We concluded that DTC hypertension can be predicted based on the clinical characteristics at the first visit. For these patients, ICT-IC is a feasible therapeutic strategy to achieve BP control.Difficult-to-control (DTC) hypertension represents a burden in real life that can be partially solved through identification of the characteristics of clinical patterns and tailoring antihypertensive strategies, including ICT-enabled integrated care (ICT-IC). In the quest for clinical predictors of DTC hypertension, we screened 482 hypertensive patients who were consecutively referred to the departmental hypertension clinic. Following a data quality check, patients were divided into controlled  and uncontrolled  groups based on their systolic blood pressure (BP) at follow-up. We then performed statistical analysis on the demographic, clinical, laboratory, and ultrasound data and observed that older age, female sex, higher BP levels, and a family history of hypertension were predictors of DTC hypertension. We then developed a pilot service of ICT-IC, including weekly home visits by nurses and patient education on self-monitoring of BP, heart rate, body weight, and oxygen saturation using 3G-connected devices. Self-monitored data were transmitted to the hospital servers on the electronic chart of the patient for remote assessment by the hospital hypertension specialists. A total of 20 UC patients  were enrolled to verify the efficacy of BP control without changes in medical treatment. After 1 month of the ICT-IC program, BP was reduced both at the office assessment (systolic BP (SBP): 162.40 ± 2.23 mm Hg, beginning of the program vs. 138.20 ± 4.26 mm Hg at 1 month,  Despite guidelines, blood pressure (BP) control (<140/90 mm Hg) in hypertensive-treated patients is <40% .BP control can be considered the collaborative success of at least two partners, namely, the attentive prescribing doctor and constant compliant patient. Reciprocally, lack of control can be considered to be a fault of either one or both partners. Doctors tend to not reinforce the importance of treatment to patients. Additionally, doctors exhibit a resistance to changing the treatment options to a more aggressive approach and opt for an inadequate use of combination therapy . From thIntensive follow-up strategies are effective in improving BP control, including the use of electronic charts and networking between general practitioners and hospital specialist centers . IntegraThe present research was therefore undertaken to fulfill two main objectives: first, to identify the predictive features of DTC hypertension at the first patient follow-up; second, to pilot an ICT-enabled integrated home care (ICT-IC) strategy to evaluate its potential in achieving BP control in DTC hypertension patients. To explore the first issue, we performed an observational retrospective analysis of clinical, laboratory, and instrumental data of outpatients at the hypertension clinic at the University Hospital of Salerno Medical School. To test the hypothesis that the use of integrated care would achieve SBP control in these patients without changes in hypertensive medical treatment, we piloted a small study to implement ICT-IC for DTC hypertensive patients.The population enrolled in the departmental hypertension clinic was included in a central database , which contained separate electronic sheets for medical history, physical examination, laboratory tests, electrocardiogram, and cardiac and carotid artery ultrasound data. All data were updated at each follow-up visit and stored on the hospital server, protected by a firewall system with user-specific password access.The database of the departmental hypertension clinic at the University Hospital of Salerno Medical School was programmed to identify patients with the following characteristics: essential hypertension; BP sitting >140/90 mm Hg at enrollment; the completion of at least one follow-up visit; completeness of the database; no previous cardiovascular events; no life-threatening comorbidities. The study protocol was approved by the University Hospital Ethical Committee, and informed consent was obtained from all subjects in compliance with the regulations of good clinical practice and privacy. The study population was registered at clinicaltrial.gov (NCT02995954)At enrollment, we collected anamnestic data including the following: family history of hypertension, cardiovascular disease, dyslipidemia, diabetes mellitus (DM) and renal failure; the age at first diagnosis of hypertension and the previous and current pressure values; the previous and current antihypertensive drugs used; any secondary hypertension indicator; the presence of renal disease and/or recurrent urinary tract infections; the existence of thyroid disease; any neurological diseases with particular emphasis to stroke and/or transient ischemic attack; any history of hypertension in pregnancy; taking drugs/substances such as oral contraceptives, liquorice, alcohol, nasal sprays, steroids, and non-steroidal anti-inflammatory drugs; physical activity habits; and a thorough collection of clinical and laboratory parameters and diagnostic tests. At the end of the work-up, optimal medical therapy was prescribed, and a follow-up visit scheduled. At the next follow-up visit, patients received cardiac and carotid artery ultrasounds . Controlled systolic BP (SBP) was defined as sitting SBP <140 mm Hg. In our medical office, BP measurement was obtained with an automated oscillometric BP device  that was properly maintained and regularly verified and validated according to international standardized protocols. Cuff placement was preceded by the selection of the appropriate cuff size for the patient’s arm circumference. The lower end of the cuff was placed 2 to 3 cm above the antecubital fossa. The BP reading using the automatic arm BP unit was obtained in the supine, sitting, and standing positions; the cuff was at the heart level in each position of the patient. At least two BP measurements were recorded in every position (spaced 1–2 min apart), and additional measurements were obtained if the first two assessments were largely different. In this study, we considered the average BP in the sitting position with compliance to the current guidelines [We assessed cardiovascular (CV) risk according to demographic and clinical data based on the charts of the Progetto Cuore of the Italian Institute of Health .From February 1, 2016 to June 30, 2016, we selected 20 uncontrolled patients, who met the following criteria: (1) poor SBP control (>140 mm Hg after at least three follow-up visits in the last year), (2) optimal drug therapy, including at least three drugs at the maximum tolerated dose, (3) suspicion of poor adherence to therapy, and (4) at least one concurrently treated chronic condition.Patients who gave informed consent received an ICT-IC program, which included a home care pathway for 4 weeks, with weekly access to a nurse and social caregiver, and telemonitoring of SBP and diastolic BP, heart rate (HR), body weight, body composition % (water and fat), and oxygen saturation using 3G-connected devices. Depending on the level of patient independence, social caregivers provided assistance for the acquisition of food and drug supplies, bureaucratic matters as well as the control of dietary and exercise programs. Nurses provided personalized assistance to the patients in terms of monitoring biometric parameters, drug use, and physical therapy.Patients who received the ICT-IC home care program were instructed to use of 3G-connected devices. They measured their BP twice in the morning and twice in the evening with an automated oscillometric BP device  connected via Bluetooth with a smartphone for data transmission over the 3G/4G data transmission network. The lower end of the appropriate cuff was placed 2 to 3 cm above the antecubital fossa, and the BP reading was obtained in a sitting position (after a resting period of 5 min) with the cuff at the heart level. If a patient was unable to attend to these tasks, their caregiver  was trained to use the devices. Each patient performed at least a scheduled (once a week) self-assessment of the above parameters. On the day of their access to the home of the patient, nurses assessed patient hemodynamics, clinical parameters, and completed quality-of-life questionnaires. Treatment compliance was verified weekly by the nurse through pill count. Data were securely transmitted through the 3G/4G with an encryption data transmission protocol to the hospital servers in Salerno and were accessible through the means of a web-based client. After 4 weeks, patients were evaluated on the hospital premises.Data were checked for quality to exclude patients whose data needed to implement the logistic regression were missing. The independent variables considered in this study included the following: sex; age; body mass index (BMI); smoking status; physical activity habits; diagnosis of DM; family history of high BP; number of years since diagnosis of hypertension; previous SBP referral in the absence of any therapy; SBP measured in the sitting position, pulse pressure (PP), HR, ankle-brachial pressure index (ABI), and New York Heart Association class at the first visit; CV risk; class of drug taken  inhibitors, and dihydropyridine calcium channel blockers); blood glucose, triglycerides, total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) calculated using the appropriate formula; left ventricular mass (LVM) index and E/A ratio; presence of plaques in the carotid arteries; and rapidity of the first follow-up visit .The data are expressed as frequencies and percentages for qualitative variables and as the means ± SEM for quantitative variables.α-value of 0.05 and a power of 90%. The result of the analysis showed that a sample size of 17 patients was needed.For the ICT-IC study, we identified the sample size needed to observe a reduction in SBP by 15 mm Hg with an Each patient represented his/her own control using a paired statistical design. Additionally, data from the two visits prior to the last visit were used as a standard care control.χ2test. The statistical significance of the means was calculated using the t test or analysis of variance as appropriate. P < 0.05 was considered statistically significant.The association between categorical variables was assessed using the Significant parameters were further analyzed using a logistic regression to determine the clinical variables associated with the non-achievement of the target BP; for the selection of variables, the stepwise backward method was used. The statistical analysis was performed using SPSS software for Windows, version 22.0 .n = 40, 50.63%) and controlled patients . The clinical features at first visit for both groups are reported in Tables Among the 482 hypertensive patients referred to the outpatient clinic, we identified 156 patients with uncontrolled BP at the first visit. After data quality control and assessment, 79 patients were included in the analysis. Based on the achievement of the target systolic pressure by the first available follow-up visit, this population was divided into two subgroups, namely, uncontrolled patients . No difference was observed in BMI, family history of maternal hypertension, smoking status, years of high BP, HR, and ABI Table .The results showed that the patients in the UC group had significantly lower HDL levels Table , consideThe two groups did not differ in ultrasound-assessed cardiac and vascular target organ damage Table ; in partThe two groups were comparable according to pharmacological therapy. As reported in Table According to the logistic regression analysis using a stepwise backward method of the significant parameters, the major predictors of therapeutic success were age, sex, SBP at the first visit, family history of arterial hypertension on the paternal side, and HDL Table .Table 3Lp < 0.01) and this was true also for self-measured telemonitored SBP   . In our Among the mechanisms underlying this observation, different genetic backgrounds should be considered. It is known that X-linked variability participates in the development of the hypertensive