Detecting CO changes may help distinguish hypovolemia or cardiac dysfunction from other causes of haemodynamic instability. We investigated whether CO2 measured as end-tidal concentration (EtCO2) and eliminated volume per breath (VtCO2) reflect sudden changes in cardiac output (CO).  Exhaled carbon dioxide , VtCO2 by 11% , and EtCO2 by 4.9% . During passive leg raise, CO increased by 21% , VtCO2 by 10% , and EtCO2 by 4.2% . Changes in VtCO2 were significantly larger than changes in EtCO2 (ventricular pacing: 11% vs. 4.9% (p < 0.001); passive leg raise: 10% vs. 4.2% (p < 0.001)). Relative changes in CO correlated with changes in VtCO2  and EtCO2  only during reductions in CO. When dichotomising CO changes at 15%, only EtCO2 detected a CO change as judged by area under the receiver operating characteristic curve.  During right ventricular pacing, CO was reduced by 21% (CI 18–24; 2 and EtCO2 reflected reductions in cardiac output, although correlations were modest. The changes in VtCO2 were larger than the changes in EtCO2, but only EtCO2 detected CO reduction as judged by receiver operating characteristic curves. The predictive ability of EtCO2 in this setting was fair. This trial is registered with NCT02070861. VtCO Haemodynamic deteriorations are frequent in many clinical situations but may initially be subtle and thus difficult to detect. Estimation of cardiac output (CO) or CO changes may help distinguish vasodilatation due to anaesthetic or sedative drugs from impairment of cardiac function or hypovolemia and help evaluate response to therapy. Thus, monitoring CO is recommended during major surgery  and circ2) reflect changes in pulmonary blood flow [2 can be expressed as end-expiratory partial pressure (EtCO2), or as volume eliminated CO2 per minute (VCO2) or per tidal volume (VtCO2). Volumetric capnography also provides information about pulmonary dead space and metabolism [2 and VCO2 as well as EtCO2 [Capnography is widely used in mechanically ventilated patients. During constant ventilation and metabolism and in the absence of lung disease, changes in exhaled carbon dioxide  or after a fluid load [2 following PLR or a fluid load are quite small (≈5%). This could limit their clinical use, as small changes are difficult to distinguish from random fluctuations. Some studies suggest that the changes in VCO2 following a preload challenge or increased positive end-expiratory pressure (PEEP) are larger [2 and CO have mainly focused on the prediction of fluid responsiveness, and EtCO2 has been investigated more often than VCO2 [2 and EtCO2 during moderate reductions in CO, although the detection and evaluation of decreases in CO is of major interest both perioperatively and during intensive care.Measurement of EtCOidelines , as EtCOc arrest . EtCO2 huid load –12 and ie larger , 14. Gooe larger , 16 and e larger , 18. Rechan VCO2 –14. Few In the present study, we used right ventricular pacing (RVP) to induce moderate reductions in CO. RVP reduces CO by approximately 20% due to loss of atrial contribution  and dyss2 and EtCO2 reflect sudden moderate reductions in CO induced by RVP as well as sudden moderate increases in CO induced by PLR. We hypothesised that VtCO2 and EtCO2 would reflect changes in CO, that the changes in VtCO2 would be larger than the changes in EtCO2, and that the changes in CO, EtCO2, and VtCO2 would be correlated.The aim of this study was to investigate to what extent VtCONCT02070861), prior to patient enrolment. Forty adult patients scheduled for open coronary artery bypass surgery or aortic valve replacements were included from April 2014 to June 2015. Written informed consent was obtained prior to surgery. Patients with atrial fibrillation or ejection fraction <40% and patients in whom oesophageal Doppler placement was contraindicated were not included. The study was conducted in the cardiothoracic recovery unit of a university hospital 1-2 h after surgery. Patients were sedated with propofol 2-3 mg/kg/h according to departmental practice. They were haemodynamically stable prior to interventions, as evaluated by the attending cardiothoracic anaesthesiologist. Patients were ventilated in pressure-regulated volume control mode, tidal volumes 6–8 mL/kg predicted body weight, positive end-expiratory pressure 5–8 cmH2O, risetime 0.20 s, FiO2 as required for SpO2 >94%, and frequency 9–13 breaths/min, adjusted to obtain an EtCO2 between 32 and 38 mmHg before interventions . Ventilation and medication were kept constant during interventions  and registered in http://www.clinicaltrials.gov 02/23/2014  with infrared absorption technology and sampled at 400 Hz in SignalExpress 14.0.0  after conversion in an analogue-to-digital converter . Flow was measured continuously by Dräger Infinity ID with hot-wire anemometer technology. Haemodynamic data, including blood pressure obtained via a 20G catheter in the left radial artery, were downloaded from GE Solar 8000i  and analysed in a custom-made program . CO was measured with oesophageal Doppler , which continuously measures flow velocity in the descending aorta and thus rapid changes in stroke volume (SV) [EtCOume (SV) . The Dop2 curves for the calculation of VtCO2, as the VtCO2 and VCO2 values from the ventilator could not be extracted for offline analyses. Digital mainstream flow curves from the ventilator were continuously sampled on a laptop computer using Medibus software  and aligned with converted side-stream EtCO2 curves in a custom-made program in LabView, thereby accounting for the relative delay of 1–4 s of the side-stream capnogram [2 curves over time were integrated, giving VtCO2 for each respiratory cycle. Respiratory cycles containing nonpaced heartbeats during the RVP sequence were omitted.The volumetric capnograms were reconstructed from flow and EtCOapnogram . The proThe experimental design is illustrated in 2, and EtCO2 were normally distributed assessed by the Shapiro–Wilk test. The effect of RVP and PLR on each variable and the difference between changes in VtCO2 and EtCO2 were tested using paired t-tests. The correlations between the relative changes from baseline to interventions in CO, VtCO2, and EtCO2 were analysed using the Spearman test of correlation, as these changes were mainly not normally distributed. Precision was calculated from the baseline sequence as 1.96 × √(within-subject mean square) in a one-way ANOVA with subjects as factors [2 and 3.8% in EtCO2 [2 and VtCO2 were calculated and compared in MedCalc Software 18.11 . Their discriminative value was evaluated by their ability to detect a change in CO of 15%. p values <0.05 were considered statistically significant and all tests were two-tailed. Calculations and analyses were performed without blinding.CO, VtCO factors  and pres factors . Analyse factors . A changin EtCO2 . Areas uTwo patients were included, but not studied, due to changes in the operative schedule. One patient was excluded due to postoperative bleeding and two because they were pacemaker-dependent after surgery. Two patients were excluded because of disturbances in the acquired data signals. Thus, 33 patients  completed the study .p < 0.001), VtCO2 by 11% , and EtCO2 by 4.9% . Relative changes in CO correlated significantly with changes in both VtCO2  and EtCO2  (p < 0.001), VtCO2 by 10% , and EtCO2 by 4.2% . None of these changes were significantly correlated ; from BL to PLR, 10% vs. 4.2% (p < 0.001)).p=0.006) . From BLrrelated . Overall2, and 1.5% and 2.1% for EtCO2. Thus, all mean changes seen after the interventions were larger than the LSC. The LSC for CO, VtCO2, and EtCO2 are indicated in Figures 2 and EtCO2 larger than the LSC implicated a reduction in CO of more than 11% for all subjects.Precision and LSC for 30 s baseline measurements were 4.8% and 6.9%, respectively, for CO, 2.4% and 3.4% for VtCO2  during RVP, whereas the ROC curve for VtCO2 was not significantly different from 0.5. Neither EtCO2 nor VtCO2 was able to discriminate changes in CO during PLR.ROC-plot analyses are shown in 2 and EtCO2 tracked sudden moderate reductions in CO. Both reductions and increases in CO with RVP and PLR coincided with reductions and increases, respectively, in EtCO2 and VtCO2  or stroke volume variations (SVVs) in the presence of arrhythmia [2 or VtCO2.In the studies by Monge García et al.  and Monne et al.  found thl et al. , who in rhythmia  or tidalrhythmia , 29. Thirhythmia , 31. How2 and CO in dynamic states is previously described [2 transport to the lungs and increased alveolar dead space; both resulting in reduced CO2 elimination. With increased pulmonary perfusion, more CO2 is brought to the lungs, underperfused lung tissue is recruited, and CO2 elimination is increased. Although reports of the nature of the relationship between exhaled CO2 and CO differ [2 after PLR [2, VtCO2, and CO during PLR in our study. Firstly, previous studies investigated patients with circulatory failure, whereas our cohort was haemodynamically and metabolically stable. The relationship between changes in CO and exhaled CO2 is stronger during unstable circulatory states, e.g., in patients with reduced CO [2 mainly depends on CO2 production. Lung perfusion and ventilation/perfusion ratio will be affected only marginally, if at all, by an increase in CO of 20% in euvolemic patients who are adequately ventilated. This is in line with the findings