measurements before and after a postural change from supine to standing position is used as a proxy for blood pressure regulation. In this study, we assessed the association of both intermittent and continuous blood pressure measurements before and after a postural change with three measures of standing balance: 1) the ability to maintain standing balance, 2) self-reported impaired standing balance and 3) history of falls, in community-dwelling elderly referred to a geriatric outpatient clinic. Results are relevant for design of routine geriatric assessment and therapeutic strategies.This cross-sectional study included 207 community-dwelling elderly who were referred to a geriatric outpatient clinic in a middle-sized teaching hospital  for a comprehensive geriatric assessment (CGA) between March 2011 and January 2012. CGA was performed during a two hour visit including questionnaires and physical and cognitive measurements. All tests were performed by trained nurses or medical staff. The study was reviewed and approved by the institutional review board of the Leiden University Medical Center , Leiden, the Netherlands). The need for individual informed consent was waived, as this research was based on patient care. Ten elderly patients (4.8%) were excluded due to missing data on standing balance, leaving 197 patients for analyses. Continuous blood pressure measurements were added to the CGA in June 2012 and were subsequently available in 62 patients. Data of four patients were excluded because of technical problems, leaving 58 patients for analysis. Of two patients who visited the outpatient clinic twice, data were used from the second visit that included the continuous blood pressure measurements.Blood pressure was measured in supine position and during 3 minutes in standing position after postural change. Patients were in supine position for at least 5 minutes. An automatic lift chair  was used to provide automated support from a supine to a raised position. Subsequently patients were asked to stand up and stand unsupported for 3 minutes.intermittent was defined as a decrease of at least 20 mmHg systolic blood pressure or 10 mmHg diastolic blood pressure at 1 or 3 minutes in standing position compared to supine blood pressure Systolic and diastolic blood pressure measurements were determined intermittently using an automated sphygmomanometer on the left arm . Blood pressure was measured after at least 5 minutes in supine position before postural change and after 1 and 3 minutes in standing position. Three blood pressure measures were determined: 1) supine blood pressure was defined as the blood pressure measured in supine position before postural change; 2) blood pressure decrease was calculated for two time points by subtracting the blood pressure taken at 1 or 3 minutes in standing position from the supine blood pressure; 3) OHcontinuous was defined as a decrease of at least 20 mmHg systolic blood pressure or 10 mmHg diastolic blood pressure after 15 to 180 seconds in standing position compared to supine blood pressure. In addition, initial OH (iOH) was included in the definition of OHcontinuous defined as a decrease of at least 40 mmHg systolic blood pressure or 20 mmHg diastolic blood pressure during the first 15 seconds compared to supine blood pressure At the same time, systolic and diastolic blood pressure measurements were determined continuously and non-invasively using a digital photoplethysmograph with a cuff placed on the right middle finger  The ability to maintain standing balance was assessed in three standing positions characterized by a progressive narrowing of the base of support performed both with eyes open and eyes closed. Patients, wearing non-slip socks, were instructed to maintain balance for 10 seconds in each standing condition. During side-by-side stance, patients were instructed to stand with the medial malleoli as close together as possible; during semi-tandem stance, with the medial side of the heel of one foot touching the big toe of the other foot; and during tandem stance, with both feet in line while the heel of one foot touched the toes of the other. Standing positions with eyes open were first assessed as part of the Short Physical Performance Battery (SPPB) Aforementioned items were part of a larger questionnaire obtaining information on marital status, living arrangements, smoking, alcohol use and use of walking aid. Body mass index was calculated by measuring body weight and height. Information on diseases and use of medication was extracted from medical charts. Multimorbidity was rated as the presence of two or more diseases including chronic obstructive pulmonary disease, heart failure, diabetes mellitus, hypertension, malignancy, myocardial infarction, Parkinson's disease, (osteo)arthritis, transient ischemic attack and stroke. The Hospital Anxiety Depression Scale (HADS) was used to detect depressive symptoms Continuous variables with Gaussian distribution are presented as mean and standard deviation; otherwise as number and percentage or median and interquartile range. The association between blood pressure measures and 1) the ability to maintain standing balance; 2) impaired standing balance; and 3) history of falls were analyzed using logistic regression models including adjustment for demographics, i.e. age and sex. P values less than 0.05 were considered statistically significant. Statistical analyses were performed using SPSS for Windows , version 20. For visualization purposes, tertiles of blood pressure decrease were calculated. Graphs were made with GraphPad Prism 5 .intermittent was present in 29 out of 197 patients (15%). OHcontinuous was present in 33 out of 58 patients (57%); in 19 patients (58%) also initial OH was present and in 5 patients (15%) only iOH was present. In 26 of 33 patients (79%) in which OH was present using continuous measurements, no OH was present using intermittent measurements.Characteristics of patients, including intermittent blood pressure measures, are presented in Ability to maintain standing balance is shown in intermittent, were not associated with the ability to maintain standing balance. Patients with OHintermittent were significantly less likely to be able to maintain balance in semi-tandem stance with eyes closed. All intermittent blood pressure measures were not associated with self-reported impaired standing balance and history of falls as presented in The associations between intermittent blood pressure measures and the ability to maintain standing balance adjusted for age and sex are presented in continuous were significantly less likely to be able to maintain balance in semi-tandem stance with eyes closed. Additional adjustments for BMI, gait speed, MMSE score and handgrip strength did not influence the results.The associations between continuous blood pressure measures and the ability to maintain standing balance adjusted for age and sex are displayed in continuous were significantly more likely to report impaired standing balance, but not to experience falls in the last 12 months. Additional adjustments for BMI, gait speed, MMSE score and handgrip strength did not influence the results.The associations between continuous blood pressure measures and self-reported impaired standing balance and history of falls adjusted for age and sex are displayed in Significant associations between continuously measured blood pressure decrease after postural change and the ability to maintain standing balance in conditions with eyes closed, self-reported impaired standing balance and history of falls were found in community-dwelling elderly referred to a geriatric outpatient clinic. Furthermore, OH determined with continuous measurements was associated with reduced ability to maintain standing balance and with increased self-reported impaired standing balance, but not with falls.This is the first study that investigated the association of blood pressure measures with ability to maintain standing balance and self-reported impaired standing balance in elderly outpatients. In previous studies, no association was found between hypertension and quality of standing balance, measured by CoP movement, in healthy elderly Previous studies investigated the association between blood pressure measures and falls. In this study continuous blood pressure measures did associate with falls, which is conflicting with other studies The association between blood pressure decrease and reduced ability to maintain standing balance may be explained by cerebral hypoperfusion. Cerebral autoregulation modulates cerebral blood flow and cerebral perfusion in order to maintain sufficient oxygenation of the brain regions with fluctuations in blood pressure The association between blood pressure decrease and the ability to maintain standing balance became apparent in standing positions with eyes closed. During this specific standing condition, the nervous system has to compensate for the elimination of visual information by use of sensory reweighting The association between blood pressure decrease and standing balance was detected using objective  as well as subjective measures of standing balance . Comparable results for the ability to maintain balance and falls were found, as impaired standing balance is a risk factor for fallsNo association was observed between supine blood pressure and the ability to maintain standing balance, self-reported impaired standing balance or history of falls. However, previous research showed that hypertension, measured in sitting position, was associated with an increase in brain damage and concurrent impairments in mobility, cognition and mood in elderly with a mean age of 75 years In this study, the largest decrease in blood pressure was found during the first 60 seconds after postural change by use of continuous blood pressure measurements, which is in accordance with previous research Strength of this study was the unique study population of elderly patients. No exclusion criteria were applied. The population is representative for the community-dwelling elderly visiting the geriatric outpatient clinic. Furthermore, the use of continuous blood pressure measurements provided additional information about the blood pressure during the first 60 seconds after postural change and made it possible to include iOH in the analyses. As blood pressure was measured during 3 minutes after postural change, delayed OH, which occurs ten minutes or more after postural change In conclusion, only by using continuous blood pressure measurements as a proxy for blood pressure regulation, associations with the ability to maintain standing balance, self-reported impaired standing balance and history of falls were found. The fact that previous associations could not be detected with intermittent blood pressure measurements, demonstrates the additional value of continuous over intermittent blood pressure measurements in routine geriatric assessment.Table S1Blood pressure measures determined with continuous measurements in subgroup of elderly patients who underwent additional continuous blood pressure measurements (n = 58).(DOC)Click here for additional data file.Table S2Association between blood pressure measures determined with intermittent measurements and reported impaired standing balance and history of falls in all elderly patients (n = 197).(DOC)Click here for additional data file.Table S3Association between blood pressure measures determined with continuous measurements and the ability to maintain standing balance in subgroup of elderly patients who underwent additionally continuous blood pressure measurements (n = 58).(DOC)Click here for additional data file.Database S1Database of 197 elderly referred to a geriatric outpatient clinic consisting of blood pressure data measured intermittently and continuously and standing balance data.(SAV)Click here for additional data file.