state . Indeed,Physical inactivity is one of the predictors of poor control of SBP. In our database, this demographic report is based on self-declared activity; nevertheless, physical inactivity is also confirmed by lower HDL levels observed among the uncontrolled hypertensives in our database. Indeed, previous reports showed that the beneficial effects on cardiovascular risk induced by physical activity are at least in part explained by the increase in HDL levels . AdditioSBP levels at the first visit is another important predictor of poor SBP control. Patients with a higher degree of hypertension are less controlled at the next follow-up visit. Guidelines and clinical experience suggest a combined therapy approach at the first visit for patients with moderate and severe hypertension , 24. OurBP control is excessively low in the hypertensive population, and in our country, it does not exceed 40%, resulting in only partial effectiveness of prevention strategies. The improvement in BP control is a very important element in reducing the burden of disease related to uncontrolled HBP and its health-related costs. The hypertension management cost in the period preceding the development of organ damage and major CV events was significantly lower compared to the social and health costs linked to the consequences of poorly controlled hypertension.The knowledge of the determinants of SBP control can undoubtedly increase the chance and percentage of achieving predetermined targets. In particular, our data indicated that therapeutic success in the first follow-up was largely dependent on anthropometric factors related to the characteristics of the patient, such as age, gender, family history, and degree of hypertension, which are risk factors that cannot be modified and that can allow us to predict therapeutic success at the first visit.Exercise and control of other risk factors, including dyslipidemia, are associated mechanisms that can be corrected using appropriate and effective measures.The strategies and interventions that can synergistically act on the multiple determinants of poor and inadequate BP control include the organization of the follow-up network in clinical and non-clinical fields; establishment of communication between specialist centers, general practitioners and patients; and based on patient empowerment, if the patient becomes an active part in managing the disease.Strategies of ICT-based home care might represent a real breakthrough in the management of chronic conditions, in particular, for patients who have multiple morbidities and poor compliance. Future large-scale studies are needed to assess the long-term effects on cardiovascular outcomes.Despite guidelines, actual BP control in treated hypertensive patients is <40%.Intensive follow-up strategies are effective in improving BP control, including the use of electronic charts.Difficult-to-treat hypertension can be predicted based on clinical features.The use of ICT-IC is a personalized strategy of therapy that can preventively be applied in patients who present features of DTT hypertension at the first visit.Supplement


Objective: Uric acid (UA) is a risk marker of CKD and SUA level in CKD 3–4 patients closely correlates with hyperuricemic nephropathy (HN) morbidity. This study was designed to evaluate the risk factors for HN in CKD 3–4 patients.Methods: The 461 CKD 3–4 patients were recruited and all patients were divided into three groups  according to the 24 h UUA level after receiving low purine food for five days. Clinical and biochemical characteristics of CKD patients were collected for the logistic regression analysis. Correlation analysis of the mRNA relative expression level of hUAT and hURAT1 with serum UA (SUA) level also was evaluated.Results: There were significant increases in characteristics including average age, waist-to-height ratio (WHR), SUA levels, HN ratio, TG/HDL ratio, body mass index (BMI), blood pressure (BP), uNgal/Cr. ratio, and uKim-1/Cr. ratio in overproduct type group in comparison with the other two groups. Logistic regression analysis showed SUA, CHO, uKim-1/Cr. ratio and uNgal/Cr. ratio were independent and multiple risk factors for HN. Moreover, hUAT and hURAT1 mRNA relative expression levels were significantly correlated with SUA level in the underexeret type CKD 3–4 patients.Conclusions: These results showed SUA and other characteristics contributed to HN morbidity in CKD 3–4 patients. Chronic kidney disease (CKD) is a clinical syndrome characterized by kidney function loss. Uric acid (UA) is a novel risk marker of CKD and might link mortality of CKD patients ,2. HyperHyperuricemic nephropathy (HN) or urate nephropathy, which is characterized by hyperuricemia, gout, tubulointerstitial nephritis, and kidney fibrosis, is a severe kidney disease mainly induced by excessive accumulation and deposition of uric acid salt in kidney ,7. HyperEpidemiological surveys show sex, age, body mass index (BMI), blood pressure (BP), triglyceride (TG), renal failure, diabetes mellitus, waist circumference, waist-to-height ratio (WHR) are independent risk factors of hyperuricemia . MoreoveGenetic factors including neutrophil gelatinase-associated lipocalin  and kidney injury molecule-1 (Kim-1), both are renal early injury marker, enhanced in pediatric patients with hyperuricemia ,16,17. UThis study was designed to evaluate the risk factors for HN in CKD 3–4 patients in Beilun, Ningbo, Zhejiang, China. Clinical and biochemical characteristics of CKD patients including sex ratio, age, BMI, WHR, SUA levels, HN ratio, TG/HDL ratio, SBP, BDP, uNgal/Cr. ratio, and uKim-1/Cr. ratio were detected and assessed. Logistic regression analysis and correlation analysis were performed to evaluate the contribution and correlation of those factors with HN risk in CKD 3–4 patients. This study would provide us with more information on the correlation of HN with CKD.The CKD 3–4 patients recruited in this study were from the Nephrology department, the Beilun People's Hospital, Ningbo, Zhejiang, China  during August 2014 and July 2016. Inclusion criteria for CDK stage 3–4 patients were: (1) aged 20- to 70-year old; (2) biopsy-proven primary glomerulopathy; (3) with new-diagnosed primary glomerulopathy without any drug therapy; (4) patients at CKD stages 3 to 4 determined according to the National Kidney Foundation criteria . Moreoven = 461) from all participants.This study was approved by the ethics review committee of the the first Affiliated Hospital of Zhejiang University, and was performed following the principles in the Helsinki Declaration II, with the written consents . Automated urine analysis was performed on the iChem Velocity instrument according to described method , and othQuantitative measurement of serum characteristics including SUA, XOR, C-reactive protein (CRP), and urine features such as UUA, creatinine (Cr), Ngal, and Kim-1 in morning serum and urine samples fasting for 12 h were measured using commercial enzymatic kits according to the manufacturers’ protocols. Serum lipid profile  were determined by the enzymatic method using the Hitachi 912 chemistry analyzer.- △△Ct method, with normalization to GAPDH expression.The expressions of hUAT and hURAT1 mRNA in biopsy samples were detected using Quantitative real time PCR (qRT-PCR). Total tissue RNA was isolated using the Trizol reagent  for synthesis of the first strand cDNA, which were then used for the amplification DNA templates. ABI7500 Real-Time PCR system (Applied Biosystems) was employed for qRT-PCR analysis and reactions were conducted as follows: 95 °C 60 s, followed by 40 cycles of 95 °C 30 s, 60 °C 30 s, and finally at 70 °C for 30 s. All reactions were run in triplicates. Relative expression levels of hUAT and hURAT1 mRNAs were detected using 2χ2 test or t test, or one-way ANOVA test for categorical variables or continuous variables followed the normal distribution, respectively. Differences among three groups were detected using Fisher's Test. Spearman’s correlation test was used for correlation analysis between SUA and hUAT or URAT1 mRNA expression levels. Prior to analysis, concentrations of Ngal and was adjusted to Cr, as Ngal/cr. Multiple linear regression models were created to determine the risk factors for CKD. For all analysis, p < .05 was regarded as significant.IBM statistics (version 17.0) or GraphPad Prism 6  was used for statistical analyses. Continuous variables were reported as means ± SEMs while categorical variables were expressed as proportions. All analyses were performed with adjustment for age and gender. Differences between two groups were analyzed using p < .0001) CKD3–4 patients were included in this present study. Age of males was younger than that of females . Primary SUA and UUA of males was higher than that of females . The HN morbidity of males was higher than that of females .The primary clinical and biochemical characteristics of these 461 CKD 3–4 participants are statistically analyzed and listed in n = 193 (41.87%), 164 (35.57%), and 104 (22.56%), respectively (p < .0001); UUA levels after 5 d = 1.9 ± 0.4 mmol/L, 3.2 ± 0.3 mmol/L, and 4.5 ± 0.8 mmol/L, respectively (p < .0001)].The 461 CKD patients were grouped into three groups according to the 24 h UUA concentrations after receiving low purine food for five days. Patients showed normal 24 h UUA level (1.2–2.4 mmol or 200–400 mg/d), underexeret 24 h UUA level (2.4–3.6 mmol or 400–600 mg/d), and overproduct 24 h UUA level (≥3.6 mmol or ≥600 mg/d) after receiving low purine food for five days were grouped into the corresponding group [p < .05). On contrast, patients of overproduct type showed lower water consumption  and eGFR . Moreover, no differences were observed in smoking (p = .0763), primary UUA levels (p = .2976), and serum CHO concentrations (p = .0827) among three groups, although there were uptrends  using qRT-PCR. We then performed the correlation analysis for hUAT and hURAT1 mRNA relative expression levels and SUA concentrations in underexeret CKD patients and confirmed the correlation of hUAT and hURAT1 relative mRNA expression level and SUA content  according to the 24 h UUA level after receiving low purine food for five days. We analyzed there were differences in clinical and basal characteristics among three groups, and evaluated that SUA level, roasted fish consumption, SBP, uNgal/Cr. Ratio, and uKim-1/Cr. Ratio are the risk factors for HN among CKD 3–4 patients. Moreover, the correlation analysis for hUAT and hURAT1 mRNA relative expression level showed the positive correlation of them with SUA content. These demonstrated that both hUAT and hURAT1 might be potential risk factors for the development of HN among CKD 3–4.Our study showed the HN incidence, male sex ratio, age, BMI, WHR, roasted fish consumption, alcohol consumption, SUA levels, SBP, uNgal/Cr. ratio, uKim-1/Cr. ratio were different in three groups with different UA metabolism. Ren et al. showed that roasted and raw fish consumption contributed to hyperuricemia . Evidencp < .0001). These suggested that the HN morbidity correlated with UA level, renal insufficiency, or UA metabolism in CKD 3–4 patients in Beilun, Ningbo.Reports show hyperuricemia is also associated with cardiovascular diseases, metabolic syndrome, renal disease, and increased mortality . HyperurRhizoma Smilacis Glabrae extract to hyperuricemic rats could reduce expression of URAT1 mRNA and UA levels [Dioscorea [URAT1 exchanges proximal tubule lumen urate, and urate secretion to the lumen is carried out by UAT ,30. In aA levels . Chen etioscorea . Sun et ioscorea . Other rIn conclusion, we found HN incidence, male sex ratio, age, BMI, WHR, roasted fish consumption, alcohol consumption, SUA levels, SBP, uNgal/Cr. ratio, and uKim-1/Cr. ratio were different in three groups with different UA metabolism, and all increased with UA dysfunction. Moreover, we demonstrated that the occurrence of HN in CKD stages 3–4 cohort was associated with sex, roasted fish consumption, alcohol consumption, CHO level, SBP, uNgal/Cr. ratio, and uKim-1/Cr. ratio. Further interventional or experimental studies would be done to confirm the causality and mechanism of these relationships.