of Ornato et al [2 decreased as CO reached normal or supranormal values, when pulmonary flow no longer represents a limitation to the CO2 elimination via the lungs. By contrast, we observed significant correlations between the relative reductions in CO, VtCO2, and EtCO2 when CO was decreased during the RVP sequence, even though the change in CO was of similar magnitude. Secondly, the mean relative increase in EtCO2 during PLR in our study was 4.2%, which is smaller than in previous studies which have reported an increase of >5%. As these studies were designed to study fluid responsiveness, EtCO2 was recorded during the maximal haemodynamic changes following PLR. We sampled CO, EtCO2, and VtCO2 over 1 min of PLR, and although the main preload increase is likely to take place within that minute, the time span includes lower values that dilute this effect. Also, it is possible that the position change during the PLR manoeuvre could affect CO2 elimination by other mechanisms than the preload increase. This could have influenced the results. In a postoperative setting with haemodynamically stable patients, the detection of a sudden decrease in CO, e.g., due to bleeding, is arguably more relevant than the prediction of preload responsiveness.The physiologic relationship between exhaled COescribed , 32. RedO differ , 32, 33,fter PLR , 11. We duced CO . In stea2 or VtCO2 in cases of decreasing blood pressure, the clinician may be aided in their therapeutic decisions.In the absence of CO monitoring, MAP is often used for haemodynamic assessment. As MAP is highly influenced by vascular resistance , it may As departmental logistics had to be considered during data acquisition, the order of interventions varied in a nonrandomised fashion. The possibility of carryover effects was minimised by ensuring sufficient time between all interventions but cannot be excluded.There was a departmental change in monitoring equipment during the study, and the available software did not allow export of invasive blood pressure data from the new monitors to the computer. Thus, MAP measurements were retrospectively obtainable from 21 patients only. This represents a limitation to the study.CO had to be monitored continuously as changes in CO induced by RVP and PLR are rapid and transient. However, CO measurement with oesophageal Doppler has some limitations. Measurements are based on assumptions regarding the diameter of the aorta, angle of insonation, and fraction of CO that enters the descending aorta . As we m2 is mostly expressed as VCO2, whereas both VCO2 and VtCO2 have been used to describe the relationship between exhaled CO2 and circulation [2 to enable a direct comparison with EtCO2, which is also measured breath-to-breath. As ventilation was kept constant throughout experiments, the choice of VtCO2 over VCO2 should not affect the results, which may therefore be seen in relation to previous studies investigating VCO2. The absolute changes in VtCO2 are small. However, they are significantly larger than the corresponding changes in EtCO2, which use is already implemented in guidelines for haemodynamic evaluation. Modern ventilators display updated VCO2 values after each breath. For clinical use, changes in VCO2 may be easier to detect than changes in VtCO2, as they appear larger.For the description of metabolism, exhaled COculation , 15, 37.2 [Any form of ventilation/perfusion mismatch may affect the relationship between CO and exhaled CO2 . Other i2 , 18. Onl2 and EtCO2 in spontaneously breathing patients.As mechanical ventilation alters pulmonary physiology and haemodynamics , further2 and EtCO2 tracked reductions in cardiac output, but correlations between the changes were modest. Judged by receiver operating characteristic curves, a CO reduction was only detected by EtCO2. Further studies are warranted to establish the role of exhaled CO2 as a clinical tool for detecting cardiac output changes in this setting.VtCO


This prospective, randomized, open-label study aimed to compare the effects of antihypertensive treatment based on amlodipine or hydrochlorothiazide on the circulating microparticles and central blood pressure values of hypertensive patients.The effects of treatments on circulating microparticles were assessed during monotherapy and after the consecutive addition of valsartan and rosuvastatin followed by the withdrawal of rosuvastatin. Each treatment period lasted for 30 days. Central blood pressure and pulse wave velocity were measured at the end of each period. Endothelial, monocyte, and platelet circulating microparticles were determined by flow cytometry. Central blood pressure values and pulse wave velocity were recorded at the end of each treatment period.No differences in brachial blood pressure were observed between the treatment groups throughout the study. Although similar central blood pressure values were observed during monotherapy, lower systolic and diastolic central blood pressure values and early and late blood pressure peaks were observed in the amlodipine arm after the addition of valsartan alone or combined with rosuvastatin. Hydrochlorothiazide-based therapy was associated with a lower number of endothelial microparticles throughout the study, whereas a higher number of platelet microparticles was observed after rosuvastatin withdrawal in the amlodipine arm.Despite similar brachial blood pressure values between groups throughout the study, exposure to amlodipine was associated with lower central blood pressure values after combination with valsartan, indicating a beneficial interaction. Differences between circulating microparticles were modest and were mainly influenced by rosuvastatin withdrawal in the amlodipine arm. Arterial hypertension is responsible for high morbidity and mortality rates around the world. After the publication of the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) blood pressure guidelines, a substantial increase in the number of hypertensive adults eligible for drug therapy is expected  were enrolled if they had systolic blood pressure (SBP) or diastolic blood pressure (DBP) in the ranges of 160-179 and/or 100-119 mmHg, respectively, without pharmacological treatment; or 140-159 and/or 90-99 mmHg, respectively, or appropriate blood pressure levels (<140 and/or <90 mm Hg) with the use of two antihypertensive drugs. The key exclusion criteria were as follows: secondary hypertension, prior coronary heart disease or stroke, estimated glomerular filtration rate less than 30 mL/min per 1.73 m®; Sanofi Aventis Pharma, 25 mg daily) or amlodipine  on circulating microparticles. At baseline, all subjects received nutritional counseling, and those using lipid-lowering drugs suspended their use. The first period of monotherapy (hydrochlorothiazide or amlodipine) was followed by the addition of valsartan  and rosuvastatin , and the withdrawal of rosuvastatin with the maintenance of the antihypertensive drugs was performed in the last 30 days of treatment. Central blood pressure and pulse wave velocity (PWV) were also measured at the end of each 30-day treatment  based on hydrochlorothiazide  .Data are expressed as the mean (± standard deviation) or median (and interquartile range) for continuous variables, and n (%) is used for categorical variables. The Kolmogorov-Smirnov test was used to evaluate normality. Continuous variables that were normally distributed were evaluated by ANOVA-GLM. Microparticles were compared (within group and between groups) using the Friedman and Mann-Whitney (nonparametric) tests, respectively. SPSS software (v. 18.0) was used for statistical analysis. A significance level of an alpha risk less than 5% was adopted for all tests.Female, elderly, and overweight individuals (n=46) were more prevalent in the sample. p<0.0001 vs. V2, V3, and V5) (No changes in glucose or creatinine serum levels were observed throughout the study. After a 4-week exposure to rosuvastatin (V4), a significant and similar decrease was observed in serum levels of total cholesterol and LDL-C in both groups ( and V5) .Brachial blood pressure was measured in both groups (AMLO and HCTZ) and showed similar values for SBP and DBP at each medical visit. However, higher values were observed at V2 in both arms. Differences within and between groups can be calculated from the data shown in Central blood pressure was monitored for 24h from V2 to V5 in eight patients in the AMLO and HCTZ groups. The mean values obtained were similar to those obtained at V2. In the HCTZ arm, no difference between medical visits was observed in the central SBP or DBP values throughout the study. However, lower central blood pressure was recorded beginning at V3 in the AMLO arm. PWV values did not change during the study, and similar results were recorded in both groups at each visit from V2 to V5. Central blood pressure values are shown in p=0.045). Regarding the HCTZ-based treatment, no difference was observed in the amount of circulating PMP or MMP throughout the study, except for a lower number of EMP at V5 . Higher levels of MMP (visit 2) and PMP (visit 5) were observed in the AMLO group . The AMLO-based treatment did not change plasma concentrations of monocyte-derived microparticles (MMP) or endothelium-derived microparticles (EMP) throughout the study. However, more platelet-derived microparticles (PMP) were observed at visit 5 