Introduction: Dyslipidemia and high blood pressure in diabetic patients increase the risk of microvascular and macrovascular complications.Objectives: This study was conducted to investigate the association between serum lipids and level of blood pressure in type 2 diabetic patients (T2D).Patients and Methods: A prospective analytical study was carried out in 60 patients with T2D of both genders. None of the patients had a history of hypertension, and none was treated with antihypertensive drugs. Resting systolic blood pressures and fifth phase diastolic blood pressures were measured three times while the subjects were seated, and the results were averaged second and third measurements. Sixty patients with T2D were enrolled to the study. None of the patients who had a history of gout, was treated with allopurinol or treated with antihypertensive drugs previously.Results: Of 60 participants, mean of serum creatinine was 0.98±0.22 mg/dL. Mean of systolic and diastolic blood pressure was 133±13 mmHg and 84±7.4 mmHg respectively. In this study, a significant positive correlation of serum cholesterol with systolic  and diastolic blood pressure  was seen. Also the associations of serum LDL-C with systolic and diastolic blood pressure were as follow  and  respectively. Associations of HDL-C with systolic and diastolic blood pressure were not significance as follow -0.05 and 0.04 respectively.Conclusion: The results of this study suggest that serum cholesterol has a strong association with levels of systolic and diastolic blood pressure in T2D patients. More attention to serum lipids and treatment of dyslipidemia could halt the progress of diabetic kidney disease. A study was conducted, to investigate the association between serum lipids level and level of blood pressure in type 2 diabetes. Sixty patients with T2D was enrolled to the study. The results suggest that serum chlesterol and LDL-C have a significant association with levels of systolic and diastolic blood pressure in type 2 diabetes patients. More attention to the serum lipid levels and treatment of dyslipidemia could halt the progress of diabetic kidney disease.Dyslipidemia and high blood pressure in diabetic patients increase the risk of microvascular and macrovascular complications . Also diThe aim of this prospective, observational study was to determine whether baseline serum lipid levels are associated with level of blood pressure in T2D.A prospective analytical study was carried out in 60 patients with T2D of both genders. None of the patients had a history of hypertension and none was treated with antihypertensive drugs. Resting systolic blood pressures and fifth phase diastolic blood pressures were measured three times while the subjects were seated, and the results were averaged second and third measurements . Hyperte1c (HbA1c) (reference range 4–6%). 24 hours urine proteinuria was measured too.Venous blood samples were obtained in the fasting state for determinations of serum creatinine, uric acid and hemoglobin A(1) The research followed the tenets of the Declaration of Helsinki; (2) informed consent was obtained; (3) the research was approved by ethical committee of Shahrekord University of Medical Sciences.t-test was used for comparison of variables between male and female subjects. Spearman’s rho coefficient correlation for evaluating relations among variables. For association of serum lipids with levels of blood pressure the partial correlation test with adjustment for age, duration of diabetes and serum creatinine was used.Results were expressed as mean (SD) and were considered as statistically significant when p<0.05. Independent-student’s 1c and creatinine, between males and females (p>0.05). Similarly, there was no significant difference of proteinuria and levels of systolic or diastolic pressure between males and females (p>0.05). In this study, a significant positive correlation of serum cholesterol with systolic  and diastolic blood pressure  was seen. Also the association of serum LDL-C with systolic and diastolic blood pressure was  and  respectively. Associations of HDL-C with systolic and diastolic blood pressure were not significance (-0.05 and 0.04 respectively), however, there were negative. Statistical analysis regarding the associations of serum cholesterol and LDL-C with systolic and diastolic blood pressure per sex are shown in Of 60 participants, 56.7% were female. Mean of age was 57 (±8.3) years. Mean of diabetes duration was 9.2 (±4.9) years. Mean of serum creatinine was 0.98 (±0.22) mg/dL. Mean of systolic and diastolic blood pressure was 133 (±13) mmHg and 84± (7.4) mmHg respectively. et al. found blood cholesterol and L-DL-C are associated closely with level of blood pressure  have been completely observed by the authors. This paper has been derived from the residential thesis. Also, this study was funded by Shahrekord University of Medical Sciences (grant# 898).


Introduction. Acute kidney injury (PRAKI) continues to be common in developing countries. The aim of this paper is to study AKI characteristics in pregnancy and identify the factors related to the unfavorable evolution. Methods. This prospective study was conducted in the University Hospital Hassan II of Fez, Morocco, from February 01, 2011 to January 31, 2012. All patients presenting PRAKI were included. Results. 37 cases of PRAKI were listed. Their ages varied from 20 to 41 years old, with an average of 29.03 ± 6.3 years and an average parity of 1.83. High blood pressure was the most common symptom (55.6%). Thirty-nine percent were oliguric. PRAKI occurred during the 3rd trimester in 66.6% of the cases and 25% of the cases in the postpartum. Hemodialysis was necessary in 16.2% of cases. The main causes were preeclampsia, hemorrhagic shocks, and functional, respectively, in 66.6%, 25%, and 8.3% of the cases. The outcome was favorable, with a complete renal function recovery for 28 patients. Poor prognosis was related to two factors: age over 38 years and advanced stage of AKI according to RIFLE classification. Conclusion. Prevention of PRAKI requires an improvement of the sanitary infrastructures with the implementation of an obligatory prenatal consultation. Acute kidney injury represents a challenging clinical when it occurs during pregnancy. The worldwide incidence of pregnancy-related acute kidney injury (PRAKI) has decreased markedly in the past 50 years from 20–40% in 1960 to less than 10% in the current series through the legalization of abortion and improvement of antenatal and obstetric care [In the recent years, the incidence of PRAKI has decreased in developed countries to only 1% to 2.8%. It is a rare complication of pregnancy following the disappearance of septic abortion and a better perinatal care . HoweverPRAKI is usually caused by septic abortion in early pregnancy, by pregnancy toxemia, hemorrhages during pregnancy (antepartum and postpartum), and acute tubular necrosis in late pregnancy , 5. AcutAcute tubular necrosis (ATN) is the most common condition with a good prognosis compared to other pathology like severe eclampsia, HELLP syndrome, and disseminated intravascular coagulation (DIC) where the glomerular involvement is preeminent , 7.The aim of this study is to investigate the characteristics of PRAKI and determine the factors associated to unfavorable evolution of kidney injury.This is an observational prospective study conducted in the nephrology department of Hassan II University Hospital , between February 01, 2011 and January 31, 2012.All pregnant and postpartum patients who developed a PRAKI, with or without oliguria were induded. Patients with preexisting renal disease or renal insufficiency before pregnancy were excluded.Population: age, sex, history, and pregnancy care.AKI: clinical, biological, date of occurrence, and etiology.Changes in the final maternal renal function.The final maternal outcome.For this prospective study, data were collected from a questionnaire, validated by an expert committee belonging to the Scientific Committee of the Moroccan society of nephrology. We studied different aspects.Preeclampsia: eclampsia was defined by a set of three signs: hypertension (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg), edema, and proteinuria after 20 weeks of gestation.Eclampsia was defined by the existence of generalized convulsions and/or loss of consciousness occurring during pregnancy or PP in preeclampsia.HELLP syndrome was defined by the existence of three main features: haemolysis, elevated liver enzymes, and low platelets count.Postpartum is the period beginning immediately after delivery and extending approximately three months.Acute kidney injury (AKI) was defined and classed according to RIFLE criteria based on changes in serum creatinine or changes in urine output, or both. The RIFLE  criteria include three levels of renal dysfunction and two clinical outcomes: “loss” and “end-stage renal disease” (ESRD).Evolution: unfavorable evolution means noncomplete renal recovery.Descriptive and univariate analyses have been conducted in collaboration with the epidemiology laboratory from Medicine and Pharmacy faculty of Fez, using the SPSS 11 software. Qualitative variables were expressed as percentages and quantitative variables as median or mean. The level of significance was set at less than 0.05.Total number of women with PRAKI was 