Neurocritical care is an ever growing specialty with paradigm changes being the norm. Some of the established practices like triple H therapy for SAH and steroids in pyogenic meningitis have seen major changes in published evidence. This article evaluates the evidence published over the last few years which resulted in a change in the authors approach to and practice of neuro intensive care.Samavedam S. Ten Papers that Changed My Practice in Neurocritical Care. Indian J Crit Care Med 2019;23(Suppl 2):S165–S168. Neurocritical care has shown a significant change in paradigms over the last 5 years, be it the window periods for stroke intervention or the role of targeted temperature management. I have put together some of the papers which have brought about these paradigm changes.1Malignant MCA infarction is generally associated with adverse outcomes and high morbidity. While the benefits of a decompressive hemicraniectomy were clearly known in younger patients (< 60 years of age), the role of the intervention in older population was not studied until the destiny investigators asked the question.Juttler et al examined whether individuals older than 60 years of age, who developed a malignant MCA infarction, do better with a hemicraniectomy. This was a non blinded RCT carried out in 13 German hospitals between 2009 and 2013. The craniectomy was done within 48 hours of the development of the infarction. The patients who underwent the craniectomy had poorer Rankin scores at 6 months. Survival of these patients however seemed to be higher. The authors concluded that early hemicraniectomy increased survival of older patients with malignant MCA infarction with significant disability.This study alerted me to be more practical while recommending hemicraniectomy for malignant MCA infarcts in older patients. I started discussing the need for rehabilitation more while recommending the procedure.2Traumatic brain injury is probably the first area of intensive care where the principles of neuromonitoring initially emerged. Monitoring ICP was considered as a standard of care for TBI. Decisions of surgery were driven by the guidelines which focused on the ICP. Therapy was always tailored along those lines. However Chestnut et al got everyone thinking about this approach after the publication of the BEST: TRIP study.The clinical question which Chestnut et al. attempted to answer was whether ICP monitoring improves mortality and neurological function among patients with severe TBI. ICP was monitored using a parenchymal probe for a mean duration of 3.6 days. Critical value of ICP was accepted as 20 mm Hg. The control group was monitored using imaging techniques.A cohort of more than 300 patients was included over 3 years in six Bolivian and Ecuadorian centers. Patients who were monitored by imaging received more hypertonic saline and more hyperventilation. Mortality did not differ in both the groups. Surgery rates also did not differ between both the groups.The authors concluded that ICP monitoring guided therapy did not confer much benefit among patients with TBI.This study alerted me to the fact that invasive ICP monitoring is probably not the only way to improve outcomes among patients with TBI. However, some form of estimation of the pathological process with imaging atleast is needed to deliver acceptable care to the patients.Therapeutic hypothermia is an integral part of “neuroprotective” measures across a spectrum of neurological emergencies. TBI being the foremost amongst these is obviously a target. Reduction in mortality and long-term disability are the main parameters to judge the efficacy of such measures including therapeutic hypothermia.3. The study sought to evaluate the effect of hypothermia (32–35° C) on 6 month disability and survival. Forty seven centers across 18 countries enrolled close to 380 patients. Patients with a closed TBI and an ICP > 20 mm Hg were included. Hypothermia was applied for atleast 48 hours and continued till ICP stabilized. The non hypothermia group appeared to do better on the Glasgow outcome scores at 6 months. The number needed to harm was reported to be 10. Six month mortality seemed to be higher in the hypothermia group. Serious adverse events were more common in the hypothermia group. However, the study was criticized for changing the age limits and the time duration of injury after the recruitment started.Andrews et al attempted to put this hypothesis to test through the Eurotherm 3235 trial This study made me to rethink about the pathophysiology of TBI vis-à-vis other forms of neurological injury. Loss of autoregulation seemed to be a differentiating factor. I now use of hypothermia more selectively and discretely after this study.Intracerebral hemorrhage is a catastrophic event, more often seen in hypertensive individuals. It seemed logical that lowering of blood pressure to “normal” levels aggressively could prevent the recurrence or expansion of the bleed.4 Qureshi et al evaluated the effect of lowering systolic blood pressure to 139–110 mm Hg among hypertensive patients who have had an intracranial bleed. The study had a follow-up period of 3 months and was run in multiple countries over 4 years. Infratentorial and intraventricular bleeds were excluded. Treatment was initiated when systolic blood pressure exceeded 180 mm Hg. The target was 110–139 mm Hg (intensive treatment) vs 140–179 mm Hg (standard treatment). Nicardipine and IV Labetalol were the two drugs used to achieve control of blood pressure.This logic was put to test by the ATACH 2 investigators.There was no significant difference in long term disability and outcome between those who had aggressive lowering of blood pressure and those who did not. Significant adverse events were more frequent in those whose blood pressure was aggressively lowered. Moreover, it was very difficult to achieve the targets of blood pressure lowering within 2 hours of initiation of therapy. The authors concluded that it is not beneficial to aggressively lower the blood pressure in hypertensive intracerebral bleeds.The enthusiasm in lowering blood pressure in hypertensive bleeds was tempered after the results of this study. The potential for harm with an aggressive approach towards blood pressure is what essentially changed my practice.Antiplatelet therapy is fairly common amongst the general population for a variety of clinical reasons. Intracranial bleeds are also becoming more frequent amongst this cohort of patients. It is a popular sentiment amongst medical professionals that platelet transfusion is essential and is beneficial in patients who develop intra cranial hemorrhage while on antiplatelet agents.5Baharoglu et al. in a small RCT examined the safety and benefits of platelet transfusions while treating patients with intracranial hemorrhage due to antiplatelet agents. The authors included all patients with non traumatic supra tentorial intra cerebral hemorrhage while on atleast a week of antiplatelet therapy. The patients all had a GCS between 8 and 15. Aspirin, clopidogrel and dipyridamole were the antiplatelet agents which were on board when the bleed happened. Intraventricular bleed category had higher representation in the intervention group at base line. Leucocyte depleted random donor platelets were used (5 for aspirin related and 10 for other drug related bleeds).The intervention group reported more deaths and disability at 3 months with no difference in the rate of increase of the hematoma. The original size of the hematoma also did not make a difference to the outcome.The authors felt that platelet transfusions cannot be recommended for the management of antiplatelet therapy related intra cranial hemorrhage.This study changed my perspective on the issue of antiplatelets and IC bleeds. My tendency to recommend transfusions to all patients with intracranial bleed if they had antiplatelets in their past medical history made an about turn.Subarachnoid hemorrhage frequently throws up challenges in terms of hemodynamics and intravascular volume management. The complications triggered by hypovolemia and low perfusion pressures are well known. Conventional hemodynamic monitoring techniques have their own intrinsic problems in execution and actionability. The arrival of sonographic assessment to the bed side raised the possibility of using this modality for management of fluids in patients with SAH.6Morretti et al. compared the distensibility of IVC with thermodilution derived cardiac index and SVV among patients with (Fisher grade 3/4) SAH.2 or a CPP <60 mm Hg were included while excluding patients with arrhythmias, ARDS and high EVLW.This study specifically evaluated patients with higher grades of SAH and lower cardiac index. It is a single center observational study done over a one year period. Patients with grade 3/4 SAH who had a cardiac index <2.5 L/min/mFluid challenge was given with 7 mL/kg of starches which is a questionable step in current practice. Two experienced sonologists performed the IVC assessment at zero PEEP. Measurements of maximum inspiratory diameter and minimum expiratory diameter were measured along with calculation of distensibility index. The parameters so obtained were compared against PICCO derived cardiac index and SVV. The reliability of dIVC in predicting fluid responsiveness was good with a highly satisfactory AUROC. Inter observer variability was also within acceptable limits.The paradigm shift from mandatory invasive monitoring for reliability toward equally trustworthy method like ultrasound was reinforced by the findings of this small study.Management of stroke has become an exact science ever since thrombolysis became an accepted intervention. The results of TLT when properly delivered are gratifying. However, the non-applicability of this therapy beyond window period necessitated a search for other modalities.7Albers et al. evaluated the role of mechanical thrombectomy done 6–16 hours after the onset of ischemic stroke related to proximal ICA or MCA.This was a multicenter RCT which centered around all patients receiving CT perfusion imaging or MRI with diffusion carried out over one year in the US. Patients who presented with occlusion of proximal MCA-M1 or ICA on CT/MR angiography, Infarct volume < 70 mL on imaging, Ischaemic tissue: Infarct volume ratio >= 1.8 and absolute volume of potentially reversible ischaemia (penumbra) >=15 mL were evaluated and included provided intervention could be initiated between 6 hours and 16 hours after the time the patient was known to be well last.Mechanical thrombectomy was compared to medical therapy which included Aspirin, IV tPA without dual antiplatelet agents and oral anticoagulants. The thrombectomy group had better Rankin scores and were more functionally independent at 90 days. The number needed to treat for a beneficial effect was 4. This study had to be stopped early because the results of the DAWN study forced an unscheduled interim analysis and the proof of benefit was unequivocally shown. Reperfusion rates were also superior with no increase in adverse events.The diagnostic and therapeutic nihilism that I tended to have when faced with an ischemic stroke beyond the conventional window period, dissipated somewhat post this publication, reinforced by the DAWN study. This study had broader inclusion criteria than the DAWN study and was not industry sponsored unlike the latter.Status epilepticus is a challenge in the neuro-ICU. Although several well validated guidelines are available, the emergence of Levetiracetam as a convenient antiepileptic drug (AED) with less drug interactions than Phenytoin have made its usage in neuro ICU more common.8Gujjar et al. evaluated the ability of phenytoin and levetiracetam in ability to control seizures in a prospective RCT. The study was carried in a single university teaching hospital in Oman. Fifty-two patients with status epilepticus and 63 patients with cluster seizures were included in this study. Levetiracetam at 30mg/kg IV over 30 minutes was compared against phenytoin 20 mg/kg IV over the same time. Benzodiazepines were common to both the groups.Control of seizures was comparable between the two groups and between the two types of seizures. Functional outcome was better with levetiracetam in the cluster seizure group but not the status epilepticus group. Mortality was also not different between the two groups.The study concluded that the safety and efficacy of levetiracetam was comparable to phenytojn.Levetiracetam being a new drug was always a second choice to phenytoin when I faced a patient with status epilepticus. I had some concerns about the safety of phenytoin when rhythm was unstable or hemodynamics were labile. This subgroup was excluded from the study. However, the study gave me the confidence that levetiracetam is an equal and effective alternative to phenytoin if I did not want to use the latter.Manipulation of blood pressure has always been an integral part of Stroke management. While aggressive lowering of blood pressure showed no benefit in hemorrhagic stroke (as discussed earlier), the method of addressing blood pressure in ischemic stroke needed further study.9 compared three ranges of blood pressure — 140–160 mm Hg (median BP achieved: 153 mm Hg), 161–180 mm Hg (median BP achieved: 163 mm Hg) and 181–200 mm Hg (median BP achieved: 178 mm Hg)—and compared the outcome against each other. Fluids were used to augment blood pressure with esmolol being used to titrate the target blood pressure.Nasi et al.The modified Rankin score did not differ the three groups. The incidence of symptomatic intra cerebral bleed was higher in the highest systolic blood pressure group. Outcome was the best in the group who did not require any manipulation of blood pressure. Adverse incidents were more often identified when noradrenaline was used to manipulate blood pressure.This study laid out the principles of not generating numbers to achieve an outcome. It also established the role of blood pressure manipulation only when the SBP crossed 180. This study gave a target (161–180) to be maintained for acute ischemic strokes.Thrombolysis is still the more easily available therapeutic modality for acute ischemic stroke. At the same time the number of patients who reach the care facilities within the accepted window period of 4.5 hours is less. Extending this therapy to patients who present later needs to be investigated.10Ma et al. looked at this issue and evaluated whether alteplase administered 4.5–9 hours after stroke onset confers a functional benefit.All patients who presented 4.5–9 hours post stroke onset underwent CT /MRI perfusion imaging. Those who had hypoperfused but salvageable regions of the brain were randomized to receive alteplase 0.9 mg/kg (max 90 mg) administered as a 10% bolus and 90% infusion over 1 hour or a matching placebo. The intervention group had better Rankin scores at 90 days and significantly better reperfusion at 24 hours.The authors feel that more studies are needed to identify longer window periods.This study brought the concept of precision medicine and individualized decision making into focus and alerted me to the fact that stroke therapy is not limited to narrow window periods.