after rosuvastatin withdrawal .Circulating microparticles, also called extracellular vesicles or shedding vesicles, are released from the endothelium, platelets, and many other cells and may have physiological or pathological effects . The diaThe first interesting finding of the study was related to MMP. During monotherapy, the four-week exposure to amlodipine was associated with higher levels of MMP than those associated with hydrochlorothiazide exposure, although in both groups, the brachial blood pressure values were higher than the recommended value range, which was expected because the majority of participants in both arms were previously treated by two antihypertensive agents. Elevated MMP values were previously reported in hypertensive subjects with type 2 diabetes, particularly among those with high SBP . In addiRegarding central blood pressure, our study also showed differences between the AMLO- and HCTZ-based therapies, with lower SBP and DBP values in the AMLO-based arm. Indeed, these differences became apparent only after the addition of valsartan, suggesting a beneficial interaction between amlodipine and valsartan, an effect not observed with hydrochlorothiazide. A recent study showed that despite similar brachial blood pressure values, ARBs were more effective than atenolol for reducing central blood pressure, indicating their potential benefit for the prevention of cerebrovascular events . FurtherAortic augmentation index (AIx) has been recognized as an indicator of arterial stiffness and wave reflection. Changes in these parameters and PWV may require long-term exposure to therapies and seem to be related to the choice of antihypertensive therapy . In factOur prospective randomized study should be considered a pilot study. First, we enrolled a relatively small number of patients and examined the effects of therapies on short-term outcomes. In addition, we were unable to compare the effects of the treatments with baseline visits (V1) due to the need to homogenize treatments via the withdrawal of antihypertensives and statins. However, after 4 weeks of monotherapy with amlodipine or hydrochlorothiazide, the central and brachial blood pressures were similar, and changes in circulating microparticles and central blood pressure were observed shortly after the addition of ARB or ARB/statin. These findings may contribute to explaining some intriguing differences in cardiovascular outcomes in trials of combined therapies, such as the ACCOMPLISH study, despite similar brachial blood pressure values achieved, especially among diabetic patients .Our observations are promising, although they are preliminary and require confirmation in larger prospective studies. Exploratory analysis of central parameters and PWV suggest that new technologies, which allow for the registry of central blood pressure, vascular compliance, and other hemodynamic data, are essential for establishing new targets beyond brachial blood pressure for the long-term treatment of patients with cardiovascular hypertensive disease.The amlodipine- or hydrochlorothiazide-based antihypertensive therapy had different effects on circulating microparticles and central blood pressure parameters. Despite similar brachial arterial blood pressures and biochemical parameters throughout the study, exposure to amlodipine was associated with lower central blood pressure values after combination with valsartan, indicating a beneficial interaction. Differences in the amount of circulating microparticles were modest but were mainly influenced by rosuvastatin withdrawal in the amlodipine group.Massunaga ND and França CN collected clinical data, performed laboratory tests, performed statistical analyses, and drafted the manuscript. Bianco HT and Ferreira CES performed screening, conducted the medical visits and contributed important intellectual content. Kato JT and Póvoa RMS performed blood pressure monitoring and contributed with important critical interpretations of the collected data. Figueiredo Neto AM and Izar MCO performed manuscript revision and provided financial support. Fonseca FAH designed the study and critically reviewed the manuscript.


Serum IL-25 level significantly decreased from 48.0 ± 17.2 pg/mL to 34.8 ± 17.1 pg/mL (p = 0.02) with same tendency in TSLP level: from 359.8 ± 71.3 pg/mL to 275.6 ± 47.8 pg/mL (p = 0.02). It has also been noticed a significant relation between changes in the blood eosinophil count and serum IL-25 level , as well as between changes in serum IL-25 and TSLP levels  after a single dose of mepolizumab. Thus, anti-IL-5 treatment with mepolizumab might diminish the production of bronchial epithelial-derived cytokines IL-25 and TSLP in patients with SNEA which is potentially related to reduced eosinophilic inflammation. This trial is registered in ClinicalTrial.gov with identifier NCT03388359.The bronchial epithelium has continuous contact with environmental agents initiating and maintaining airway type 2 inflammation in asthma. However, there is a lack of data on whether reduced airway eosinophilic inflammation can affect the production of epithelial-derived mediators, such as interleukin-25 (IL-25) and thymic stromal lymphopoietin (TSLP). The aim of this study was to investigate the changes in serum levels of IL-25 and TSLP after a single dose of mepolizumab, a humanized monoclonal antibody to interleukin-5 (IL-5), in patients with severe non-allergic eosinophilic asthma (SNEA). We examined 9 SNEA patients before and four weeks after administration of 100 mg mepolizumab subcutaneously. The fractional exhaled nitric oxide (FeNO) level was analysed using an electrochemical assay . Serum IL-25 and TSLP levels were measured by ELISA. Four weeks after the single dose of mepolizumab, blood eosinophil count significantly decreased from 0.55 ± 0.20 × 10 Asthma is a common, life-lasting airway disease, associated with a high social and economic burden. About 3–8% of all asthma patients have severe asthma, suffering from frequent symptoms and recurrent exacerbations despite the combined treatment with high-dose of inhaled steroids and long-acting bronchodilators, often supplemented with oral steroids , 2. All Eosinophilic airway inflammation has a key position in the pathogenesis of severe eosinophilic asthma , 6. AfteIt is unknown whether anti-IL-5-directed treatment affects only eosinophilic inflammation or also other mediators which are involved in airway type 2 inflammation. In this study, we aimed at assessing the changes in serum levels of epithelial-derived mediators as IL-25 and TSLP on mepolizumab, a humanized monoclonal antibody to IL-5, treatment in patients with severe non-allergic eosinophilic asthma (SNEA). We designed to use a single dose of mepolizumab to avoid asthma exacerbations that could influence the intensity of type 2 inflammation, whereas positive drug effect on reduction in blood eosinophils and lung function improvement is observed already after the first dose , 20.ClinicalTrials.gov with identifier NCT03388359.The study was conducted with the permission of the Regional Biomedical Research Ethics Committee of the Lithuanian University of Health Sciences (BE-2-13) and after signing the informed consent forms. The study was registered in the U.S. National Institutes of Health trial registry The study included patients with adult-onset SNEA (the inclusion criteria listed below). Non-allergic asthma was chosen to eliminate allergens as an uncontrollable factor which damage the epithelium and may significantly alter cytokine levels and affect airway type 2 inflammation activity.The participants were men and women between the ages of 18 and 65 years, recruited from the Department of Pulmonology at Hospital of the Lithuanian University of Health Sciences Kaunas Clinics.9/l during the screening visit or documented ≥0.30 × 109/l blood eosinophil count in the 12-month period before the screening denying other possible common causes of eosinophilia ; no other reasons that could lead to poor control of asthma symptoms; documented at least 12-month treatment of high doses of inhaled steroids combined with long-acting beta-agonist ± long-acting antimuscarinic agent ± episodic use of oral steroids prior to inclusion in the study; and in the 12 months before the screening visit ≥2 exacerbations of asthma that required treatment with systemic steroids.Inclusion criteria were as follows: asthma diagnosis for at least 12 months; non-allergic phenotype, confirmed by the absence of allergy-specific symptoms  and with negative skin prick tests; blood eosinophil count ≥0.15 × 10The study was open for non-smokers only.Exclusion criteria included asthma exacerbation, active airway infection, and use of oral steroids 1 month prior to the study; clinically significant permanent allergy symptoms; and treatment with targeted  therapy  at the screening visit.1 was measured, and blood samples were collected for evaluation of blood eosinophil count and epithelial-derived mediators concentrations. After all the procedures, mepolizumab 100 mg was injected subcutaneously. The second study visit was scheduled for 4 weeks. Then, FeNO and FEV1 were re-evaluated, and blood samples were re-taken. Only patients without asthma exacerbation during this 4 weeks period were re-evaluated. The study design scheme is presented in At the screening visit, the inclusion/exclusion