37 in Hassan II University Hospital of Fez where 5600 deliveries have been performed in the study's time span. The incidence of PRAKI was near 0.66 percent. The patient's age ranged from 18 to 40 years with an average of 29.03 ± 6.3 years . The meaThe stage of AKI according to RIFLE criteria was as follows: risk in 40%; injury in 27%; and failure in 33% of cases. The average creatinine was 34.8 ± 25.4 mg/L (8 to 105), proteinuria average 1.68 ± 1.53 (0–7 g/d) with nephrotic syndrome in 45.9% of cases, and nonnephrotic in 43.2%. Anemia was reported in 67.5% of patients, a thrombocytopenia in 56%, and hepatic cytolysis in 67% of patients.Pregnancy toxemia is the most common cause of PRAKI (66.6%), followed by pregnancy hemorrhages (25%) and functional kidney injury (8.3%).The evolution of our patients was marked by the use of vascular filling in 32.43%, vasoactive drugs in 5.4%, and transfusion in 42.9% of cases. Antihypertensive treatment by syringe pump was administered in 51.4% of cases and seven patients (18.9%) received diazepam. Five patients, 13.9%, presented a nosocomial infection. One of them died from respiratory infection.Dialysis was required during hospitalization in 16.2%. Complete recovery of renal function was observed in 76% (28 patients) and partial recovery in 16.2% (6 patients). Two patients remained dependent on dialysis.The univariate analysis assigned factors associated to unfavorable evolution of PRAKI which were older age, elevated creatinine level at admission, and RIFLE stage of acute kidney injury. The etiology of acute kidney injury was not associated to unfavorable evolution .Acute kidney injury (AKI) occurring during pregnancy is a serious complication, involving the prognosis of the mother and the child . Its speThe PRAKI has become a rare complication of pregnancy in developed countries. For example, in France, the incidence of AKI in pregnancy has decreased from 40% in 1966 to 4.5% in 1978. This striking decline reflects the decrease of postabortion ARF and the better perinatal monitoring , 21.P = 0.01). In the literature, this factor was associated to increase perinatal complications, including premature delivery [The average age of onset for PRAKI is between 25 and 32 years according to various authors . In our delivery , 9, 22.In our series, PRAKI was more frequent in the 3rd trimester (61%) and 22% in the postpartum. Similar results have been reported in Pakistan, where the majority of PRAKI occurred in the 3rd trimester (86%). Whereas in India, the PRAKI occurred during the postpartum in 75.6% of cases , 16.The mean serum creatinine was 34.8 mg/L ± 25.4 with a maximum value of 105 mg/L and a minimum value of 14 mg/L. These results are comparable to those published by Randeree et al. , but sigP < 0.02).In this study, the RIFLE stage in AKI is the related to unfavorable evolution , with eclampsia in five cases (13.5%), and HELLP syndrome in 21 cases (58.3%). HELLP syndrome was described by Weinstein  in 1982,The PE as a cause of AKI varies depending on the series from 12% in Pakistan  to 75.2%Septic abortions were the principal infectious cause of acute renal failure and a major public health problem in developing countries. However, there was no septic abortion in our series.The obstetric hemorrhage was a significant cause of PRAKI. It was observed in 28% in Pakistan and 5% of cases in India .Total recovery was obtained in 76% of the cases, which is similar to the results found in some other studies. Arora et al. , GoplaniCurrently, maternal mortality due to PRAKI represents less than 10% in Europe and North America but remains high in the developing countries . Recent PRAKI remains a critical situation in developing countries where preeclampsia is the most frequent etiology, followed by sepsis and hemorrhagic shock. Advanced age and the RIFLE stage of AKI are associated with unfavorable evolution.In this context, prevention is the best and least expensive solution. Preventing abortions, assuring a good perinatal care and a better management of obstetrical complications, are the crucial tools to implement this purpose.


KIT may influence GIST patient outcome is unclear.Tumor genotype plays a crucial role in clinical management of GIST. Whether genetic polymorphism of KIT exon 10 variant (c.1621 A > C), KITL541, in a transfected cell line (3 T3 L541) and in two retrospectively collected series of 109 GIST patients in total. The control group consisted of 60 healthy donors collected at the French department of blood transfusion.We investigated the biological and clinical significance of the presence of L541 protein exhibited a spontaneous phosphorylation status comparable to that of wild-type KIT but displayed a phosphorylation pattern of AKT and ERK1/2 that was found similar to that of the classical mutated forms of the KIT receptor. Of 109 patients enrolled in this retrospective translational research study, 24 (22 %) harboured KITL541, similarly to the control group of healthy donors . A higher prevalence of the variant KITL541 was observed in patients with metastatic status at diagnosis . In addition, patients with KITL541 and localized GIST had a higher rate of relapse at 5 years and lower relapse free survival at 5 years in univariate, as well as in multivariate analysis. Response rate and duration of response to imatinib was similar in KITL541 and KITM541 patients.In the 3 T3 L541 cell line, KITKITL541 genotype is associated with a higher risk of metastasis at diagnosis and a higher risk of relapse in GIST patients.The online version of this article (doi:10.1186/s12885-015-1817-5) contains supplementary material, which is available to authorized users. KIT (75-80 %) and PDGFRA (5–10 %), which encode for mutated proteins with ligand independent constitutive activation of tyrosine kinase receptor. There are a variety of KIT and PDGFRA mutations, on different portions of the receptors. These different mutations are associated with different risk of relapse after resection of the primary tumor but also impact on the activity of imatinib (selective inhibitor of KIT and PDGFR-α) [GIST  are the most common mesenchymal tumors of gastro-intestinal tract and account for 15 to 20 % of soft tissue sarcomas and 1 to 3 % of all malignant digestive tumors [PDGFR-α) –6.Tumor genotype plays a crucial role in clinical management of GIST and should now be recommended as a standard procedure when possible, according to ESMO guidelines . Beyond KIT exon ten, encoding for the substitution of a methionine in position 541 by a leucine (KITL541) in the mature KIT protein, has already been reported to be associated with several diseases, including aggressive fibromatosis (AF) [A SNP of sis (AF) –15, chrosis (AF) , pediatrsis (AF)  and moresis (AF) . The potL541 signalling in transfected cell lines and then exploring the prevalence and prognostic value of KITL541 in GIST patients, investigating 2 distinct series of patients.In the present work, the clinical and biological significance of the presence of the variant protein in GIST was investigated using two approaches: first exploring KITKIT cDNA either 1) wild-type (WT) with M541, 2) encoding for canonical GIST mutations (del557-558 = D6 or del564-581 = D54), 3) encoding for both WT KIT and canonical mutations (WT/D6 or WT/D54), 4) encoding for homozygous polymorphic KIT (1621 A > C = L541), or 5) with the empty vector (MIGR) [Murine fibroblast cell lines (NIH3T3) were stably infected with oncoviral vectors containing the full-length human r (MIGR) . The star (MIGR) .KIT, so that both the expression and the activation state of WT and mutant forms of KIT were equivalent. Treated cells medium was supplemented with 1 μM of Imatinib (Novartis) 24 h before lysis.Cells were cultured at 37 °C humidified atmosphere containing 5 % CO2 in DMEM with 10 % newborn calf serum (Life Technologies), 2 % penicillin/streptomycin, 1 mM L-Glu. For transfected cells, medium was supplemented with 1/1000 G418 (Invitrogen) to maintain a selective pressure for vectors’ expression. Fifty ng/mL of Chinese hamster ovary–mouse rhSCF  were added for cells expressing WT Cells were lysed in Petri plate using RIPA buffer  plus protein inhibitors 30 min at 4 °C. Proteins were quantified using a Dc protein assay kit (Biorad®). Migration was performed using gradient gel  in NuPAGE® MES SDS running buffer (Invitrogen®). After electrophoretic separation, proteins were electrotransferred on a polyvinylidene difluoride membrane (Millipore®). The membrane was then blocked for 1 h at room temperature with ECL™ Advance Blocking Agent 0.2 %  in TBS/Tween 0.1 % and primary antibody incubated for one night at 4 °C. The membrane was washed three times in TBST 0.1 %, and secondary antibodies were incubated for 1 h at room temperature. Antibodies characteristics are presented in Additional file This study was performed as a retrospective translational research program on tumor and blood samples of 109 GIST patients. The first series included 87 resected primary GIST untreated until recurrence and the second series included 22 metastatic or locally advanced/unresectable at diagnosis GIST. A control group consisted of 60 blood samples from healthy donors collected at the French department of blood transfusion.44 included in “EMS” project  from Feb35 patients “off-protocol” treated in Centre Léon Bérard from May 2004 to June 