Experimental evidence indicates that oral L-citrulline (L-Cit) may reduce resting blood pressure (BP) as well as BP responses to exercise and cold exposure (non-resting). However, results from human intervention trials are inconsistent. This study aims to summarize the clinical evidence regarding the effects of L-Cit supplementation on brachial systolic blood pressure (SBP), brachial diastolic blood pressure (DBP), in addition to aortic SBP and aortic DBP at rest and non-resting conditions.Multiple databases including PubMed, Embase, Cochrane library, Web of Science, and Clinical Trials were searched systematically. Randomized controlled trials of human participants were quantitatively meta-analyzed.P = 0.002) and brachial DBP . Nine of the trials were meta-analyzed for aortic BP which showed that L-Cit intervention significantly reduced aortic SBP , but not aortic DBP . The observed reducing effects of L-Cit appeared stronger for non-resting than for resting brachial SBP (P for difference = 0.044).Fourteen trials contained in eight studies were available for quantitative syntheses for brachial BP. Results showed that L-Cit supplementation significantly reduced both brachial SBP (− 4.490 mmHg, 95% CI: − 7.332 to − 1.648, L-Cit supplementation significantly decreased non-resting brachial and aortic SBP. Brachial DBP was significantly lowered by L-Cit regardless of resting status. Given the relatively small number of available trials in the stratified analyses and the potential limitations of these trials, the present findings should be interpreted cautiously and need to be confirmed in future well-designed trials with a larger sample size. Globally, approximately 20–50% of adults are affected by hypertension, a major powerful predictor of cardiovascular disease (CVD) and premature death . ReductiGenerally, brachial BP is used for the diagnosis and management of hypertension. However, brachial BP does not reflect aortic BP and cardiac load accurately . It has L-citrulline (L-Cit), a colorless, water-soluble amino acid, is an effective endogenous precursor of L-Arginine (L-Arg)  and nitrThree meta-analyses –19 have We performed this systematic review with meta-analysis to evaluate the effect of L-Cit supplementation on brachial and aortic BP, taking the differences between resting BP and non-resting BP into account.This systematic review was performed in accordance with the principles outlined in the Cochrane Handbook 5.1.0  for systStudies were included if they met all of the following criteria: 1) the design was a RCT; 2) the participants were adults aged 18 years or older; 3) L-Cit was given as the only intervention by oral administration; 4) the intervention lasted at least for one week; and 5) sufficient data on BP at baseline and at the end of follow-up or the changes of BP in each group were reported. Conference abstracts or studies lacking a controlled group were not considered.The following data were extracted from each of the included trials: the first author’s name, year of publication, study location, study design, blinding status, sample size, dose of L-Cit, intervention duration, participants’ characteristics including sex, age, health status and BP values.According to RevMan , several trial components including “random sequence generation”, “allocation concealment”, “blinding of participants and personnel”, “blinding of outcome assessment”, “incomplete outcome data”, “selective reporting” and “other bias” were used to assess the quality of the included RCTs. The included trials were categorized as having ‘high’, ‘low’, or ‘unclear’ risk of bias according to the assessment criteria.STATA 14.0  was used for data analyses. For parallel trials, the net changes of each outcome in intervention and control groups were calculated as differences between mean values before and after treatments. For crossover trials, the net changes were calculated as the difference in the post-treatment values of each group. Standard deviations (SDs) of BP net changes, if not reported, were calculated by the following formulas according to the Cochrane Handbook 16.1.3.2 :\documeQ in addition to the I2 statistics. A fixed-effect meta-analysis was performed to pool the weighted mean difference (WMD) between experiment and control groups because of limited heterogeneity observed across the analyses. Stratified analyses by sex, age and BP resting status were also conducted, followed by meta-regression analyses exploring potential sources of heterogeneity. Both Begg’s rank correlation and Egger’s linear regression tests were conducted to assess the potential publication bias. P < 0.05 was considered statistically significant.Heterogeneity was quantified by the Cochrane n = 7), used phytochemicals combined with L-Arg or watermelon (n = 3), investigated acute effects (intervention duration < 1 week) (n = 8), had no adequate data (n = 2), were articles from the same study (n = 3), were conference abstracts or letters to editors (n = 5). Finally, eight eligible studies [The initial search yielded a total of 2389 records, of which 1150 independent records were screened after removing the duplicates. By reading further the abstracts, 36 relevant articles remained for full-text evaluations. Among these, 28 studies were further excluded because they did not have a control group , and on aortic DBP by both Begg’s and Egger’s tests . The overall estimates remained unchanged after using the “trim-and-fill” method to adjust for the bias.Results for risk-of-bias assessment of the included studies are summarized in Fig. Compared to control, oral L-Cit resulted in BP changes from − 14.00 to 4.00 mmHg, from − 16.00 to 2.10 mmHg, from − 15.00 to 3.00 mmHg, and from − 15.00 to 2.00 mmHg in brachial SBP, brachial DBP, aortic SBP, and aortic DBP, respectively. Results of meta-analyses showed that L-Cit supplement significantly reduced brachial SBP, brachial DBP, aortic SBP, but not aortic DBP. The estimated overall WMDs were: − 4.49 mmHg (95% CI: − 7.33 to − 1.65) for brachial SBP Fig. , − 3.63 P for difference = 0.044)  . Similar to the effect on brachial SBP, L-Cit supplementation significantly decreased non-resting aortic SBP by 10.06 mmHg (95% CI: − 15.74 to − 4.39), and had no significant effect on resting aortic SBP . However, no significant difference was observed between them (P for difference = 0.131)    to − 4.00  for brachial SBP, − 4.03  to − 3.35  for brachial DBP, − 8.25  to − 5.98  for aortic SBP, and − 4.33  to − 2.60  for aortic DBP. In summary, the overall estimated WMD of neither brachial BP nor aortic BP were remarkably altered by excluding any single trial  . KoenersL-Cit is an effective exogenous precursor of L-Arg, a natural substrate for NO . As an eIn this regard, several mechanisms underlying the BP-lowering effect of L-Cit supplementation have been proposed, including: 1) up-regulation of endothelial-NO synthase (eNOS) , a key eIn addition, a stronger effect of oral L-Cit was observed on non-resting BP, including during the post-exercise period, metaboreflex activation, and cold exposure. Elevated BP response to exercise is probably caused by inadequate perfusion of the active muscles, which is a consequence of a mismatch between supply and demand mediated by increased sympathetic vasoconstriction . In thisSome limitations of our meta-analysis need to be discussed. First, additional stratified-analysis according to other participant or trial characteristics such as race/ethnicity, health status, dose and duration of intervention were not performed due to the limited number of eligible trials. Dose-response relationship between BP reduction and baseline BP is also yet to be elucidated. Second, the reliability of the results was lowered by the low-quality trials that were included. Nevertheless, sensitivity analyses did not suggest heterogeneity caused by those low-quality trials. Third, potential impacts of publication bias on our findings cannot be excluded, given the tendency to publish larger studies or small studies with encouraging findings.L-Cit supplementation significantly decreased non-resting brachial and aortic SBP. Brachial DBP was significantly lowered by L-Cit regardless of resting status. Given the relatively small number of available trials in the stratified analyses and the potential limitations of these trials, the present findings should be interpreted cautiously and need to be confirmed in future well-designed trials with a larger sample size.Additional file 1: Figure S1. Stratified analysis of the effect of L-Citrulline on brachial systolic blood pressure according to BP status. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training; WMD, weighted mean difference.Additional file 2: Figure S2. Meta-regression analysis of brachial systolic blood pressure according to BP status. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training; WMD, weighted mean difference.Additional file 3: Figure S3. Stratified analysis of the effect of L-Citrulline on brachial diastolic blood pressure according to BP status. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training; WMD, weighted mean difference.Additional file 4: Figure S4. Meta-regression analysis of brachial diastolic blood pressure according to BP status. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training; WMD, weighted mean difference.Additional file 5: Figure S5. Stratified analysis of the effect of L-Citrulline on aortic systolic blood pressure according to BP status. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training; WMD, weighted mean difference.Additional file 6: Figure S6. Meta-regression analysis of aortic systolic blood pressure according to BP status. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training; WMD, weighted mean difference.Additional file 7: Figure S7. Stratified analysis of the effect of L-Citrulline on aortic diastolic blood pressure according to BP status. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training; WMD, weighted mean difference.Additional file 8: Figure S8. Meta-regression analysis of aortic diastolic blood pressure according to BP status. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training; WMD, weighted mean difference.Additional file 9: Figure S9. Sex-stratified analysis of the effect of L-Citrulline on brachial systolic blood pressure. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training; WMD, weighted mean difference.Additional file 10: Figure S10. Age-stratified analysis of the effect of L-Citrulline on brachial systolic blood pressure. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training; WMD, weighted mean difference.Additional file 11: Figure S11. Sex-stratified analysis of the effect of L-Citrulline on brachial diastolic blood pressure. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training; WMD, weighted mean difference.Additional file 12: Figure S12. Age-stratified analysis of the effect of L-Citrulline on brachial diastolic blood pressure. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training; WMD, weighted mean difference.Additional file 13: Figure S13. Sensitivity analysis of the effect of L-Citrulline on brachial systolic blood pressure. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training.Additional file 14: Figure S14. Sensitivity analysis of the effect of L-Citrulline on brachial diastolic blood pressure. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training.Additional file 15: Figure S15. Sensitivity analysis of the effect of L-Citrulline on aortic systolic blood pressure. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training.Additional file 16: Figure S16. Sensitivity analysis of the effect of L-Citrulline on aortic diastolic blood pressure. Abbreviations: CPT, cold pressure test; IHG, isometric handgrip; PE, post-exercise muscle ischemia (metaboreflex); WBVT, whole-body vibration training.Additional file 17: Table S1. Summarised search strategies to identify the effects of L-citrulline interventions on blood pressure. (DOCX 15 kb)