criteria were assessed, and informed consent was obtained. During the first study visit, FeNO level was analysed, FEV1 using an ultrasonic spirometer  and compared with the predicted value matched for age, body height, and sex according to the standard methodology. FEV1 was measured three times and recorded only the highest of three reproducible measurements.The lung function was evaluated for all study subjects by measuring baseline FEVAll study subjects underwent FeNO analysis with an online method using a single-breath exhalation and an electrochemical assay , according to ATS-ERS guidelines . PatientDermatophagoides pteronyssinus, Dermatophagoides farinae, cat and dog dander, mixture of pollen of 5 grasses, birch pollen, mugwort, Alternaria, Aspergillus, and Cladosporium. Negative control was performed with diluent  and positive control with histamine hydrochloride (10 mg/mL). Results of the test were evaluated 15 min after application. The skin prick test was estimated to be positive when the mean wheal diameter reaches ≥3 mm.All study subjects were screened for allergies by the skin prick test at least 6 months prior to enrollment. Standardized allergen extracts  were used for the following allergens: μl of serum samples was used for experiments. Blood was collected into BD Vacutainer® SST™ II Advance Blood Collection Tubes and allowed to clot for 30 min. After that, the tubes were centrifuged at 1300 ×g 10 min at room temperature to separate serum from clotted blood. Serum immediately was collected and divided into 1 mL cryogenic tubes that were frozen in −80°C for further proteins level analysis. ELISA measurements were performed after a sufficient amount of samples was collected. The results were expressed as protein concentration per 1 mL of serum.Protein (IL-25 and TSLP) levels in blood serum samples were measured by the enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions. The following ELISA kits were used for experiments: IL-25  lower limit of detection (LLD)—11.7 pg/mL and TSLP  LLD—7.8 pg/mL. 100 p < 0.05 was considered as statistically significant.Statistical analysis was performed by using GraphPad Prism 6 for Windows . Protein concentration data were represented as the mean ± standard error of the mean or with specific values for each subject, including the overall mean. Significant differences between two dependent groups were determined using the Wilcoxon matched-pairs signed-rank test. Spearman rank correlation coefficient was used to evaluate correlations. In this study, we examined 9 patients with adult-onset SNEA at two time points: before and 4 weeks after 100 mg subcutaneous injection of mepolizumab. The subjects with SNEA were middle or elderly aged with a tendency to overweight, on the Global Initiative for Asthma (GINA) step 4-5 treatment, and had impaired lung function, increased blood eosinophil count, and elevated FeNO level , 4 weeks after a single dose of mepolizumab   .Significant correlations were observed between changes in the blood eosinophil count and serum IL-25 level (p=0.008) , as wellp=0.004) . HoweverIn this study, attention was drawn to the bronchial epithelium dysfunction and how the level of epithelial-derived cytokines changes during treatment with anti-IL-5 drug when eosinophilic inflammatory activity is reduced. It was found that a single dose of mepolizumab in patients with SNEA significantly decreased blood eosinophil count and improved lung function, whereas FeNO did not. We have also noticed that anti-IL-5 treatment reduced the serum level of epithelial-derived cytokines, such as IL-25 and TSLP.1) during treatment with mepolizumab have been demonstrated in many studies to confirm the appropriateness of mepolizumab during severe eosinophilic asthma [Blood eosinophil depletion and lung function improvement (measured by FEVc asthma , 22–24. IL-25 and TSLP are epithelial-derived cytokines that play an essential role in stimulating Th2 cytokine response and initiating airway type 2 inflammation in asthma –18. By iAccording to the study data, blood levels of certain cytokines are unlikely to accurately reflect the processes in the lungs as we did not find a reliable correlation between changes in TSLP and blood eosinophil count. These insights are also observed in a study with atopic dermatitis, where serum TSLP level did not significantly correlate with disease severity, blood eosinophil counts, and serum total immunoglobulin E levels, suggesting that TSLP does not mainly enter the blood circulation  or relatAdditionally, FeNO is attributed to eosinophilic inflammatory biomarkers, and the relationship with eosinophilia and FeNO level is established , but, acThe study is limited by the lack of a control group for comparison of the effect of mepolizumab on the levels of epithelial-derived cytokines. However, this was a brief observation study for 4 weeks to minimize the risk of exacerbations and course variability of asthma that could have an impact on TSLP and IL-25 production. Thus, only clinically stable severe asthma patients, free of systemic steroids at least 1 month before the study, were included and patients without asthma exacerbation during 4 weeks period after a single dose of mepolizumab were re-evaluated. Additionally, all study subjects were non-atopic and non-smokers, so it could be presumed that contact with inhaled non-specific air particles, which trigger the epithelium, is constant.Our study results demonstrate that anti-IL-5 treatment with mepolizumab might diminish the production of bronchial epithelial-derived cytokines IL-25 and TSLP in patients with SNEA which is potentially related to reduced eosinophilic inflammation. These findings indicate that mepolizumab by modulation of bronchial epithelium function could provide a broader impact on the severe eosinophilic asthma pathophysiology. This may be important when making clinical decisions for patients non-responsive to other biologics for severe refractory asthma.


In atherosclerotic renal artery disease, the benefit of revascularization is controversial. A clinical decision-making process based on a multidisciplinary meeting was formalized in the Lyon university hospital.To investigate whether this decisional process ensured a clinical benefit to patients assigned to renal revascularization.Single-centre retrospective cohort study, including patients diagnosed from April 2013 to February 2015 with an atherosclerotic renal artery disease with a peak systolic velocity >180cm/s. For each patient, the decision taken in multidisciplinary meeting  was compared to the one guided by international guidelines. Blood pressure values, number of antihypertensive medications, presence of an uncontrolled or resistant hypertension, and glomerular filtration rate at one-year follow-up were compared to baseline values. Safety data were collected.p = 0.007), diastolic blood pressure , number of antihypertensive medications , and number of uncontrolled or resistant hypertension (p = 0.022 and 0.031) at one-year follow-up. Those parameters were not modified among patients assigned to medical treatment alone. There was no grade 3 adverse event.Forty-nine patients were included: 26 (53%) were assigned to a medical treatment and 23 (47%) to a renal revascularization. Therapeutic decision was in accordance with the 2013 American Health Association guidelines and with the 2017 European Society of Cardiology guidelines for 78% and 22% of patients who underwent revascularization, respectively. Patients assigned to revascularization presented a significant decrease in systolic blood pressure (-23±34mmHg, Based on a multidisciplinary selection of revascularization indications, patients on whom a renal revascularization was performed exhibited a significant improvement of blood pressure control parameters with no severe adverse events. Atherosclerotic renal artery disease represents a frequent and severe medical condition, the treatment of which remains controversial. Options for atherosclerotic renal artery disease treatment are medical therapy alone or medical therapy combined with renal artery revascularization, either with an endovascular technique or during an open surgery.Currently, the benefit of revascularization has been challenged since three large randomized controlled trials failed to demonstrate any improvement in clinical outcomes after endovascular revascularization compared to medical therapy –3. HowevTo deal with the lack of valid scientific data applicable to all patients, a multidisciplinary renal artery disease meeting has been conducted every two weeks in a French university hospital starting from April 2013. We hypothesized that a multidisciplinary and individualized selection of revascularization decisions in atherosclerotic renal artery disease patients could ensure a clinical benefit to revascularized patients. Herein, we described the clinical decision-making process, and analysed whether patients who benefited from a revascularization exhibited clinical improvement.In accordance with the recommendations established in 2011 by the European Society of Cardiology (2011 ESC Guidelines)  and in 2Patients diagnosed with a renal artery disease had their charts reviewed during a multidisciplinary meeting. For the present study, patients whose chart had been reviewed between April 2013 and February 2015 were