201219 patients included in “BFR14” trial  from JunParaffin-embedded tissues samples of 98 GIST, at initial diagnosis, obtained by biopsy or surgical excision to establish the diagnosis of the diseaseDry pellets of peripheral blood mononuclear cells (PBMC) frozen of 11 patients included in “BFR14” trial.All samples of the 109 patients were obtained from pathology department:All patients signed informed consent to participate to research according to the French laws. Of note, for patients included in the BFR14 study, the protocol and its connected informed consent form (ICF) were reviewed and validated by a national ethics committee (CPP Sud-Est IV); for the others patients, an Institutional Review Board  reviewed and agreed with the study protocol and the ICF.QIAmp DNA FFPE Kit, QIAamp RNeasy FFPE Kit and Universal Kit  according to the manufacturer’s instructions, and quantified by spectrophotometry . After several washing with toluene and ethanol, FFPE tumors were lysed using ATL buffer and proteinase K and incubating at 56 °C for 24–48 h and 90 °C 1 h. DNA and RNA extraction was carried out using QIampMiniElute Spin Column and RNeasy MiniElute Spin Column.Total DNA and RNA was extracted from tumors and PBMCs, using AllPrep DNA spin column and Rneasy Mini spin column.PBMCs were lysed using RLT buffer and proteinase K. DNA and RNA extraction was carried out using KIT exon 10. The primers used were designed by Primer Express and generated by Beckman Coulter Genomics: 5’-GTA-ATC-GTA-GCT-GGC-ATG-ATG-TG-3’ (sense) and 3’-AAC-CAT-TTA-TTT-GTT-CTC-TCT-CCA-GAG-5’ (antisense). PCR was carried out using Taq DNA polymerase  with the following cycle conditions: denaturation at 95 °C, followed by 10 cycles at decreasing temperatures between 66 and 61 °C with a decrement of 0.5 °C per cycle, and additional extension at 72 °C. The primers used for sequencing were the same as those used for amplification. Before sequencing, PCR products were purified using Centriprep centrifugal filter device . The purified PCR product was then subjected to automated sequencing performed by Beckman Coulter Genomics. Results of that double detection of the SNP, by sequencing and CAST®-PCR, were always consistent.The detection of the SNP was performed by Competitive Allele-Specific Taqman® PCR technology provided by Applied Biosystems®, using the method extensively described by Dufresne et al. . We bothKITL541 prevalence in GIST and in the normal donor series.Compare Study the distribution of known prognostic factors  according to the presence of the SNP.KITL541 and clinical and biological characteristics of GIST .Investigate the possible correlation between Statistics were performed using SPSS statistical software . Chi-2 test, Fisher’s exact test and multivariate analysis (logistic regression and Cox model) were performed in order to:KITL541 variant were plotted using the after Kaplan-Meier method and compared by log-rank test.Relapse free survival (RFS) and overall survival (OS) of patients harboring or not KITL541) displayed the same expression and phosphorylation pattern as WT cell line upon SCF stimulation. D6 and D54 transfected mutants showed an increased spontaneous phosphorylation status on both residues. The immature 125-kDa form was also phosphorylated on both tyrosines but not in cell lines with WT or L541. In cells transfected with WT and D6 or D54 mutated KIT, phosphorylation status of both Y-703 and Y-823 was found increased, in line with reported KIT activation status in tumors exhibiting homo/heterozygous mutations of the receptor [KIT function and phosphorylation status was investigated using western blotting analyses Fig. . No basareceptor . OverallKIT signaling pathways and the phosphorylation status of AKT (PI3K-AKT pathway), RAF, ERK1 and ERK2 (MAPK pathway) was assessed in these cell lines.L541 cell line was found to activate AKT at a similar level than the D6 and D54 mutants. After imatinib exposure, P-AKT increased in MIGR cell line, remained stable in WT and D54 cell lines, and decreased in D6 and in L541 cells.RAF phosphorylation was similar in WT, D6 and D54 cell lines and was not affected by imatinib exposure. In contrast, the downstream ERK proteins were found to display phosphorylation, varied according to KIT mutation status: high levels of spontaneous phosphorylation are detectable in MIGR control, D54, D54/WT and in L541 cell lines, in particular ERK2 (42 kDa). Lower levels are observed in D6 cell lines cells whereas it is undetectable in WT cell lines. Exposure to imatinib was found to increase ERK phosphorylation in WT, D6, D54 and WT/D6 cell lines but not in WT/D54 and L541 cell lines.KITL541 and clinical presentation and prognostic in GIST patients was then investigated.The association between the presence of the variant This retrospective case–control study was conducted on two different series: 87 resected primaries GIST untreated until recurrence and 22 metastatic at diagnosis  GIST. The characteristics of the two series of GIST are presented in Table n = 52, 60 %) and a majority of KIT exon 11 mutation . With a median follow-up of 68 months, there were 17 (20 %) local or metastatic relapse at 5 years: 7 of 12 (59 %) KIT exon 11 mutated, 1 of 12 (8 %) KIT exon nine mutated, 1 of 12 (8 %) KIT exon 13 mutated, 2 of 12 (17 %) with mutations in PDGFRA , 1 of 12 (8 %) WT and five with an undetermined mutational status.Within the first series, clinical and biological characteristics are similar to those described in literature, with a median age at diagnosis at 65 years old (range = 22–84), a sex ratio about 1 (42/45), a majority of gastric location .As expected, tumor’s parameters of the second series  were worse according to Miettinen classification: higher median size , higher mitotic rate and more small bowel location  and the median age was 45 years old (range 19–63).KITL541, similarly to the control group of healthy donors . The variant was always detected in both GIST tumor cells and dry pellets PBMC when both types of samples were available (n = 15), confirming that it is not a mutation but a somatic genetic variant. Distribution of the clinical and biological characteristics of GIST harboring or not KITL541 are detailed in Table KIT and PDGFRA mutations. Importantly, prevalence of KITL541 was statistically higher in this series of GIST patients metastatic at diagnosis vs non-metastatic patients at diagnosis .Of all 109 patients, 24 (22 %) harboured KITL541 (17 %). KITL541 was significantly correlated to a higher rate of local or metastatic relapse at 5 years , resulting in a lower relapse free survival (RFS) .In the first series of 87 non-metastatic patients, 15 had a KITL541 status, tumor size, location, mitotic index and mutation status) using Cox model, KITL541 was independently and directly associated to a lower RFS at 5 years (p = 0.004), together with tumor size  and mitotic rate  . In the subgroup of WT and PDGFRA mutated GIST, KITL541 was associated to a lower RFS at 5 years . In the subgroup of KIT mutated GIST, RFS of the 2 groups was not different although a trend was observed .Overall survival of the 2 groups was not significantly different . Pooling this series of patients with all 24 relapsing patients from group 1 (17 relapses at 5 years and seven beyond 5 years) yield a group of 46 patients. In this pooled series as well, PFS and OS at 5 years of the metastatic patients receiving imatinib and harbouring or not KITL541 were also not significantly different  indicating that KITL541 is a prognostic factor for relapse but not a predictive factor for response to imatinib.In the second series of 22 metastatic GIST at diagnosis, PFS and OS at 5 years of the patients harbouring or not KITL541 in GIST patients, its potential role in carcinogenesis and the potential predictive value of this variant for GIST patients outcome.In this work, we investigated the biological and clinical significance of the SNP L541 was found to exhibit a similar maturation and activation pattern than WT KIT but induced a mutant-like intracellular signalling in the presence of SCF. The role of the transmembrane domain in tyrosine kinase receptors dimerization and signalling is well known and mutations in this region can result in constitutive activation [in vitro experiments of this study suggest that cells expressing KITL541 may have a proliferative and survival advantage. The substitution of a methionine into a leucine in position 541, at the end of the transmembrane domain, seems to increase the ability of the receptor to activate PI3K/AKT and MAPK signalling pathways as compared with WT KIT.Using transfected cell lines, KITtivation , 23. TheKITL541 was both detected in tumors and PBMCs DNA; it is a constitutional SNP variant unlike activating mutations of KIT and PDGFRA. We reported in this study a similar prevalence of KITL541 in healthy donors and GIST patients. This SNP is not associated with specific activating mutations of KIT or PDGFRA and the proportion of KITL541 does not differ between WT GIST and other. These results suggest that KITL541 is not per se a risk factor for GIST development. However, KITL541 was found associated with a higher risk of tumor progression and dissemination. In the first series of GIST patients, KITL541 was associated with a higher risk of relapse, resulting in a lower relapse-free survival at 5 years. Importantly, this