Kidney macrophages expressed GLP-1R, and DPP4 inhibition promoted macrophage polarization toward the anti-inflammatory M2 phenotype. Finally, high degrees of NADPH oxidase 4 expression and oxidation of nucleic acids, lipids, and proteins were reduced upon DPP4 inhibition. Our study provides evidence of renoprotection by DPP4 inhibition in a nondiabetic hypertension-induced model of chronic cardiorenal syndrome, indicating that DPP4 pathway remains a valid object to study in the context of chronic multiorgan diseases.Cardiovascular diseases frequently coexist with chronic kidney disease that constitutes a major determinant of outcome in patients with heart failure. Dysfunction of both organs is related to chronic inflammation, endothelial dysfunction, oxidative stress, and fibrosis. Widespread expression of serine protease DPP4 that degrades varieties of substrates suggests its involvement in numerous physiological processes. In this study, we tested the effects of selective DPP4 inhibition on the progression of renal disease in a nondiabetic model of hypertensive heart disease using Dahl salt-sensitive rats. Chronic DPP4 inhibition positively affected renal function with a significant reduction in albuminuria and serum creatinine. DPP4 inhibition attenuated the inflammatory component by reducing the expression of NF- Multimorbid chronic diseases are an increasing burden on individuals, communities, and health care services. For example, the coexistence of chronic heart and kidney diseases, referred to as cardiorenal syndrome, has a recognized pathophysiological significance. The high prevalence of chronic kidney disease (CKD) in patients with heart failure (HF) and vice versa associates both organs' dysfunction to increased morbidity and mortality . Most pan = 10; HS + SITA group; 10 mg/kg/day by oral gavage, reflecting human exposure levels) and vehicle-treated rats . The control group (n = 10) were fed with a low-salt (LS) diet . All the rats were sacrificed under anaesthesia with ketamine (100 mg/kg) and medetomidine (0.25 mg/kg) eight weeks later, and the blood, urine, and kidney tissues were collected. Serum (creatinine and blood urea nitrogen) and urine  samples were analyzed by the Abbott Lab Chemistry Analyzer ci 8200 .In this study, the animal research was in accordance to the National Ethical Guidelines , approved by the local ethics committee, and conformed to ARRIVE guidelines . Experimμm thickness were cut [After abdominal aorta was cannulated, a perfusion with 10% phosphate-buffered formalin was performed. Finally, tissue was embedded in paraffin and histological sections of 5 κB (NF-κB)  was also evaluated. Peroxynitrite formation and its action on the proteins were assessed by nitrotyrosine detection  [Histological sections were deparaffinized with xylene and rehydrated with aqueous solutions of decreasing ethanol concentrations. Masson's trichrome staining  was used to detect tissue fibrosis . The ext, Italy) . Oxidatiβ (TGF-β), TGF-β receptor (TGF-βR), SMAD3, tumor necrosis factor α (TNFα), interleukin 6 (IL-6), Nox2, Nox4, E-selectin (Abcam), NF-κB, interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1) (Santa Cruz Biotechnology), eNOS (Thermo Fisher Scientific), and phospho-SMAD3Ser423/425 . Loading conditions were determined with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (Sigma-Aldrich). Peroxidase-conjugated secondary antibodies were employed to detect primary antibodies (Santa Cruz Biotechnology). Antibody binding was visualized by chemiluminescence, and images were collected and analyzed using a ChemiDoc-It Imager .Proteins were extracted with a lysis buffer containing 0.1% Triton X-100 and a cocktail of protease and phosphatase inhibitors (Sigma-Aldrich), and their concentration was measured by Bradford assay (Bio-Rad). The proteins were separated on (8%–12%) SDS-PAGE and transferred onto polyvinylidene fluoride membrane . Membrann = 5 per group for each data set. Data distribution was determined by a normality test. Significance among groups was determined by one-way ANOVA and Bonferroni's posttest. All p values are two-sided, and p < 0.05 was considered statistically significant.Data were analyzed using GraphPad Prism . The results are presented as mean ± SD, and the number of replicates was at least Treatment with sitagliptin had a beneficial impact on overall animal health and prevented weight loss. Levels of blood glucose were unchanged in all experimental groups excluding involvement of glycemic control in a pathological condition. During eight weeks of treatment, rats remained severely hypertensive and a significant reduction of blood pressure was only observed at 19 weeks of age. Thus, it is unlikely that this change could exclusively account for the beneficial effects of sitagliptin, although blood pressure reduction may have participated in functional and structural modifications. Finally, effective DPP4 inhibition was confirmed by the increase in levels of circulating GLP-1.For a more detailed reading, refer to our previous publication .In HS rats, serum creatinine was significantly elevated while blood urea showed a nonsignificant upwards trend . Urine aβ signaling induced by high-salt diet. Increased levels of TGF-β were accompanied by a consistent rise of TGF-βR and increased phosphorylation of SMAD3. Sitagliptin partially suppressed the TGF-β pathway with a significant reduction of phospho-SMAD3 expression indicating the amelioration of a profibrotic phenotype , and reduced albuminuria resulting in improvement of renal damage, in both rodent models and humans [+/H+ exchange [Our data show that DPP4 inhibition reduced macrophage infiltration of the injured kidney and induced a marked macrophage polarization toward the anti-inflammatory M2 phenotype that secretes anti-inflammatory cytokines and participates to wound healing and tissue repair , 45. Thed humans , 48, 49.d humans . Also, td humans . While td humans , 52. Morexchange . Our datInflammation is strongly related to endothelial dysfunction when the decreased nitric oxide bioavailability restricts endothelial vasodilatory, antiadhesive, and anti-inflammatory properties. Our data show that endothelium also benefits from DPP4 inhibition by means of the increase in eNOS expression and the reduction in UAC ratio.β/SMAD3 signaling and kidney fibrosis. This is also in line with the evidence of the involvement of GLP-1 signaling, through protein kinase A, in reducing renal Nox4 expression and ROS accumulation [Oxidative stress and inflammation create a vicious loop that drives the progression of kidney disease. NADPH oxidases are main source of ROS that play a recognized role in development and progression of kidney disease –56. Overmulation . High deNCT01897532), a placebo-controlled clinical trial specifically designed to evaluate renal outcomes with linagliptin, in patients with type 2 diabetes at high risk for cardiovascular events.This study provides evidence that DPP4 inhibition exerts renoprotective effects through anti-inflammatory actions in a nondiabetic, hypertension-induced model of cardiorenal syndrome. Suppression of macrophage infiltration and decrease in endothelial dysfunction and oxidative stress interrupt a vicious circle that feeds CKD progression . Thus, D


We conducted a double blind, multi-centric, placebo-controlled, randomized trial to compare the Pressure Ulcer Scale for Healing (PUSH) and Pressure Sore Status Tool (PSST) scores and wound area measurements at 16 weeks of subjects with pressure ulcers who were given standard care plus one of two types of collagen hydrolysate (CH-a), which contained low levels of prolylhydroxyproline (Pro-Hyp) and hydroxyprolylglycine (Hyp-Gly), and CH-b, which contained high levels of Pro-Hyp and Hyp-Gly) with the placebo group. A total of 120 subjects with stage II or III pressure ulcers were entered into the trial and 112 subjects completed the study. The subjects were randomized to receive CH-a (n = 39), CH-b (n = 39), or a placebo (n = 42) twice daily (10 g per day) for 16 weeks. The PUSH score, PSST score, and wound area of the CH-b group were significantly lower than the placebo group at week 16 . The PUSH score of the CH-a group was significantly lower than the placebo group at week 16 (P < 0.05). This study demonstrated that CH-b ingestion helps healing of pressure ulcers as an add-on to the standard therapy. Malnutrition is an independent risk factor for the development of pressure ulcers. Appropriate nutrition is imperative for preventing and treating such wounds. Reddy M et al.2 reviewed that protein supplementation of long-term care residents improved wound healing compared with a placebo . For undernourished patients, supplementation with high amounts of energy and protein is recommended. In addition, various vitamins, zinc, and arginine and collagen hydrolysates should be supplied3.A pressure ulcer is defined as an area of localized damage to the skin and/or underlying tissue  caused by pressure, or pressure in combination with shear stress. Pressure ulcers develop when continuous pressure affects cellular metabolism and impedes or obstructs capillary blood flow to the skin and underlying tissue, resulting in tissue ischemia6.Collagen hydrolysate (CH), which is also referred to as collagen peptides, is widely utilized as a nutritional supplement. It is a mixture of peptides of different molecular weights derived from gelatin, a form of heat-denatured collagen, via enzymatic hydrolysis. Orally ingested CH is absorbed as both free amino acids and oligopeptides, such as prolylhydroxyproline (Pro-Hyp) and hydroxyprolylglycine (Hyp-Gly), and these oligopeptides are considered to be the major factors responsible for the physiological activity of CH8. As for the effect of CH on pressure ulcers, Lee SK et al.9 reported that the combined oral administration of CH, an amino acid mixture, and the standard treatment resulted in an improvement in the PUSH score after 8 weeks’ treatment. The objective of the present study was to assess the clinical effectiveness of CH supplementation in terms of its ability to induce remission in subjects with stage II or III pressure ulcers and the safety of this approach.Concerning the effects of CH on the skin, we reported that orally ingested CH containing Pro-Hyp and Hyp-Gly improved the water content, elasticity, and roughness of the skin in healthy womenThe placebo, maltodextrin TK-16, was purchased from Matsutani Chemical Industry Co., Ltd. . Two pork skin gelatin-derived CH, which were composed of different proportions of free-form Pro-Hyp and Hyp-Gly, were used in this study. The first CH (CH-a) had a low dipeptide content (<0.01 g dipeptides per kg of product). The other CH (CH-b) had a high dipeptide content (>1 g dipeptides per kg of product). The mean molecular weights of CH-a and CH-b were 5,000 and 1,200, respectively. These products were provided by Nitta Gelatin, Inc. , and are commercially available under the Wellnex brand. The characteristics of the test samples are shown in Table 10; had a body mass index of 18.5 to 34.9 kg m−2; exhibited a pressure ulcer surface area of <80 cm2 (multiplication of the major and minor diameters of the wound surface); were suffering from a stage II or III pressure ulcer (regardless of its location) with a PUSH (version 3.0) score of ≥5 that was likely to heal during the 6-month study period; and demonstrated moderate exudate production and a Braden score of ≥6.The inclusion criteria were as follows: inpatients or outpatients of either sex who were aged between 18 and 70 years; had been diagnosed with