included. Patients with a fibromuscular dysplasia were excluded.For the present study, medical records and meeting reports were analysed retrospectively. Uncontrolled hypertension was defined as a systolic and/or a diastolic measurement above 140 or 90mmHg, respectively. Resistant hypertension was defined as uncontrolled hypertension despite three antihypertensive medications belonging to three different drug classes. Estimated glomerular filtration rate (eGFR) was calculated based on the Chronic Kidney Disease-Epidemiology Collaboration (CKD-epi) formula. Worsening of renal function was defined as a decrease in eGFR ≥20% as compared to its baseline value. For patients with a bilateral disease, the radiological parameters related to the side with the highest peak systolic velocity were recorded.For each patient, the decision taken during the multidisciplinary meeting  was collected and compared to the one guided by international guidelines, that is to the one that would have been taken if the 2011 ESC , 2013 AHAfter a one year follow-up, the following data were collected: systolic and diastolic blood pressure, number of concomitant anti-hypertensive drug classes, eGFR and/or initiation of a dialysis treatment, proteinuria, survival status, grade 3 complications related to the procedure, and procedure failures.2 test for categorical variables, and Student’s t-test or Mann-Whitney-Wilcoxon for continuous variables. In each treatment group, parameters at one year were compared to pre-meeting data: continuous parameters were compared using paired-t-tests or Wilcoxon signed rank test for paired samples; categorical parameters using McNemars’ tests. Intergroup comparisons of the data relating patient evolution during follow-up was not performed owing to the existence of selection biases between groups. As previous studies reported negative results, we could not calculate a prospective or a priori power. A two-sided P-value <0.05 was considered statistically significant. Analyses were performed using Statistical Package for the Social Sciences (SPSS) version 19.0 .Continuous data were reported as mean ± standard deviation (SD). Categorical data were reported as count and percentage. Univariate inter-group comparisons were performed using Fischer’s exact test or ChiThis study agrees to the Principles of Helsinki Declaration. It was approved by the Institutional Review Board. Written informed consent did not apply because of the observational and retrospective design of the study. Data were anonymized prior to analysis. The use of these data was authorized and registered with the national data protection commission .The meeting took place twice a month. The contribution of at least one physician of each of the following core disciplines was necessary: an interventional radiologist, a vascular surgeon, an angiologist, and a nephrologist.The discussion of each patient’s chart was conducted using a systematic approach. 1/ The physician in charge of the patient reported his/her history, comorbidities, clinical aspects  and the patient’s wishes or opinion regarding treatment. 2/ A radiologist presented and commented the patient’s radiological exams. 3/ The referent physician listed the arguments for and against a revascularization among a list established collectively. Arguments favouring revascularization included a resistant hypertension, an unexplained worsening of renal function, an unexplained sudden pulmonary oedema ,10, an uAccording to current standards , medicalPercutaneous endovascular revascularization was performed by senior interventional radiologists or senior vascular surgeons. The procedures were performed through a femoral approach unless the angle between the aorta and the renal artery needed a humeral approach. A 6-F introducer sheath was first placed in the aorta. A standardised endoarterial bolus of 2,500UI of unfractioned heparin was administered. A 0.018-inch guide wire was inserted through the catheter. The stenosis was pre-dilated with a 5-6mm balloon . Then a 5-6mm balloon-expandable stent  was deployed. The length of the stent was adapted to the length of the stenosis.Forty-nine patients were included . BaselinTwenty-six patients (53%) were assigned to medical treatment alone and 23 (47%) to medical treatment + revascularization. Among patients with a decision of revascularization, 3 (13%) were assigned to open surgery . For theThere was no significant difference between the medical treatment and the revascularization groups except for diastolic blood pressure and peak systolic velocity Doppler data .Respectively 24% (12 patients), 12% (6 patients), and 37% (18 patients) of decisions were not consistent with the 2013 AHA, the 2011 ESC, and the 2017 ESC guidelines.According to the 2013 AHA guidelines, revascularization was recommended (guideline class I to IIa) for 19 patients (39%), could be considered (guideline class IIb) for 13 patients (27%), and was not recommended for 17 patients 35%; . Among tAccording to the 2011 ESC guidelines, revascularization was recommended for no patient (0%), could be considered for 24 patients (49%), and was not recommended for 25 patients 51%; . Among tAccording to the 2017 ESC guidelines, revascularization was recommended for no patient (0%), could be considered for 8 patients (16%), and was not recommended for 41 patients 84%; . Among tThe endovascular revascularization procedure failed due to impossible renal artery catheterization for 2 patients. One per-procedure stent thrombosis occurred, followed by thrombo-aspiration and the deployment of a new stent during the same intervention. Three patients developed minor local hematomas without need for a transfusion. No re-stenosis was observed during follow-up. No grade 3 adverse event was reported related to endovascular or open surgical procedures.In the Medical treatment group, at one-year follow-up, patients experienced no significant change in blood pressure values, number of antihypertensive drugs, eGFR and proteinuria Tables  and 4. Ap = 0.007), diastolic blood pressure  and a reduction of the number of antihypertensive drugs . The restoration of renal perfusion pressure consecutive to revascularization may have, at least for some patients, reduced the hypersecretion of renin by the juxtaglomerular apparatus, and thus facilitated blood pressure control. The improvement of blood pressure control, although an intermediate criterion, may be of clinical significance, as each difference of 20 mmHg of systolic blood pressure (or 10 mmHg of diastolic blood pressure) is associated with a more than two-fold difference in stroke-related death . As oppoWe did not identify any significant change in eGFR and proteinuria among patients who benefited from revascularization over the one-year follow-up. As demonstrated in a recent study , in the No significant improvement in blood pressure values and number of antihypertensive drugs was observed in the medical treatment group. Even if we cannot exclude that this negative result is related to a lack of power or to sampling fluctuations, the change in blood pressure over the one-year follow-up, an increase of 6 mmHg for the systolic blood pressure and a decrease of 1 mmHg for the diastolic blood pressure, had no clinical relevance. Many patients included in the study had benefited from years of specialized medical follow-up prior to the diagnosis of arterial renal disease. In the medical treatment group, patients were already prescribed a mean±SD 2.4±1.1 antihypertensive drugs, and 81% were treated with angiotensin converting enzyme inhibitor or angiotensin receptor-blocker. Thus, room for improvement based on antihypertensive drug optimization may have been quite limited in this context. Moreover, mean blood pressure values in this group were not that high (142/76mmHg) and therefore not all patients needed blood pressure optimization.There are several limitations to the study. The generalizability of the results may be limited by its single-centre and retrospective nature. The restricted sample size precluded from proper multivariate analyses, and restricted conclusions to significant results. Our methodological approach prevented us from conducting comparisons between patients evolution according to the treatment received: the group assignment resulted from a medical decision and not from a randomization; thus, the two treatment groups were not comparable. Follow-up was restricted to one year and only intermediate criteria were considered. The final decision is not fully transparent because it resulted from physicians’ experience and knowledge; providing an algorithm is therefore impossible since it is a “patient-based” tailored approach. Lastly, albuminuria, which may help in the identification of patients who could benefit from revascularization ,33,34, wIn conclusion, based on a renal artery disease multidisciplinary meeting, revascularization decisions were in accordance with the 2013 American Health Association and the 2017 European Society of Cardiology guidelines for only 78% and 22% of patients, respectively. Patients on whom we performed a renal artery revascularization exhibited a significant improvement in blood pressure control with few adverse events. Whether or not this beneficial effect results from this decisional process should be formally tested in a prospective randomized controlled trial.