impact of KITL541 was conserved in multivariate analysis using Cox model. Moreover, KITL541 prevalence was higher in patients presenting with metastatic GIST at diagnosis. These results suggest that this variant is a prognostic factor for relapse and progression.The prevalence of this variant was investigated in two series of GIST patients and in a control group. KITL541 was not found to be a predictive biomarker for the efficacy of imatinib in advanced phase. However, it must be noted that the power of the study remained limited by the small size of the cohort treated by imatinib, as well as subgroup analysis in subgroup of WT and PDGFRA mutated GIST (6 cases) could not be performed.Conversely, KIT have been described to play an important role in cancer. Rare SNP on KIT exon 10 (A533D and F522C) are identified in systemic aggressive mastocytosis [KIT (KITL541) has previously been described in CML, AF, systemic mastocytosis and Merkel cell carcinoma. Inokuchi and al. [in vitro experiments on KITL541 Ba/F3 cells, showing that tyrosine kinase activation and proliferative response of KITL541 cells were slightly higher than WT KIT in medium containing 0.1 ng/ml SCF. Moreover, in a cohort of 80 patients with CML, KITL541 was associated to a statistically lower median overall survival [KITL541 showed an enhanced proliferative response to low levels of stem cell factor (SCF) (≤6.25 ng/ml). Grabellus et al. [KITL541 in aggressive fibromatosis did not differ from the general population, suggesting that this variant was not involved in carcinogenesis of these tumors. In 2006, Gonçalves et al. [KITL541. Conversely, Dufresne et al. [KITL541 for response to imatinib for patients with AF. Currently, the significance of the KITL541 variant in AF remains unclear. More recently, Iurlo et al. [KITL541 in chronic eosinophilic leukemia could be a predictive factor of imatinib sensitivity.Sequence variations (SNP) of ocytosis  and lead and al.  performesurvival . In vitrsurvival  demonstr(SCF) ≤6. ng/ml. Gs et al.  publishee et al.  did not o et al.  suggest KIT exon 11 codons 557–8). Besides, a few germline genetic variants of receptor tyrosine kinase  were previously found to be associated with clinical outcome [KITL541 belongs to this novel class of predictor of the risk of relapse in patients with GIST. Its detection could be useful for clinical management of GIST patients. However, the way to use those additional prognostic markers in routine remains unclear and further investigations are necessary.Currently, GIST recurrence potential after complete surgery resection is measured using a set of predictive parameters: tumor size, mitotic rate, organ site, tumor rupture and nature of the driver mutation. These biomarkers still remain imperfect to identify accurately patients who will relapse and may be candidate to adjuvant imatinib treatment. Additional factors such as germline genetic variations and epigenetic phenomena  were found to be associated with GIST patient outcome , 8–12. O outcome –12, sugg outcome  suggest KITL541 was not found associated with increased risk of development of GIST but represents a predictive factor for relapse in localized GIST. Conversely, KITL541 is not a predictive factor for response to imatinib in patients with GIST.In conclusion, the variant


The lack of control of diabetes and hypertension contributes to the high rates of morbidity and mortality from cardiovascular disease. Better blood pressure control can effectively reduce such outcomes and reduce micro and macrovascular complications in patients with these comorbidities.To analyze the control of hypertension in a follow-up cohort of ten yrs. and compare the blood pressure control rates among hypertensive patients with and without diabetes. Materials and Methods: a cross-sectional study of historical cohort of hypertensive/diabetic (GDM) and nondiabetic (GHAS) in regular treatment for at least 10 yrs. in special service for compliance with hypertension. Initial assessment of the cohort in 2004; used variables: gender, race, age, physical inactivity, alcohol consumption, smoking, amount of drugs, levels and control blood pressure, weight and height. For the control of blood pressure among nondiabetic hypertensive patients were considered values <140/90 mmHg and for hypertensive diabetic values <130/80mmHg. Association analysis of variables with chi-square test and means were compared with Student's t-test, with 5% significance. Project approved by the ethics committee.The study included 126 patients , with average length of treatment in 2004 of 6.8 yrs. Females were predominated in both groups  and also white race (62.5%). The average age of the cohort was 57.7 yrs. . The overall mean BMI was 28.9 kg/m2; for GDM average was 30.8 kg/m2 (29.6 to 32.2 95% CI) and the GHAS 26.4 kg/m2 (25.4 to 27.5 95% CI) p <0.001. The overall mean systolic blood pressure was 134.6 mm Hg (95% CI 131.1 to 140.2), and diastolic pressure was 84,1mmHg ; no significant difference between groups. The pressure control was unsatisfactory for 68.9% of hypertensive patients with diabetes and hypertension 31.1% without diabetes (p <0.001). The numbers of antihypertensive drugs prescribed was similar between groups; there was no association between the amount of medication and blood pressure control.The presence of diabetes as comorbidity reflected in worse hypertension control rates, even with amount of antihypertensive medication similar. Diabetic hypertensive patients should receive more effective control actions in order to reduce cardiovascular outcomes because their blood pressure goals are stricter.


Given reports on the increased prevalence of thromboembolic incidents in patients with eosinophilic granulomatosis with polyangiitis , we investigated whether fibrin clot properties are unfavorably altered in EGPA.Ex vivo plasma fibrin clot characteristics, including clot permeability, turbidimetry and efficiency of fibrinolysis using two assays, were investigated in 34 consecutive patients with remission in EGPA according to the Birmingham Vasculitis Activity Score version 3 , aged 48  years. The control group comprised 34 age- and sex- matched volunteers.s, 7.30±0.93 vs 10.14±1.07 10−9 cm2), faster fibrin polymerization , thicker fibrin fibers , higher maximum levels of D-dimer released from clots (DDmax 4.10±0.46 vs 3.54±0.35 mg/L), and prolonged clot lysis time ; all p<0.0001. Scanning electron microscopy images confirmed denser plasma fibrin networks composed of thinner fibers formed in EGPA. Antineutrophil cytoplasmic antibody status and C-reactive protein did not affect clot variables. Multivariate analysis adjusted for fibrinogen showed that Ks was predicted by eosinophil count, peak thrombin generation, factor VIII, and soluble CD40 ligand, whereas eosinophil count, peak thrombin generation and antiplasmin predicted t50%.Compared with controls, patients with EGPA were characterized by denser fiber clots (estimated pore size, KThis study is the first to show that EGPA is associated with prothrombotic plasma fibrin clot phenotype, which may contribute to thromboembolic manifestations reported in this disease. Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare disease characterized by necrotising vasculitis involving small and medium blood vessels accompanied by eosinophilia in the peripheral blood, eosinophilic infiltration of the tissues and the presence of bronchial asthma [l asthma , 2. Throl asthma . Patientl asthma . Severall asthma . Of partl asthma . Moreovel asthma . It has l asthma . It has l asthma , howeverl asthma .The final step of blood coagulation is the formation of fibrin clots. Fibrin clots composed of tightly packed fibers displaying resistance to lysis , 12 haveGiven common thrombotic manifestations and enhanced inflammation in EGPA we tested the hypothesis that EGPA is another rheumatic disease in which abnormal structure and function of a fibrin network can be observed. The aim of our study was to investigate plasma fibrin clot properties and their determinants in EGPA patients.We enrolled 34 consecutive white patients with EGPA in remission of the disease. The control group comprised 34 age- and sex-matched healthy volunteers recruited from hospital personnel and acquaintances. The Bioethics Committee of the Jagiellonian University approved the study protocol and informed written consent was obtained from the participants in accordance with the Declaration of Helsinki. The patients were enrolled in the study if they met the following criteria: the EGPA diagnosed according to the American College of Rheumatology (ACR) classification criteria (1990), age over 18 years, and clinically stable disease according to the Birmingham Vasculitis Activity Score version 3 (BVAS v.3) , 21. TheWe collected clinical data based on the EGPA, BVAS v.3, Vasculitis Damage Index (VDI), Five-Factor Score (FFS), and the Asthma Control Test (ACT), which correlates with asthma control according to the Global Initiative for Asthma (GINA) guidelines .After an overnight fast blood was collected to determine blood cell count, glucose, creatinine using routine laboratory assays. Plasma fibrinogen was measured by the Clauss method and C-reactive protein (CRP) by nephelometry . Eosinophil count was determined manually with a Bürker’s chamber. Serum ECP was measured using a fluoroimmunoassay , with a detection limit of 2 μg/L. Antineutrophil cytoplasmic antibodies (ANCA) were measured using an immunofluorescence . The further identification of anti-proteinase (PR) 3 and anti-myeloperoxidase (MPO) antibodies was performed by the immunoenzymatic assays .