stage II or III pressure ulcers, as defined by the National Pressure Advisory Panel of the USA (2007)−1; patients with any condition that would interfere with wound healing ; patients who were malnourished; patients with wounds caused by malignancy; patients with burns or scalds; patients who had used any form of complimentary alternative medicine in the preceding 2 months; patients that were known to exhibit hypersensitivity reactions to protein products; patients with any dermatological condition or disorder that might interfere with the appropriate assessment or treatment of ulcers; current smokers; patients who had participated in any other clinical study during the 3 months prior to this trial; patients who were unwilling or unable to comply with the study procedures; patients who were considered to be unsuitable candidates by the investigator for any reason.The exclusion criteria were as follows: women who were pregnant or lactating; women of childbearing potential who were not taking adequate contraceptive measures; patients with stage IV pressure ulcers; patients that were being fed via a tube; patients with diabetic foot ulcers; patients who received immunotherapy or cytotoxic chemotherapy within the 60 days before enrollment; patients who had taken systemic steroids within the 30 days prior to enrollment; patients that had received topical therapy other than steroidal therapy during the 7 days prior to enrollment; patients who were human immunodeficiency virus-, hepatitis B virus-, or hepatitis C virus-positive; patients with pre-existing demyelinating disorders; patients with hepatic, renal, or metabolic disease that was likely to interfere with their participation in or completion of the study; patients with arterial or venous disorders that had the potential to cause ulcerated wounds; patients with a history of established diabetes mellitus and a fasting blood glucose level of >200 mg dLThis was a 16-week double-blind, multi-centric, placebo-controlled, randomized clinical study that aimed to determine the effectiveness, safety, and tolerability of CH (CH-a or CH-b) as an add-on nutritional supplement during the management of subjects with stage II or III pressure ulcers.th, 2009). The study was conducted in accordance with the ethical principles laid out in the current version of the Declaration of Helsinki and the ICH-GCP guidelines and was registered  with the Clinical Trial Registry, India. Written informed consent was obtained from all subjects who participated in this study. The subjects were advised to orally consume 5 g of CH or the placebo, dissolved in 250 ml water or milk in the morning and night after eating food. Regarding the standard therapy, the subjects were treated with antimicrobials, antiseptics, wound debridement, and wound dressing, as required.The subjects were enrolled according to the inclusion and exclusion criteria. After enrollment, a centralized allocation method was used to assign the study subjects to the CH-a, CH-b, or placebo group. The subjects were allocated independently to each group using computer-generated randomization code and the SAS® software by a doctor of Aurous Health Care Research and Development Private Limited. The trial sites were also subjected to centralized allocation. The randomization was balanced, and access to the code was strictly controlled. The study protocol, informed consent documents, and case reports, along with all of the secondary documents used for the study were reviewed and approved by an independent ethics committee .The variables used to assess the efficacy of the treatments included the PUSH score, the Pressure Score Status Tool (PSST) score as first outcomes, and wound area according to photographic measurements as a second outcome  the primary improvement was a reduction in the PUSH score of ≥5 points and a reduction in the PSST score of ≥10 points between the baseline and week 16, and (2) the secondary improvement was a reduction in the PUSH score of 3–4 points and a reduction in the PSST score of 5–9 points between the baseline and week 16.Clinical laboratory and biochemical evaluations, including blood and urine analyses, were used to assess the safety of CH-a and CH-b. Vital signs, such as temperature, pulse rate, respiratory rate, and systolic and diastolic blood pressure, and other parameters related to safety were analyzed.The following three individual variables were measured to calculate the PUSH Score: (1) Length X Width: The greatest length and the greatest width of the wound were measured in square centimetres. The two values were multiplied and corresponding score from the PUSH table  was noted as the first variable; (2) Exudate Amount: The amount of exudate, post removal of dressing and before the application of any topical agent was estimated. The corresponding score from the PUSH table was noted as the second variable.; (3) Tissue Type: The tissue of the wound was examined. The corresponding score from the PUSH table was noted as the third variable.These three variables were added to get the PUSH Score.The PUSH score was calculated as baseline and periodically upon treatment to show improvement metrics.The PUSH Score was calculated as per the PUSH Table.Each of the 13 variables has 5 choices that the assessor could choose from, based on the nature and presentation of wound on the day of examination.The choices ranked from Score 1 to Score 5.The assessor marked a score corresponding to the presentation for each of the 13 variables.The sum total of all the scores gave the PSST Score.The PSST Score was calculated based on the assessment of 13 different variables as follows: Size, Depth, Edges, Undermining, Necrotic Tissue Type, Necrotic Tissue Amount, Exudate Type, Exudate, Skin Color Surrounding Wound, Peripheral Tissue Edema, Peripheral Tissue Indurations, Granulation Tissue, Epithelialisation.t-test. ANCOVA was used to adjust for baseline differences among the treatment groups. For non-normal data, the Kruskal-Wallis and Friedman tests were used for intergroup and intra-group comparisons, and comparisons between the baseline and week-16 data were carried out with the Wilcoxon signed rank test. Evaluations of the proportions of subjects who exhibited improvements in their PUSH scores, PSST scores, or wound area were conducted using the chi square test or Fisher’s exact test.The Kolmogorov-Smirnov Z test was performed to assess the normality of the PUSH score, PSST score, and wound area data. For normally distributed data, two-way ANOVA was used during comparisons between groups , and repeated-measures ANOVA was employed for intra-group comparisons. Comparisons between the baseline and week-16 data were conducted using the paired The demographic characteristics of the subjects are shown in Table The changes in the patients’ PUSH scores, PSST scores, and wound area measurements are shown in Fig. These findings agreed with the response rates of each group. Specifically, >71% of the subjects in the CH-b group exhibited improvements in their PUSH and PSST scores, while no such improvements were seen in the CH-a or placebo groups, as shown in Table As part of the safety assessment, laboratory analyses of various serological and urinary biochemical parameters were performed. The baseline and week 16 data are shown in Table As an indicator of the subjects’ nutritional status, we focused on the serum albumin level. Compared with those seen at the baseline, the serum albumin levels of the CH-a and CH-b groups were significantly increased at week 16, indicating that the nutritional statuses of these two groups had significantly improved. Furthermore, the serum albumin levels of the CH-a group and placebo group differed significantly at week 16, indicating that the nutritional status of the CH-a group was significantly better than that of the placebo group at week 16. On the other hand, in the placebo group there was no significant increase in the serum albumin level, and hence, the patients’ nutritional status did not significantly improve during the study period.Among the 39 subjects treated with CH-a, two experienced moderate constipation, and one suffered mild diarrhea. Of the 39 subjects who received CH-b, two developed moderate diarrhea, and one of the 42 subjects treated with the placebo experienced a mild headache. It is possible that all of these adverse events were caused by the administered treatment/placebo. However, they only persisted for one day and were resolved with concomitant medication. Upon re-challenge, none of the adverse events reappeared.9. These results suggest that although all CH are derived from similar raw materials, it might be possible to control the healing effects of CH on pressure ulcers by altering their dipeptide content, e.g., by modifying the processes used to produce CH.The present study demonstrated that the oral ingestion of CH-b, which contains higher concentrations of the free-form bioactive peptides Pro-Hyp and Hyp-Gly, resulted in significantly greater improvements in the PUSH score, PSST score, and wound area compared with the ingestion of a placebo. Moreover, the ingestion of CH-a, which contains lower concentrations of these bioactive peptides, produced significantly greater improvements in the PUSH score than the placebo. This effect of CH-a was supported by the previous finding that the ingestion of CH together with an amino acid mixture led to a significant improvement in the rate of change in the PUSH score within 8 weeksAlthough the examined CH and placebo contained similar amounts of energy Table , it is c2. However, nutrition doesn’t induce the production of extracellular matrices which are the key in tissue repair. Moreover the indication for this clinical study is Pressure Ulcer which is usually a resistant wound to many therapies available currently. The direct supplementation of safe and oral CH, especially CH-b which contains higher concentrations of Pro-Hyp and Hyp-Gly, will definitely boost the extent of repair and significantly reduce the time taken for wound healing. This is what we like to claim as important and special in the treatment of pressure ulcers.Good nutrition definitely plays an important role in wound healing11. Furthermore, in an experimental study in which [14C]-Pro-Hyp was orally administered to rats it was reported that the Pro-Hyp reached the skin within 30 minutes12. Pro-Hyp and Hyp-Gly increased the proliferation of fibroblasts that had migrated from skin pieces on a collagen gel culture system5, and Pro-Hyp promoted hyaluronan synthase 2 mRNA expression and hyaluronic acid synthesis by hyaluronan synthase 2 in cultured skin fibroblasts13. Furthermore, an experimental study involving a pressure ulcer rat model reported that Pro-Hyp and Hyp-Gly were absorbed into the blood in the CH oral administration group, and the wound area ratio was significantly lower in this group than in the control group14. These findings suggest that the Pro-Hyp and Hyp-Gly absorbed into the blood after the ingestion of CH act on fibroblasts in the dermal layers of pressure ulcers and also might affect stem cells15, resulting in re-epithelialization and improved healing.The significant improvements in the PUSH and PSST scores and wound area induced by CH-b can be attributed to the physiological functions of the oligopeptides absorbed into the subjects’ blood. We previously reported that large amounts of Pro-Hyp and Hyp-Gly were absorbed into the blood after the ingestion of CH-b by healthy subjectsIn order to confirm that the ingestion of CH promotes the healing of pressure ulcers, it will be necessary to (1) elucidate the mechanism responsible for the accelerated pressure ulcer-healing induced by oligopeptides, such as CH-derived Pro-Hyp and Hyp-Gly, and (2) carry out a large-scale double-blind study.