Controversies exist regarding the optimal blood pressure (BP) level that is safe and provides cardiovascular protection in patients with type 2 diabetes mellitus (T2DM) and coexistent coronary artery disease. Several new glucose-lowering agents have been found to lower BP as well, making the interaction between BP and T2DM even more complex.With the reference to recent literature, this review article describes the potential mechanisms of increased risk of hypertension in T2DM and outlines the possible optimal BP levels based upon recommendations on the management of hypertension by the current guidelines, in combination with our research findings, for type 2 diabetic patients with coronary artery disease.The development of hypertension in T2DM involves multiple processes, including enhanced sympathetic output, inappropriate activation of renin-angiotensin- aldosterone system, endothelial dysfunction induced through insulin resistance, and abnormal sodium handling by the kidney. Both AGE-RAGE axis and adipokine dysregulation activate intracellular signaling pathways, increase oxidative stress, and aggravate vascular inflammation. Pancreatic β-cell specific microRNAs are implicated in gene expression and diabetic complications. Non-pharmacological intervention with lifestyle changes improves BP control, and anti-hypertensive medications with ACEI/ARB, calcium antagonists, β-blockers, diuretics and new hypoglycemic agent SGLT2 inhibitors are effective to decrease mortality and prevent major adverse cardiovascular events. For hypertensive patients with T2DM and stable coronary artery disease, control of BP < 130/80 mmHg but not < 120/70 mmHg is reasonable, whereas for those with chronic total occlusion or acute coronary syndromes, an ideal BP target may be somewhat higher (< 140/90 mmHg). Caution is advised with aggressive lowering of diastolic BP to a critical threshold (< 60 mmHg).Hypertension and T2DM share certain similar aspects of pathophysiology, and BP control should be individualized to minimize adverse events and maximize benefits especially for patients with T2DM and coronary artery disease. Epidemiologic studies have shown that hypertension and type 2 diabetes mellitus (T2DM) are global public health issues and become the major cause of disease burden and mortality , 2. The Obviously, the actual mechanism of hypertension in T2DM is complex and multi-factorial,including enhanced sympathetic output, inappropriate activation of the renin-angiotensin-aldosterone system (RAAS), oxidative stress, inflammation, insulin resistance-mediated endothelial dysfunction, and abnormal sodium handling by the kidney Fig. . NeverthApproximately 50% of hypertensive patients manifest systemic insulin resistance or hyperinsulinemia, which plays an important role in the development of both T2DM and hypertension . Loss ofObesity  is a key pathogenic factor behind the coexistence of both T2DM and hypertension . There i2 synthase may play a role . The C1q/TNF-related protein 1 (CTRP1) is expressed at high levels in adipose tissue by proinflammatory cytokines, and increased levels of CTRP1 are associated with the extent of coronary atherosclerosis [Dysregulation of adipose tissue-derived adipokines is involved in the development of proliferative and inflammatory vascular diseases, including hypertension. Adiponectin, a protein widely implicated in the pathogenesis of insulin resistance, has a profound effect on metabolism and vasculature and conveys anti-hypertensive properties , 33. In y a role . Adiponey a role . Leptin,y a role . The C1qclerosis  and reduclerosis , 39. It clerosis . In addiclerosis –42. TakeChronic hyperglycemia and altered redox state in T2DM increase the formation and accumulation of advanced glycation end-products (AGE). Binding of AGE to receptor for AGE (RAGE) triggers several intracellular signaling pathways and increases the expression and release of inflammatory cytokines, generation of ROS, and activates nuclear factor kappa-B. These alterations might produce contraction of the arterial wall , which cIt is well recognized that kidney and cardiovascular system are inextricably interlinked as determinants of ambient BP levels in both normal and diseased conditions. The complex interplay between renal disease and hypertension appears to be especially evident in patients with T2DM, who are inherently at high risk for progressive glomerular damage via vascular fibrosis, calcification, prothrombotic effects, and vascular damage . It has Recent studies showed that a number of pancreatic β-cell specific microRNAs, a group of noncoding RNAs that are multifunctional, are implicated in the gene expression and various disease processes. For example, diabetic vascular complications are associated with increased levels of miR-223, miR-320, miR-501, miR-504 and miR-1 and decreased levels of miR-16, miR-133, miR-492 and miR-373 .The beneficial effects of anti-hypertensive drugs on clinical and cardiovascular outcomes are well established , and strData from several landmark trials and meta-analyses demonstrate benefit of decreased systolic BP with intensive BP control in reducing the risk of ischemic as well as hemorrhagic stroke for patients with T2DM and hypertension –58. ReceSince physiological coronary blood flow predominantly occurs during diastole, diastolic BP would be expected to have greater clinical relevance. The INVEST study showed that cardiovascular risk was reduced for type 2 diabetic patients with a diastolic BP < 90 mmHg but was increased for those with a diastolic BP < 70 mmHg . SimilarThe importance of optimal diastolic BP levels in determining clinical outcomes for patients with coronary artery disease was further substantiated by several recent studies. Peri-Okonny et al. assessed the relationship between reduced diastolic BP and occurrence of angina in a cohort of 1259 patients with stable coronary artery disease (more than one-third of them had diabetes). In the unadjusted model, diastolic BP was associated with angina with a J-shaped relationship (p for nonlinearity = 0.027), with a progressive increase in odds of angina as diastolic BP below 70–80 mmHg. Patients with a diastolic BP of 60 mmHg had 1.37-fold increased risk of angina compared with those having a diastolic BP of 80 mmHg. This association remained significant after adjustment for demographics, comorbidities, heart rate, systolic BP, and anti-angina and anti-hypertensive medications .Angiographically-documented CTO occurs in around 20–30% of type 2 diabetic patients with or without hypertension, especially for those with multi-vessel disease . PercutaRecently, White et al. evaluated the relationships between achieved clinician-measured BP and cardiovascular outcomes in 5380 patients with T2DM and recent acute coronary syndromes of the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) trial. Risks of major adverse cardiac events and cardiovascular death or heart failure were analyzed using a Cox proportional hazard model with adjustment for baseline covariates in 10 mmHg increments of diastolic BP from ≤ 60 to > 100 mmHg and systolic BP from ≤ 100 to > 160 mmHg during 2-year follow-up. Systolic BP of 131 to 140 mmHg and diastolic BP of 81 to 90 mmHg were used as reference groups. They observed a U-shaped relationship between cardiovascular outcome and BP. Importantly, average follow-up BP < 130/80 mmHg was associated with worsened cardiovascular outcomes, and the degree of risk was notably greater for those who had achieved average follow-up BP of < 120/70 mmHg .The anti-hypertensive strategies most appropriate to type 2 diabetic patients with coronary artery disease have been widely studied.It becomes increasingly important to individualize BP treatment to minimize adverse events and maximize benefits. Non-pharmacological modalities include weight loss, increased potassium-based diet, reduced total intake of sodium and fat , and regular physical activity and exercise. Although the cardiovascular benefits of lifestyle changes were not evaluated in type 2 diabetic patients, their implementation seems reasonable as these measures could favorably affect glycemia, lipid profile and BP level . CertainNot so infrequently, elderly patients with T2DM with or without coronary artery disease may experience a high systolic BP in the presence of a low diastolic BP, reflecting increased aortic stiffness. In this circumstance, the lowering of systolic BP (< 140 mmHg) is clearly beneficial even at the price of further lowering diastolic BP. However, for patients with coronary artery disease and diastolic BP below 60 mmHg, caution is advised during treatment. Alternative medications for angina  and revascularization or other non-pharmacological interventions may be more beneficial as opposed to further titration of anti-hypertensive medications.Several classes of anti-hypertensive agents have been used in the treatment of patients with T2DM and coronary artery disease.ACEI/ARB are the first-line anti-hypertensive drugs in type 2 diabetic patients with coronary artery disease because they have at least similar  or even Calcium antagonists are commonly used for treating hypertension in type 2 diabetic patients with or without coronary artery disease, particularly in the elderly with isolated systolic hypertension . In typeDespite some concern about the increased risk for metabolic and electrolytic disturbance, diuretics are effective for the treatment of hypertension in type 2 diabetic patients. In post hoc analyses of patients with hypertension and T2DM, thiazide resulted in a significant reduction in cardiovascular events, all-cause mortality, and hospitalization for heart failure compared to placebo, and generally was shown to be non-inferior to other antihypertensive agents. Benefits attributed to thiazide diuretics in terms of cardiovascular event reduction outweigh the risk of worsening glucose control in type 2 diabetic patients . Low dosHypertension is underpinned by high sympathetic nerve activity especially in younger or middle-age subjects. β-blockers reduce heart rate, decrease catecholamine-induced inflammatory reaction, and improve endothelial shear stress,which exert a beneficial effect on coronary blood flow and clinical outcomes . β-blockThe role of certain new anti-diabetic medications including dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon like peptide 1 (GLP-1)agonists, and sodium-glucose cotransporter 2 (SGLT 2) inhibitors, in BP control besides their glucose lowering effects in diabetic individuals has been investigated.DPP-4 inhibitors increase endogenous GLP-1 by inhibiting the endogenous substance responsible for its degradation . SeveralThe CAROLINA (Cardiovascular Outcome Study of Linagliptin vs. Glimepiride in Type 2 Diabetes) randomized clinical trial examined the effect of treatment with the DPP-4 inhibitor linagliptin vs. the commonly used sulfonylurea glimepiride on cardiovascular safety in patients with relatively early T2DM and cardiovascular risk factors or established atherosclerotic cardiovascular disease. The results showed that the use of linagliptin compared with glimepiride over a median 6.3 years led to a noninferior risk of composite cardiovascular outcome . LikewisThese agents belong to a new class of unique oral glucose-lowering drugs and at the same time pertain multifaceted effects on hemodynamic and metabolic parameters beyond glycemic control , 103. ReThe use of SGLT2 inhibitors also impacts favorably clinical outcome especially in patients with T2DM and cardiovascular disease . In the The mechanism underlying the BP decrease by SGLT2 inhibitors remains unclear, and may include diuresis due to their chronic natriuretic and osmotic diuretic effects, weight loss, nephron remodeling, decrease in sympathetic overactivity and arterial stiffness, and increase in HDL cholesterol levels –120. TheIt is generally accepted that coronary revascularization with either drug-eluting stent-based PCI or coronary artery bypass grafting confers a substantial benefit to long-term outcome , 121. InThe available literature and results of recent clinical studies and meta-analyses suggest that the primary BP goal in patients with established coronary artery disease is below 140/90 mmHg. Control of BP < 130/80 mmHg but not < 120/70 mmHg is reasonable for hypertensive and type 2 diabetic patients with stable coronary artery disease, whereas for those with CTO or acute coronary syndromes, an ideal BP target may be somewhat higher (< 140/90 mmHg) as recommended by the current guidelines , 17. CauMost previous studies concerning the BP management of type 2 diabetic patients with coronary artery disease rely heavily on in-office BP measurement, however, ambulatory BP monitoring certainly improves baseline BP assessment and risk stratification after anti-hypertensive treatment , 127. ReThe mechanism of hypertension in T2DM is complex, involving multiple neuro-humoral and metabolic factors, and both conditions share several similar aspects of pathophysiology. For type 2 diabetic patients with coronary artery disease, the optimal BP targets  vary based on clinical status in a given individual, and the strategy of BP control should be individualized to minimize adverse events and maximize benefits. Novel information as such is useful for clinicians and researchers to further add new knowledge on pathophysiology and therapeutic goal in diabetes and hypertension.