® Plasma TAFI Activity Kit . Plasma platelet activation markers, soluble CD40 ligand (sCD40L) and soluble P-selectin, were assessed by ELISAs . Factor (F)VIII activity was measured using a coagulometric assay with FVIII deficient plasma .Commercially available immunoenzymatic assays were used to determine plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigens . Plasma α2-antiplasmin (α2AP) and plasminogen were measured by chromogenic assays . Measurement of thrombin activatable fibrinolysis inhibitor (TAFI) antigen was performed with an ELISA . Plasma TAFI activity was measured by a chromogenic assay using the ACTICHROME2, 60 mg/mL bovine albumin, and 2.5 mmol/L Z-Gly-Gly-Arg-amidomethylcoumarin). We assessed the peak thrombin level. Plasma samples were analyzed in duplicate, and the intraassay variability was 6%.Plasma thrombogenic potential was assessed using calibrated automated thrombography (CAT)  in a 96-well plate fluorometer  at 37°C according to the manufacturer’s instructions. Eighty microliters of platelet poor plasma were diluted with 20 μL of a commercially available TF-based activator  containing 5 pmol/L recombinant TF, 4 micromolar phosphatidylserine/phosphatidylcholine/phosphatidylethanolamine vesicles, and 20 μL of FluCa solution  and centrifuged within 30 min at 2500 g for 10 min. Plasma was frozen at -80°C until analysis. Technicians unaware of the sample status performed the tests. Intra- and interassay coefficients of variation ranged from 5% to 8% for the fibrin variables listed below.s), which indicates the pore size, was calculated from the equation: Ks = Q x L η/t A x Δp, where Q is flow rate in time t, L is the length of fibrin gel (13 mm), ŋ is the viscosity of liquid (1/100 poise), A is the cross section area (0.049 cm2), Δp is differential pressure in dyne/cm2, and t is percolating time.Fibrin clot permeation was assessed as described , 23. PlaFor turbidity measurements, plasma samples were diluted 2:3 with a Tris buffer and addition of 1 U/mL human thrombin  and 15 mmol/L calcium chloride to plasma initiated polymerization [rate) and maximum D-dimer (DDmax) concentrations detected at 80 or 100 min were analyzed.Plasmin-mediated fibrinolysis was evaluated using two assays as described . In assa50%) was a marker of the clot susceptibility to fibrinolysis.In assay 2, 100 μL of citrated plasma were diluted with 100 μL of a Tris buffer, containing 20 mmol/L calcium chloride, 1 U/mL human thrombin , and 1 μg/mL rtPA. Assembly kinetics was monitored by spectrophotometry at 405 nm. The time required for a 50% decrease in clot turbidity  solution for 2 hours. Fixed clots were removed, washed and then dehydrated in graded water-ethanol solutions, dried by the critical point procedure and sputter coated with gold. Samples were scanned in 6 different areas (microscope HITACHI S-4700). Quantitative fibrin network analysis was performed using the Image J software . Fiber thickness was measured via generating 100 x/y coordinates at random and then calculating a fiber diameter at or nearest to each of the 100 coordinates only if fiber margins were clearly defined.®, Version 9.0.0. SAS Institute Inc., Cary, NC, 1989–2007.The study was powered to have a 90% chance of detecting a 10% difference in clot lysis time using a p-value of 0.05, based on the values in the published article . In ordeA total of 34 patients with EGPA were included in the final analysis. The median disease duration was 3 years . The median duration of asthma was 6 years (3 to 12 years). The median BVAS v.3 score was 2. ANCA were present in 11 (32%) patients, including perinuclear antineutrophil cytoplasmic antibodies (pANCA) in 6 (17.6%) and cytoplasmic antineutrophil cytoplasmic antibodies (cANCA) in 5 (14.7%) individuals. Three (8.8%) patients experienced VTE in the past.Thirty-two EGPA patients (94%) were treated with oral glucocorticoids, predominantly methylprednisolone at a median daily dose of 8 mg (range from 4 to 32 mg). Eighteen patients (53%) also received one of the 3 immunosuppressive drugs, i.e. cyclophosphamide , methotrexate , or azathioprine . Low dose aspirin was taken in 5 (14.7%) subjects.Regarding clinical manifestations of EGPA, skin involvement mostly in the form of elevated purpura was observed in 27 (79%) subjects. The upper respiratory tract was involved in all patients, and pulmonary infiltrates were present in 32 patients (94%). Seventeen patients (50%) reported gastrointestinal symptoms. Seventeen patients (50%) had cardiovascular manifestations. The kidneys and nervous system were involved in 8 (23.5%) and 20 patients (58.8%), respectively.The patients in remission and controls had comparable eosinophil counts , howeverAs shown in Peak thrombin generation was 19.3% higher in EGPA patients (p<0.001) with a positive association with eosinophil count  and ECP , but not with the ANCA presence. Plasma P-selectin was 26.5% higher in the patients (p<0.0001) with no association with eosinophil counts. Another platelet marker, sCD40L was similar in both groups .s indicating more compact fibrin network formation was found in the EGPA patients compared with the control group  and ECP . Moreover, there were associations of Ks with FVIII (r = -0.35), peak thrombin (r = -0.45), and sCD40L  in patients with EGPA. Using multiple linear regression analysis for Ks (adjusted for fibrinogen) we observed that eosinophil count, peak thrombin generation, FVIII and sCD40L were independent predictors of this variable . The same held true for various clinical manifestations of EGPA.s, 7.73±0.90 vs 6.83±0.72 10−9 cm2, p = 0.003), faster lysis time , lower clot mass  and higher rate of lysis  compared with the remaining patients . However, fibrinogen  was lower in the former patients, with no differences in eosinophil count, thrombin generation and other laboratory variables.Fibrin clots formed in patients who received immunosuppressive drugs  were characterized by thinner fibrin fibers , slower clot formation , increased permeability (KRepresentative SEM images of patients with EGPA and controls are presented in This is the first study to show that fibrin clot structure and function are unfavorably altered in EGPA patients. We demonstrated that EGPA in clinical remission is associated with faster formation of significantly less permeable and poorly lysable fibrin clots, similarly to other diseases leading to thrombotic complications , 12. We Mechanisms underlying prothrombotic fibrin clot phenotype in EGPA are unclear and involve two major contributors, i.e. eosinophils and thrombin formation potential. To our knowledge, our study is the first to demonstrate that increased absolute eosinophil count is associated with decreased clot permeability and prolonged lysis time. Xu and Hakansson showed that stimulated eosinophils incubated with fibrinogen released large amounts of ECP, which indicates that adhesion to fibrinogen and fibrin may play a role in eosinophil degranulation and release of ECP . We alsoThrombin generation potential, assessed using the CAT method, is known as a useful reproducible measure of the kinetics of thrombin generation in patients at risk of thrombotic disorders . Of partLess effective fibrin clot dissolution in a global lysis test is a novel finding in EGPA. We used two different assays to assess capacity of fibrinolysis induced by different final rtPA concentrations like in our previous studies , 17. We Previous studies demonstrated that plasma fibrinogen is a major modulator of a fibrin network. In our study, fibrinogen was higher in patients with EGPA, which is consistent with the inflammatory nature of this disease , 2. DespWe found no correlation between fibrin clot variables and organ involvement or scores obtained in both FFS and VDI in EGPA patients. All EGPA patients were in remission according to the BVAS v.3. Since we showed unfavorably altered plasma fibrin clot properties in our patient group, it is likely that the unfavorable fibrin clots alterations persist in EGPA also in remission. Based on the current evidence we may suspect that the relapse will lead to more pronounced abnormalities in clot structure.Improved clot properties including greater permeability and accelerated clot lysis observed among EGPA patients on immunosuppressive drugs, including cyclophosphamide, methotrexate, and azathioprine, deserve a comment. This observation appears to be largely associated with lower fibrinogen in these patients, which is a major modulator of fibrin phenotype ,12. ContOur study has several limitations. Firstly, the number of study participants was limited since EGPA is a rare disease , 36. HowIn conclusion, we have shown that EGPA patients in remission have less porous plasma fibrin clots displaying reduced susceptibility to t-PA mediated lysis. Our study suggests a novel prothrombotic mechanism observed in patients with EGPA and highlights a potential role of eosinophils in the regulation of fibrin formation and degradation. A contribution of abnormal fibrin structure to an increased risk of thromboembolic events in EGPA is worth investigating.