A multicenter prospective cohort in Brazil showed that a 1-unit increase in systolic blood pressure Z-score was associated with a 1.5-fold higher risk of disease progression. Since renin-angiotensin-aldosterone system activation is the most important mechanism of hypertension in these children, the first-line therapy involves the use of inhibitors of this axis, including angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers type I, which also promote an anti-fibrotic effect. Recent studies have shown a good safety profile for use in patients with chronic kidney disease and also in those with solitary kidneys. Hypertension is an independent risk factor for kidney disease progression and should be promptly managed for renal protection, especially among patients with CAKUT, the primary cause of chronic kidney disease in the pediatric population.Patients with congenital kidney and urinary tract abnormalities (CAKUT) will often develop end-stage renal disease at some point and the need for renal replacement therapy is associated with high rates of morbidity and mortality. Hence, efforts to slow the progression of the disease are essential. Hypertension has been proven to be an independent risk factor for faster decline of glomerular filtration rate in renal patients, but studies involving only children with CAKUT are scarce. We performed a literature review to explore the association of hypertension with faster chronic kidney disease progression in children with CAKUT and also treatment options in this condition. A recent study reported an annual decline in GFR of 1.8 ml/min/1.73 m Congenital anomalies of the kidney and urinary tract (CAKUT) are the primary cause of chronic kidney disease (CKD) in the pediatric population –4. BilatMany CAKUT patients will progress to end-stage renal disease (ESRD) because the congenital reduction in nephron mass ultimately overloads the remaining nephrons. In severe dysplasia cases, ESRD occurs in the first years of life, while in other malformations there is an initial transient period during which glomerular filtration rate (GFR) can increase, leading to hypertrophy of the remaining nephrons. This period can span several years and is generally followed by a phase of stability. Progressive loss of residual renal function occurs and often, at between 15 and 25 years of age, these patients require renal replacement therapy –9. In a ESRD is associated with high morbidity and mortality rates and therefore strategies to reduce the rate of CKD progression and thus delay renal replacement therapy can be crucial for improving life expectancy and quality of life of patients. Concerted efforts have been made in recent years to elucidate the risk factors associated with CKD progression and to provide treatment for renal protection. Hypertension has been shown to be one of these risks. Although studies involving only children with CAKUT are scarce, we performed a literature review to explore the association of hypertension with faster chronic kidney disease progression in children with CAKUT and also treatment options in this condition.A number of studies have shown that high blood pressure plays a role as an independent risk factor for faster GFR decline in renal patients , 10–13. 2 if normotensive and without proteinuria. In the presence of hypertension, however, this annual decrease in GFR rose to 1.8 ml/min/1.73 m2  had a mean annual GFR decline of 0.8 ml/min/1.73 mA study conducted by our group in Brazil on data from a prospective multicenter cohort involving 209 children aged 1–17 years with CKD stages 3 and 4, found that 73% of the patients had CAKUT as the CKD etiology. A 31% greater risk of CKD progression was noted in patients with high BP at first visit in the study. A one unit increase in Z-score for systolic BP at start of follow-up was associated with a 1.3-fold higher risk of attaining the combined outcome of the study  .Hypertension is a risk factor that generally develops early in pediatric patients with CKD and consequently has a high prevalence in this population. In reports of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) for 1994 and 2001, an estimated 67% of the 3,861 children with CKD were hypertensive . HyperteThe underlying mechanism of the BP effect on CKD progression is similar to that hypothesized to explain the BP effect on the cardiovascular system, with high BP playing a major role in causing vascular stiffening, secondarily impacting renal microcirculation . Many diHowever, it is noteworthy that pediatric CAKUT patients are generally at lower risk of developing hypertension than patients with glomerulopathies. This is probably because children with CAKUT often have tubular dysfunction associated with vasopressin insensitivity, with consequent salt and water loss .Controlling BP, therefore, becomes fundamental in the management of CKD patients to both reduce traditional cardiovascular risk and preserve residual renal function over the long-term. Life-style changes with dietary modification and physical activity are essential in this control, supporting drug therapy. Some studies in adult CKD patients have shown that dietary salt restriction can help better control BP, and also favor the anti-hypertensive and anti-proteinuric effect of RAAS blockers . All casThe use of more than one class of antihypertensive is sometimes required to achieve sufficient BP control. Dual therapy combining ACEI and ARB is, in contrary to adults, not precluded in children. It is not indicated to adults, given there is no evidence supporting its use, in addition to data from studies that raise safety concerns , 28. HowAnother promising class is beta-blockers, which have the added effect of reduction of renin and proteinuria. Diuretics can be useful for hypervolemia situations. Calcium channel blockers are not recommended as monotherapy, since they fail to reduce proteinuria, although may be useful as an additional agent .2) compared with those with normal renal function (eGFR ≥ 90 ml/min/1.73 m2). The authors concluded that the inclusion of these drugs for the treatment of this patient group should be considered. However, it is important to note that all of the trials excluded children with severe renal dysfunction (eGFR < 30 ml/min/1.73 m2).Many anti-hypertensive agents currently used in children are administered off-label. Historically, explicit approval for pediatric use was generally not applied by manufacturers because clinical trials in children are more difficult than trials in adult patients for ethical, biometric, and practical reasons . This isNevertheless, there is some reticence in prescribing RAAS blockers to CKD patients. These concerns are grounded on the potential acute decline of GFR, hyperkalemia, and worsening of the anemia associated with the drug. Wuhl et al. analyzed these adverse effects using data from the ESCAPE trial, a prospective, randomized controlled trial performed in Europe involving children aged 3–18 years with CKD stages 2–4. The primary objective of the study was to assess the effect of strict control of blood pressure and of ACEI in CKD progression in pediatric patients. The agent used was ramipril and it was discontinued due to adverse effects in only 2.4% of the patients. Serum creatinine increased in 1.3% (5 out of 352 patients) during the first 6 months of treatment, confirmed by the decline in calculated creatinine clearance of over 25%. The incidence of this event did not differ from the pretreatment observation period. In addition, ramipril had to be discontinued due to persistent hyperkalemia in only one patient (0.3%), vs. 1.2–1.6% in adult trials, and mean serum potassium increased by only 0.3 mmol/L. With regard to anemia, it is acknowledged that RAASs can alter hematopoiesis and in the study, there was a drop in mean hemoglobin levels of 0.6 g/dL in 2 months, and stabilization thereafter. Thus, the safety profile of the drug in children appears to be good .Another controversial issue is the use of RAAS inhibitors in patients with congenital or acquired solitary kidneys. According to literature reports, RAAS plays a central role in maintaining renal function in patients with a single kidney, being essential for the compensation mechanism. However, its degree of expression can influence progression of renal injury. Recently, Simeoni et al. carried out a literature review assessing the effect of the drug in these patients . DespiteIn 2009, the above-mentioned ESCAPE trial addressed not only choice of therapy but also target BP . The objThe most recent guidelines were published by the Kidney Disease Improving Global Outcomes (KDIGO) in 2012 and by the American Academy of Pediatrics (AAP)—Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents (CPG) in 2017 , 25. In The current American Heart Association guidelines consider ABPM the gold standard for monitoring BP control . The jusHowever, a more recent study published in 2018 analyzing 513 children from the CKiD cohort, concluded that systolic BPs carefully collected using the standardized protocol of auscultatory technique, were not inferior to the ambulatory BPs for stratifying risk in children with CKD. Both approaches can yield similar prognostic information, including on the risk of progression to ESRD . This reProteinuria, besides hypertension, is another important independent risk factor for the progression of renal disease , 8, 21. Much of the data resumed in the present manuscript stems from studies and guidelines aimed at CKD children and not specifically CAKUT children since there is limited literature for this. However, CAKUT is the leading cause of CKD in childhood, and we suppose that data from CKD patients represent mainly children with CAKUT.Congenital anomalies of the kidney and urinary tract (CAKUT) are the primary cause of CKD in children and these patients will often progress to ESRD and require renal replacement therapy. A number of risk factors associated with kidney disease progression were assessed and hypertension proved deleterious in most of the studies.In summary, the available evidence suggests that management of BP is essential in children with CAKUT-associated CKD in order to slow the progression of the disease. RAAS inhibitors are the first-line medications for the efficacy of their anti-hypertensive, anti-proteinuric, and potential renal anti-fibrotic effects. Target ABPM values should be below the 50th percentile in proteinuric and below the 75th percentile in non-proteinuric CKD children.PK: conceived the manuscript and revised the whole text. MG: conceived, wrote, and revised the manuscript.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.