There is limited data on the prevalence of thyroid dysfunction in Ghanaian individuals with chronic kidney disease (CKD). Studies exploring the effect of thyroid hormones on renal function decline are also scanty. Unrecognized thyroid dysfunction in CKD may increase the burden of adverse health outcomes. The aim of this study was to determine thyroid hormone status and lipid profiles in patients with CKD attending the Renal Unit of the Korle-Bu Teaching Hospital.60 clinically euthyroid patients with CKD, and 65 clinically euthyroid subjects without CKD were recruited for this study. Estimation of effective glomerular filtration rate (eGFR) was done using the 4-variable Modification of Diet in Renal Disease (MDRD) formula with subsequent staging of CKD (stages 2-4). Collected venous blood samples from all study participants were analyzed for creatinine, free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), total cholesterol (TC), high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) and triglycerides (TG).Levels of TC, HDL, LDL, and TSH levels did not differ significantly between the two study groups. However, TG, VLDL, FT3 and FT4 levels were significantly higher in CKD patients than in the control group. TC, TG, HDL, LDL, VLDL and TSH levels were not significantly different between stages of CKD in study subjects, although FT4 and FT3 levels were significantly different between all stages of CKD.Higher levels of FT3 and FT4 but not TSH, are associated with the incidence of CKD and eGFR decline in Ghanaian CKD patients. Chronic Kidney Disease (CKD) is a disease spectrum characterized by progressive loss of renal function over a period of time. It is manifested by decreased kidney function that lasts longer than three months, as quantified by measured or estimated glomerular filtration rate . A trendThis case control study was conducted over a 12 month period from July 2014 to June 2015 at the Renal Unit of the Korle-Bu Teaching Hospital (KBTH), Korle-Bu, Accra. KBTH is the leading national referral center in Ghana and the only tertiary health facility in the southern part of Ghana. There are clinical services for both adult and pediatric renal patients. 60 non-dialysis CKD patients of different CKD stages (stages 2-4) with no previous history of thyroid dysfunction accessing services at the Renal Unit of the KBTH and 65 apparently healthy control subjects residing in the nearby communities surrounding KBTH were recruited for this study. All recruited patients with non-dialysis dependent CKD stages 2-4 were assessed for thyroid function. Informed consent was obtained from all study participants prior to their inclusion in this study. CKD patients were made to understand that opting out from this study would not affect their medical care. A questionnaire was administered to each patient at recruitment to obtain demographic and anthropometric data, as well as full clinical history including diabetes status and polycystic kidney disease. At the assessment, a dipstick urinalysis was also performed. Blood pressure (BP) was measured by first allowing the study participant to rest for 15 minutes prior to measurement.1]. Proteinuria was defined as a dipstick reading of trace or 1+, or heavy . Stages of non-dialysis-dependent CKD (stages 2-4), were defined according to the American National Kidney Foundation as follows: Stage 2: eGFR 60-89 ml/min/1.73 m2, stage 3: eGFR 30-59 ml/min/1.73m2 and stage 4,15-29 ml/min/1.73 m2 [1].Chronic kidney disease (CKD) was defined as the occurrence of kidney damage or decreased kidney function manifested by abnormal albumin excretion and quantified by measured estimated glomerular filtration rate (eGFR) of ≤90 mL/min that persisted for more than three months with proteinuria. The eGFR was calculated using the abbreviated Modification of Diet in Renal Disease (MDRD) study formula [Participants consented by endorsing a written consent form before samples were collected. 5ml venous fasting blood sample was collected from each participant and dispensed into different sample tubes. Samples in plain tubes were processed for total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-c), VLDL, serum creatinine, TSH, FT3 and FT4 estimation. Thyroid hormone Assay  kits, purchased from CentronicGMbH  were used to assay TC, TG and serum creatinine. HDL-c was determined using kits from Biosystems . The manufacturer's protocol was followed for all tests using Vital Scientific Microlab 300M (VSM 300) automated analyzer. LDL-c was calculated using Friedwald equation . Quantifinstitutional ethical clearance and approval for the conduct of the study was given by the ethical and protocol review committee of the College of Health Sciences (CHS), Korle-Bu.Continuous data were presented as mean and standard deviation (mean ± SD). Student t-test was used to compare two group means and ANOVA for three or more group means using Graphpad Prism 5.0. Hypertension prevalence, CKD stages and thyroid dysfunction groups were expressed in percentages.125 participants who met the inclusion criteria were recruited for this study. Clinical parameters and demographic data of the study population are presented in Comparison of biochemical parameters of CKD patients and the control group is presented in Various biochemical parameters and thyroid hormone profiles stratified by CKD stage are presented in Results of thyroid function status for our study groups are shown in The impact of thyroid dysfunction on renal function is linked to the role of the kidneys in metabolism, degradation and excretion of several substances including thyroid hormones. It is therefore expected that any impairment in kidney function could lead to altered thyroid physiology . Current2 [Conversely, cardiac output and circulating blood volume are increased in hyperthyroidism, resulting in increased creatinine clearance and decreased serum creatinine . Althoug2 . The dis2 . Only 2%2 . In futu2 .We found that higher levels of FT3 and FT4, but not low levels of TSH, to be associated with incident CKD and an eGFR decline. To improve upon the biochemical criteria for diagnosing thyroid dysfunction, additional criteria for calculating eGFR and larger sample size may be required in assessment of thyroid hormone status.Thyroid dysfunction causes significant changes in kidney function and kidney diseases can be associated with thyroid disorders;Alterations in Thyroid hormone status and dyslipidemia are common disorders in patients with CKD.The equation developed from the MDRD study may not provide a more accurate estimation of GFR in our study group;Our findings highlight the importance of regular screening for thyroid dysfunction in patients with CKD using improved biochemical criteria for diagnosing thyroid dysfunction.