Chronic kidney disease is strongly linked to neurocognitive deficits in adults and children, but the pathophysiologic processes leading to these deficits remain poorly understood. The NiCK study  seeks to address critical gaps in our understanding of the biological basis for neurologic abnormalities in chronic kidney disease. In this report, we describe the objectives, design, and methods of the NiCK study.The NiCK Study is a cross-sectional cohort study in which neurocognitive and neuroimaging phenotyping is performed in children and young adults, aged 8 to 25 years, with chronic kidney disease compared to healthy controls. Assessments include (1) comprehensive neurocognitive testing ; (2) detailed clinical phenotyping; and (3) multimodal magnetic resonance imaging (MRI) to assess brain structure , functional connectivity , and blood flow . Primary analyses will examine group differences in neurocognitive testing and neuroimaging between subjects with chronic kidney disease and healthy controls. Mechanisms responsible for neurocognitive dysfunction resulting from kidney disease will be explored by examining associations between neurocognitive testing and regional changes in brain structure, functional connectivity, or blood flow. In addition, the neurologic impact of kidney disease comorbidities such as anemia and hypertension will be explored. We highlight aspects of our analytical approach that illustrate the challenges and opportunities posed by data of this scope.The NiCK study provides a unique opportunity to address key questions about the biological basis of neurocognitive deficits in chronic kidney disease. Understanding these mechanisms could have great public health impact by guiding screening strategies, delivery of health information, and targeted treatment strategies for chronic kidney disease and its related comorbidities. Chronic kidney disease (CKD) is strongly linked to neurocognitive dysfunction in adults and children -4, but tAlthough these studies have increased awareness of neuroanatomical abnormalities in CKD, a key question remains: What are the specific physiologic disturbances in CKD that lead to neurocognitive changes? Potential mechanisms include metabolic neuronal injury  and, perThe Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults with Chronic Kidney Disease (NiCK) Study was designed to address this critical gap in our understanding of the biological basis for neurologic abnormalities in CKD. With funding from the Pennsylvania Department of Health, this study uses a comprehensive interdisciplinary approach and leverages unique resources at the Children’s Hospital of Philadelphia and the University of Pennsylvania to combine comprehensive neurocognitive assessments and state-of-the-art multimodal magnetic resonance imaging (MRI) in children and young adults with CKD.In this report, we describe the objectives, design, and methods of the NiCK study, and outline how the study provides the opportunity to address key questions in the field. We will then describe our approach to data analysis, focusing on the challenges and opportunities posed by the multitude of variables inherent in clinical, neurocognitive, and neuroimaging data of this scope. Finally, we will outline future directions for this rich dataset, including the potential for novel unbiased scientific discovery, and discuss the potential public health impact of this study.a comprehensive battery of traditional neurocognitive testing, anda computerized neurocognitive batteryDetailed neurocognitive description of children and young adults with CKD, along with concurrent age-matched healthy controls, using:Detailed clinical description to explore the impact of clinical risk factors such as hypertension and anemia; andStructural MRI to explore the effects of CKD on brain structureResting state blood oxygenation level dependent functional MRI (BOLD fMRI) to evaluate connectivity within brain networks that modulate specific neurocognitive functionsArterial spin labeled perfusion MRI to evaluate global and regional cerebral blood flow.Multimodal magnetic resonance imaging (MRI) to identify differences in brain structure, functional connectivity, and cerebral blood flow, using:The overarching objectives of the NiCK study are (1) to determine how CKD and its associated comorbidities affect neurocognitive function, and (2) to understand the neurobiological basis for cognitive abnormalities in CKD. The NiCK study seeks to achieve these objectives using the following three-pronged approach:This multifaceted approach will allow us to integrate findings from neurocognitive testing, clinical phenotyping, and multimodal MRI to develop a unique multi-parametric neurocognitive phenotype for CKD. This innovative approach to assessment will provide new knowledge to further our understanding of mechanisms underlying neurological dysfunction in CKD.2, including dialysis and post-transplant), compared to healthy controls matched on age and socioeconomic status (using insurance status as a proxy).The NiCK study consists of a cross-sectional study of 90 pediatric and young adult subjects, aged 8 – 25 years, with Stage 2 to 5 CKD .Table The lower age limit of 8 years ensures improved compliance with imaging procedures. Since the selected neurocognitive measures are standardized largely in English, participants must have English as their primary language. To ensure that study results reflect the effects of kidney disease, patients with a number of comorbidities that independently affect brain function  or the ability to complete test measures  are excluded from participating , past medical history, family history, and current medications. Participants then undergo clinical, imaging, and neurocognitive assessments as described below.Participants’ blood pressure (BP), heart rate, respirations, height, weight, and body mass index are measured. Laboratory data collected includes complete blood count, comprehensive metabolic panel, calcium, phosphate, cystatin C, lipid panel, and urine studies for total protein, albumin, and creatinine. Urine pregnancy testing is performed in post-pubertal girls prior to MRI scanning. All participants undergo 24-hour ambulatory blood pressure monitoring (ABPM).A battery of age-specific neurocognitive assessments Table  is perfoIn addition to the traditional neurocognitive assessments outlined in Table After appropriate MRI safety screening, participants undergo non-sedated, non-contrast MRI of the brain, acquired on a Siemens Verio 3 T scanner equipped with a 32-channel head coil. The FDA- and manufacturer-approved sequences used are shown in Table An automated processing pipeline consisting of extensively validated methods is applied for processing sMRI images. The processing pipeline includes: extraction of the brain parenchymal tissue using multi-atlas skull-stripping ; inhomogBy summarizing the very high dimensional image data with much fewer variables, calculated volumetric measurements allow us to perform quantitative analyses of regional brain volumes and fractional anisotropy, and to evaluate the extent of brain atrophy and cerebrovascular disease such as infarcts and leukoareosis.BOLD fMRI is used to evaluate connectivity within specific cognitive networks in the absence of external stimuli (resting state BOLD fMRI). Following standard registration procedures (implemented via the program FIRST) , fMRI daASL MRI uses spin-labeled blood water as an endogenous tracer to measure regional cerebral blood flow (CBF). This study acquired pseudocontinuous ASL  sampled A sample size of 90 CKD subjects and 90 healthy controls was calculated based on the assumption that the prevalence of MRI abnormalities in CKD subjects will be 12.5% and will be 1% in normal controls. This sample size provides 80% power to detect such a difference with 95% confidence.The comprehensive approach employed in the NiCK study provides the opportunity to address some key issues and challenges in the field.Vascular disease is a well-known independent risk factor for cognitive impairment and dementia in adults . Adults By comparing neurocognitive test results with MRI data, we will be able to evaluate whether specific deficits correlate with changes in structure, connectivity, or CBF in particular regions of the brain. For example, executive function is a domain known to be affected in children with CKD . We woulHypertension has been associated with neurocognitive dysfunction in adults -32 and cBrain maturation involves a complex series of structural and functional changes throughout childhood, adolescence, and young adulthood . By stud2) allows us to explore neurologic changes across the continuum of disease severity. However, this diversity also introduces a greater number of covariates that must be accounted for in our analyses.The data collected in the NiCK study provides great opportunities to test hypotheses regarding differences in brain structure and function between individuals with CKD and healthy controls. However, the heterogeneous nature of CKD participants in this study presents both challenges and opportunities. Their wide range of kidney function  assessment for correlation between ABPM variables – the variables chosen for our primary analyses were those that were not highly correlated with each other, and thus potentially most informative about different aspects of BP physiology.There are a large number of blood pressure (BP) variables generated by 24-hour ABPM. These include measures for systolic and diastolic BP (SBP and DBP) and heart rate (HR), and can be broken down into waking hours, sleeping hours, and the total 24 hours. Potential variables include mean BP, mean BP index , BP load , nocturnal BP dipping (percent decrease in mean BP from waking to sleeping), hyperbaric index (area enclosed by the line of ambulatory BP readings above and the 95th percentile limit line for BP readings below), and