Endothelial dysfunction may play a key role in non-obstructive coronary artery atherosclerosis. Our study aimed to evaluate the vascular endothelial function and its influencing factors in patients with non-obstructive coronary artery atherosclerosis.A total of 131 consecutive patients with non-obstructive coronary artery atherosclerosis were enrolled. Flow-mediated dilatation (FMD) was measured at baseline and 1-year follow-up. Endothelial progenitor cells (EPCs) were counted by staining the fasting venous blood with antibodies against CD34 and vascular endothelial growth factor receptor 2.n = 65) were significantly higher than those with baseline FMD ≥ 6% (n = 66). Baseline FMD was negatively associated with EPC counts  and systolic blood pressure . The 1-year FMD was significantly increased compared to the baseline FMD . Independent predictors of FMD improvement included elevated EPC counts  and decreased levels of serum creatinine .Systolic blood pressure, pulse pressure and the levels of HbA1c in participants with baseline FMD < 6% (Family history of premature cardiovascular diseases, hypertension, elevated systolic pressure, and HbA1c > 6.5% are independent risk factors for endothelial dysfunction in non-obstructive atherosclerotic patients. Elevated peripheral blood EPC counts and decreased levels of serum creatinine are independent predictors of endothelial function improvement. Non-obstructive coronary artery atherosclerosis is characterized by coronary artery stenosis less than 50% –3. VascuEndothelial function can be directly evaluated by measuring the changes of arterial diameter in response to vasoactive drugs like nitric oxide that is directly injected into the coronary artery or the brachial artery –12. HoweIt has been shown that high-sensitivity C-reactive protein levels and neutrophil-to-lymphocyte ratio are significantly associated with vascular endothelial dysfunction , 18. EndOur study aimed to investigate the influencing factors of vascular endothelial function in patients with non-obstructive coronary artery atherosclerosis.The prospective observation study included 131 consecutive patients with non-obstructive coronary artery atherosclerosis with atypical symptoms and/or non-specific electrocardiogram changes at the Xuanwu Hospital of Capital Medical University. Non-obstructive coronary atherosclerosis was diagnosed using angiography as the absence of obstructive coronary artery disease, i.e. no coronary artery stenosis ≥50% in any coronary artery. This includes patients with normal coronary arteries (no stenosis to stenosis < 30%) or mild coronary atheromatosis (stenosis of 30 to 50%) [PMID: 28158518]. The study was carried out from August 2013 to August 2015. All patients underwent coronary angiography or coronary computed tomographic angiography and had been conformed with coronary stenosis < 50%.Patients with the following conditions were excluded: (1) coronary artery stenosis > 50% shown by imaging, or previous history of coronary artery interventional therapy or coronary artery bypass graft; (2) previous positive treadmill test, or transient elevation of ST-segment; (3) previous imaging suggesting myocardial ischemia; (4) previous tests showing levels of troponin I, troponin T, or creatine kinase-MB exceeding the upper limits of normal ranges; (5) patients with symptomatic heart failure, atrial fibrillation, cardiomyopathy or valvular diseases; (6) history of aortic dissection aneurysm, stroke or symptomatic peripheral artery diseases; (7) surgery, trauma or infection within 30 days; (8) renal or liver dysfunction; (9) secondary hypertension, hypertension emergency, or diabetes emergency; (10) rheumatic diseases, cancers, thyroid dysfunction, severe anemia, or use of glucocorticoid; (11) the informed consents were not signed.Patient general information such as gender, age, smoking, height and weight were collected. The family history of premature cardiovascular disease was defined as having a first-degree male relative aged < 55 years and/or a first-degree female relative aged < 65 years.Blood pressure was measured using a mercury sphygmomanometer for three times with intervals of 2 min . The meaPatients were followed 1 year ±30 days later from the time of enrollment. The following events during the year were registered: myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, heart failure, angina, hospitalization related to cardiovascular diseases, stroke (ischemic and/or hemorrhagic), transient ischemia attack, cardiac death and all-cause death.Vascular endothelial function was evaluated using the flow-mediated dilatation (FMD) on the day after admission and on the morning of follow-up visit . ParticiEPCs in the whole blood were identified and counted by detecting the expression of CD34 and vascular endothelial growth factor receptor 2 (VEGFR2) using flow cytometry  –27. The Data normality was examined using the Kolmogorov-Smirnov test. Quantitative variables with a normal distribution were presented as means ± standard deviations. Variables with a skewed distribution were presented as medians (interquartile ranges). Categorical variables were shown as numbers and percentage values.One-way analysis of variance test or Kruskal-Wallis test was used to compare the continuous variables. Chi-square test or Fisher’s exact test was used for comparing the categorical variables. Spearman or Pearson correlation coefficient was used to represent the relationships between the variables.Multivariate logistic regression was used to analyze the influencing factors of FMD. The dependent variable was FMD, and the independent variables were age > 65, male gender, smoking, hypertension, family history of premature cardiovascular diseases, HbA1c ≥ 6.5%, total cholesterol, low-density lipoprotein cholesterol, systolic blood pressure, pulse pressure and EPC count.P < 0.05. All analyses were performed with SPSS statistical software version 19.0 .Differences were considered statistically significant if the two-sided Our study included 131 consecutive patients with non-obstructive coronary artery atherosclerosis Tables . No sign6 cells. Heart rate, systolic blood pressure and pulse pressure in patients with EPC counts < 43 cells per 106 cells were significantly lower than that in those with EPC counts ≥43 cells per 106 cells. FMD in patients with lower EPC counts was significantly higher than that in those with higher EPC counts (Table P < 0.05), and that FMD was negatively associated with systolic blood pressure . However, no significant correlation was noticed between EPC count and systolic blood pressure/heart rate/white blood cell count, FMD and heart rate/white blood cell count, and systolic blood pressure and heart rate/white blood cell count.The mean EPC count was 43 cells per 10Multivariate logistic regression showed that hypertension , family history of premature cardiovascular , HbA1c ≥ 6.5%  and elevated systolic blood pressure  were independently related to FMD decline at 1-year follow-up (Table P < 0.001). The use of antiplatelet therapy, angiotensin-converting-enzyme inhibitor / angiotensin II receptor blockers, β-blockers and statins were significantly higher at 1-year follow-up than that at baseline (Table Five participants were lost to follow-up (3.82%). The 1-year FMD was significantly improved from the baseline .It has been shown that the phenotypic EPCs are independently associated with the severity of coronary artery lesion and carotid intima-media thickness and can be used as an independent predictor of cardiovascular outcomes , 31. OurA previous study found that high-sensitivity C-reactive protein was an independent risk factor for coronary heart disease and its level was significantly associated with the risk of future cardiovascular events, such as sudden death, acute myocardial infarction, and peripheral vascular disease , 33. AnoAll our participants received intensive blood-pressure control, antiplatelet and statins therapy. No major cardiovascular events occurred during the 1-year follow-up. We found participants with worse baseline endothelial function had greater increase in 1-year FMD. Our study suggests that patients with hypertension, elevated systolic blood pressure and elevated pulse pressure at baseline are more likely to benefit from antihypertensive treatment. It has been shown that aliskiren, a direct renin inhibitor, can improve endothelial function and arterial stiffness when being used as an antihypertensive agent . Another study showed that bisoprolol improved endothelial function in patients with hypertension and stable angina [PMID: 23609363]. Further research is needed to illustrate the detailed mechanisms between antihypertensive treatment and endothelial dysfunction.In our study, participants with diabetes and elevated HbA1c did not show FMD improvements despite the same antihypertensive, antiplatelet and antihyperlipidemic treatments with the non-diabetic participants. We speculate the conventional antidiabetic medications have limited protective effect for vascular endothelial function. Diabetes can induce endothelial dysfunction, leading to increased risks of cardiovascular diseases [PMID: 28044409]. In addition, hyperglycemia is associated with EPCs dysfunction and endothelial dysfunction [PMID: 28718318]. Dapagliflozin is used to treated type 2 diabetes and showed improvements in endothelial function and arterial stiffness [PMID: 29061124]. New antidiabetic drugs, such as dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists also showed differentia effect on endothelial function and arterial stiffness [PMID: 30622967].Chronic kidney disease and cardiovascular disease share similar risk factors. It has been shown that vascular endothelial function and FMD decreased significantly in patients with end-stage renal disease , 39. SimOur study has limitations. Our study excluded patients with non-obstructive coronary atherosclerosis who present with symptoms of typical myocardial ischemia and acute coronary syndrome, suggesting worse endothelial dysfunction. This may underestimate the incidence and severity of endothelial dysfunction in patients with early atherosclerosis. At the 1-year follow-up, blood pressure, low-density lipoprotein cholesterol and HbA1c were not included in the analysis, making it difficult to assess the effect of anti-atherosclerosis treatment on vascular endothelial function.Family history of premature cardiovascular diseases, hypertension, elevated systolic pressure, and HbA1c > 6.5% are independent risk factors for endothelial dysfunction in non-obstructive atherosclerotic patients. Elevated circulating EPC counts and decreased levels of serum creatinine are independent predictors of endothelial function improvement. Our findings may help to facilitate the risk stratification of patients with mild coronary atherosclerosis, and to explore intervention methods to repair vascular endothelial function.