BP and HR variability (coefficient of variation of BP readings and HR). Many of these variables are highly correlated with each other (e.g. mean BP and BP load); however, a growing number of studies show that certain ABPM variables, for example abnormal nocturnal dipping or increased BP variability, are independent predictors of adverse cardiovascular and neurocognitive outcomes. Our approach in selecting which ABPM variables to focus our analyses on has been two-pronged: (1) review of the literature to create an This study includes comprehensive neurocognitive phenotyping in youth with CKD. Although traditional neurocognitive batteries (TNB) have been used extensively in individuals with CKD, this is the first study to utilize a computerized testing (the Penn CNB) in this population. Both the TNB and CNB provide comprehensive assessments of multiple neurocognitive domains. However, since the exact tests differ between the two batteries, one challenge we encounter is aligning specific tasks in each battery with neurocognitive functions tested. Table Interpretation of performance across the TNB and CNB presents another challenge. Most TNB tests measure only accuracy, whereas most CNB tests measure both accuracy and speed. This is potentially important, as recent studies have shown that deviations from normal brain developmental trajectories are associated with significant deviations in performance for speed, but not accuracy . For somOur primary approach for analysis of sMRI, fMRI, and ASL MRI data in the NiCK study is to compare group differences in pre-specified ROIs, based on anatomic partitioning into structural/functional brain regions.Using these pre-specified ROIs, we can explore specific hypotheses – for example, ROIs encompassing the prefrontal cortex and frontotemporal areas would be hypothesized to be affected by CKD, given literature describing deficits in executive function in this population . We can Whole brain approaches can also be used to explore the global effects of specific CKD comorbidities – for example, using ASL, we can examine the effects of hypertension and anemia on global cerebral blood flow (CBF), or CBF within gray matter and white matter compartments.a priori correlations with the neurocognitive data will be explored in an effort to identify underlying neurological processes for manifest neurocognitive dysfunction.Additionally, a priori partitioning into anatomical ROIs. This unbiased discovery approach has the potential to yield new, previously unsuspected connections between regional brain abnormalities and CKD comorbidities.Although the primary analyses in NiCK will be hypothesis-driven, the nature of the imaging data collected also provides the opportunity to explore potential new connections and generate new hypotheses. For example, one hypothesis-free approach to analysis of the sMRI data uses voxel-based analysis ,39 – thiA new machine learning methodology, the brain development index (BDI) , summariThe long-term goal of the NiCK study is to develop a multi-parametric neuroimaging biomarker for patients with CKD. Using machine learning and pattern recognition methods, a classification system incorporating all the imaging measurements can be developed for individual patients. Multivariate pattern classification combining signals from sMRI, ASL and fMRI can be performed using the COMPARE   method. The NiCK Study represents the most comprehensive neurocognitive and neuroimaging phenotyping ever performed in children and youth with CKD. Our innovative approach of integrating multimodal MRI with neurocognitive and clinical data provides a unique opportunity to answer key questions in the field. These include understanding the independent neurologic impact of CKD, the neurologic effects of hypertension and other cardiovascular risk factors, and the consequences of CKD on neurodevelopment from childhood through young adulthood. Understanding these mechanisms could have great potential public health impact. First, this study could help to identify improved screening strategies to identify patients at high risk of adverse neurocognitive outcomes . Second, neurocognitive impairment may affect adherence to the complex medical regimens that are routinely prescribed to patients with CKD. By improving our recognition of these deficits in our patients, we may be able to deliver health information in a more individualized and effective manner. Finally, by identifying mechanisms through which modifiable risk factors such as anemia and hypertension affect neurocognition, this study may help to guide targeted treatment strategies to prevent future cognitive decline.


Orthostatic intolerance is the inability to tolerate the upright posture and is relieved by recumbence. It most commonly affects young women and has a major impact on quality of life and psychosocial well-being. Several forms of orthostatic intolerance have been described. The most common one is the recurrent vasovagal syncope (VVS) phenotype which presents as a transient and abrupt loss of consciousness and postural tone that is followed by rapid recovery. Another common type of orthostatic intolerance is the postural orthostatic tachycardia syndrome (POTS) which is characterized by an excessive rise in heart rate upon standing and is associated with symptoms of presyncope such as light-headedness, fatigue, palpitations, and nausea. Maintenance of arterial pressure under condition of reduced central blood volume during the orthostasis is accomplished in large part through sympathetic efferent nerve traffic to the peripheral vasculature. Therefore sympathetic nervous system (SNS) dysfunction is high on the list of possible contributors to the pathophysiology of orthostatic intolerance. Investigations into the role of the SNS in orthostatic intolerance have yielded mixed results. This review outlines the current knowledge of the function of the SNS in both VVS and POTS. Orthostatic intolerance is defined by the inability to tolerate the upright posture. It is usually associated with signs and symptoms including sensation of warmth, nausea, lightheadedness, dizziness, fatigue, abdominal pain, and visual blur. If recumbence is not achieved rapidly, syncope, defined as a temporary loss of consciousness and postural tone, can follow quickly. Syncope resolves almost immediately when the patient assumes the supine position, however after recovery, patients may complain of a “washed out” and tired feeling , a condition characterized by a heart rate (HR) increment of 30 beats/min or more within 10 min of standing in the absence of orthostatic hypotension. The orthostatic intolerance in these patients is typically accompanied by symptoms of cerebral hypoperfusion similar to those experienced by patients suffering recurrent VVS but syncope does not occur in many of them  is primarily regulated by mechanoreceptors, sensing changes in pressure and, to a smaller degree, by chemoreceptors. The arterial baroreceptors (high pressure receptors) are located in the carotid sinus and the aortic arch, and cardiopulmonary baroreceptors (low pressure receptors) are located in the great veins, atria , and ventricles (Bezold-Jarisch reflex). These mechanoreceptors are stretch-activated ion channels, which influence sympathetic outflow  and to less distention of the aortic arch and carotid sinus baroreceptors and subsequently reduced afferent baroreflex traffic to the brainstem. The unloading of the baroreceptors triggers reciprocal changes in autonomic activity with parasympathetic inhibition and sympathetic activation resulting in an increase in both HR and total peripheral resistance in order to minimize orthostatic reduction in blood pressure (BP). Increased fluid absorption has also been described in response to the increases in peripheral vascular resistance  and low systolic BP (70–100 mmHg)  fall is the predominant physiological event that determines hypotension. In a study of 56 patients presenting with suspected VVS who underwent head up tilt, stroke volume was computed from pressure pulsation data  was identified that encoded a dysfunctional protein with dramatically reduced noradrenaline reuptake compared to wild-type NET. While neither this mutation, nor single nucleotide polymorphisms (SNPs) in the NET gene have been found in other unrelated POTS patients  may lead to transcriptional repression of SLC6a2  is the main means of inactivation of noradrenaline in the heart and a key factor in regulation of delivery of noradrenaline to myocardial adrenoceptors (Eisenhofer et al., Both VVS and POTS are important clinical problems and although often generally considered benign conditions, frequent and recurrent episodes of syncope or presyncope can negatively affect quality of life and are associated with substantial morbidity. Understanding the pathophysiology of these conditions has proven difficult. VVS may result from withdrawal of sympathetic tone, baroreflex failure, a fall in the CO or a combination of both. POTS on the other hand may involve sympathetic denervation in the lower limbs, a hyperadrenergic state and/or abnormalities in the NET. While sympathetic dysfunction may be center to both conditions, results from studies are divergent which most likely reflects the pathophysiologic heterogeneity of orthostatic intolerance and the presence of multiple comorbidities not directly related to the actual orthostatic stress. It is therefore not surprising that patients with orthostatic intolerance pose a particular challenge in terms of management. Various drugs acting on sympathetic activity have been used. For example, β-blockers are proposed to reduce the degree of mechanoreceptor activation and block the effects of circulating catechoamines. In patients with VVS, the evidence for the use of β-blockers is however scant and of dubious quality (Parry and Kenny, 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.