Combined and sequential liver–kidney transplantation (CLKT and SLKT) is a definitive treatment in children with end-stage organ failure. There are two major indications: - terminal insufficiency of both organs, or - need for transplanting new liver as a source of lacking enzyme or specific regulator of the immune system in a patient with renal failure. A third (uncommon) option is secondary end-stage renal failure in liver transplant recipients. These three clinical settings use distinct qualification algorithms. The most common indications include primary hyperoxaluria type 1 (PH1) and autosomal recessive polycystic kidney disease (ARPKD), followed by liver diseases associated with occasional kidney failure. Availability of anti-C5a antibody (eculizumab) has limited the validity of CLKT in genetic atypical hemolytic uremic syndrome (aHUS). The liver coming from the same donor as renal graft (in CLKT) is immunologically protective for the kidney and this provides long-term rejection-free follow-up. No such protection is observed in SLKT, when both organs come from different donors, except uncommon cases of living donation of both organs. Overall long-term outcome in CLKT in terms of graft survival is good and not different from isolated liver or kidney transplantation, however patient survival is inferior due to complexity of this procedure. Combined liver–kidney transplantation (CLKT) is a procedure in which liver  and kidney allografts, coming from the same (deceased in most cases) donor, are transplanted to the pediatric recipient during a single surgical procedure. Sequential liver–kidney transplantation (SLKT) is divided into two distinct stages: isolated transplantation of the liver (or kidney) and  – transplantation of the kidney (or liver) allograft, coming from different (deceased) or the same living-related donors. This review describes aspects of surgical and post-transplant management, immunosuppression-related issues, several specific indications for CLKT and SLKT, as well as the outcomes of both procedures.Combined liver and kidney transplantation (CLKT) is a very uncommon procedure  usually does not exceed 30 cases), therefore should be performed by experienced surgical and multidisciplinary teams, as its complexity may be the reason of early failure with fatal consequences, especially in young children of low body weight . CLKT isIn anuric patients, e.g., in children with ARPKD after bilateral native nephrectomy performed early in life , CLKT isIn cases of CLKT performed in patients with hyperoxaluria type 1 (PH1), the intensive hemodiafiltration should be continued after transplantation to remove the excess oxalate, intensively mobilized from the body deposits to plasma and urine. This approach is mandatory in cases of delayed renal graft function, however it might also be used in cases of immediate renal graft function in selected patients with severe systemic oxalosis and high oxalate burden. The aim is to protect the transplanted kidney against rapid recurrence of nephrocalcinosis. The optimal duration of post-transplant hemodiafiltration is not defined, however it is reasonable to monitor plasma oxalate concentration and maintain extracorporeal removal of oxalate until stable normalization below the saturation level (< 30 μmol/l) is achieved with good renal function –6.During the whole CLKT surgery, particular attention should be given to achieving good surgical hemostasis and controlling coagulation. In patients with liver-related coagulopathy, the major disturbances should be corrected before surgery with fresh frozen plasma (FFP), cryoprecipitate, or platelets, if necessary. The infusion of tranexamic acid may be given to control fibrinolysis during surgery, particularly in patients with a history of previous abdominal surgeries or advanced portal hypertension with multiple intra-abdominal varices and hypersplenism, as in these cases native hepatectomy is difficult and associated with marked blood loss. One the other hand it is important not to overcorrect coagulation, as it may lead to vascular thrombotic complications after reperfusion of both organs, thus administration of FFP, platelets, cryoprecipitate, fibrinogen formulations, and other procoagulants during surgery should be limited to the minimum necessary. Apart from routine laboratory tests, the best intraoperative monitoring of coagulation during CLKT is provided by repeated thromboelastometry, which shows real clinical coagulation status and guides adequate treatment. In some cases the infusion of catecholamines (dopamine and norepinephrine) should be given to maintain adequate blood pressure without fluid overload..H2O by supplementation of 100% of abdominal drainage volumes and hourly diuresis. Hematocrit is kept between 25 and 30% during the whole perioperative period and coagulation should not be corrected unless there is clinically symptomatic bleeding or the international normalized ratio (INR) exceeds 3–3.5. Administration of blood-driven products  should be kept to a minimum and related to the current needs of the recipient, measured losses, and results of laboratory tests. Our center uses anticoagulants (fractionated or low molecular weight heparin) postoperatively for 7–14 days as routine antithrombotic prophylaxis.Doppler ultrasound examination should be done in the operating room before wounds are closed to ensure adequate blood flow through vascular anastomoses. Early post-operation care requires staying in the pediatric intensive care unit as mechanical ventilation may be necessary for 1–2 days. Very close monitoring of the patient and both transplanted organs is mandatory in the early postoperative period. Very detailed fluid balance (both water-electrolyte and volume), including all drained losses and hourly urine output should be kept to promote perfusion of the grafts and maintain adequate diuresis from the transplanted kidney . CentralPatency of vascular anastomoses should be checked twice daily with Doppler ultrasound during the first 7 days after transplantation and then less frequently until discharge.In most clinical situations of sequential procedure (SLKT), the liver transplantation precedes kidney transplantation, with the exception of a few patients with renal polycystic disease and liver fibrosis. The transplantation surgery of each individual graft in SLKT is not different from combined transplantation and is just performed as two separate procedures. In SLKT, most often one of the organs may be procured from a living donor and another one from a deceased donor, however using the same living-related donor has also been reported .There are data suggesting a protective effect of the liver to the kidney when procured from the same donor and transplanted during one surgical procedure (CLKT), which translates to a low rate of acute rejection compared to isolated kidney or liver transplantation, and results in improved renal allograft survival , 8. TherP = 0.002) and overall kidney graft survival (P = 0.015) were significantly diminished among sensitized patients. Differences in patient survival translated to an estimated half-life of 10.3 years among nonsensitized recipients, versus 7.8 years among sensitized recipients. Therefore, presensitization may need to be considered in a risk stratification of CLKT   . The lat as well , 25. Theive CLKT .Recent advances in developing RNA interference (RNAi)-based therapeutics, targeting glycolate oxidase and hydroxyproline dehydrogenase, aimed at treating liver-related diseases , may change the policy of final treatment of PH1. The new drugs  are able to modify oxalate turnover to the extent that they probably will replace other therapies and limit the indications for performing CLKT/SLKT in the future .GRHPR). Despite the generally milder clinical course (compared to PH1) and fact that expression of this enzyme is not limited to the liver, cases (both pediatric and adult) of renal allograft failure due to recurrence of oxaluria and presence of oxalate deposits in transplanted kidneys have been described [There are reports on failure of isolated kidney transplantation in hyperoxaluria type 2 (PH2), associated with genetic mutations resulting in decreased activity of glyoxylate reductase/hydroxypyruvate reductase  presents in early infancy with severe renal disease, congestive heart failure, and pulmonary hypoplasia. The second group  presents predominantly progressive renal failure and Caroli syndrome in the liver, whereas the two remaining groups—infantile and juvenile—present milder renal disease and more severe hepatic complications, mostly expressed as hepatic fibrosis [2) with successful outcome, showing that the rule of qualification may be individual. Moreover, successful CLKT was associated with significant improvement of life quality and improvement of growth velocity in this series [Autosomal recessive polycystic kidney disease (ARPKD) is one of the ciliopathies and is caused by mutations of the fibrosis , 30. Manfibrosis –33. Therfibrosis –36. Therfibrosis . Howevers series . The avaTMEM67 gene) has been identified [Up to 5% of patients with nephronophthisis present hepatic fibrosis and this clinical pattern is known as Boichis syndrome. The relevant genetic background . The defect of this enzyme leads to multiorgan failure and disability caused by chronic intoxication with methylmalonic acid and creating megamitochondria in affected organs [Methylmalonic acidemia (MMA) is heterogenous inborn error of metabolism most typically caused by mutations in the vitamin-B12-dependent enzyme methylmalonyl- CoA – mutase  is a genetic disease caused by mutations in the gene antation . Membranantation . The preantation . Isolateantation . Successantation .Type 1a glycogen storage disease (GSD1) is an autosomal recessive disorder with deficiency of glucose-6 phosphatase and related multiorgan accumulation of glycogen resulting in multiple dysfunctions, including hepatomegaly and liver failure, development of hepatocellular adenomas, and renal failure in the course of secondary glomerulosclerosis. Two successful case reports of CKLT in GSD1 have been published , 51.Combined liver–kidney transplantation was used as a therapeutic option in patients with genetic aHUS at high risk of recurrence before the availability of anti-C5 monoclonal antibody (eculizumab), and the relevant recommendations concerning eligibility of patients for CLKT or isolated liver transplantation have been released by the consensus group. Successful CLKT may be curative in aHUS, however this procedure is not free from significant complications and peri-transplant overall mortality rate is about 15% –54. Curr2 at 5–10 years after liver transplantation is about 30% [2). However, conversion to mTORi was associated with a higher risk of acute rejection  and study discontinuation due to adverse events  up to 1 year after randomization [There are two distinct subgroups of patients who develop renal failure after liver transplantation. One includes patients who received liver transplant having developed CKD at stage 4/5 or developing chronic post-acute renal failure in the course of hepatorenal syndrome (HRS). The second group includes patients with normal renal function at the moment of liver transplantation, but who develop chronic kidney injury several years thereafter, mainly due to nephrotoxicity of calcineurin inhibitors (CNI). There are no specific pediatric recommendations regarding this, however there is ongoing discussion on optimal therapy in the first setting, conducted among transplant physicians and surgeons treating adult patients. The consensus guidelines divide (adult) candidates for CLKT into two renal categories: (1) persistent acute kidney injury (AKI) ≥4 weeks, or eGFR ≤35 ml/min (by MDRD-6 formula) or eGFR ≤25 ml/min , and (2) CKD for 3 months before qualification, defined as eGFR ≤40 ml/min (by MDRD-6 formula) or eGFR ≤30 ml/min  or proteinuria ≥2 g/day or chronic pathology in renal biopsy  or metabolic disease involving kidneys . These cbout 30% , howeverbout 30% . There about 30%  and the bout 30% . There hmization . A similmization . ClinicaP = 0.005) [P = 0.4), which is in contrast to the opinion of a protective effect of the liver on the renal graft. Overall, the early post-transplant period in CLKT is associated with high risk for patients , while long-term graft survival is not inferior compared to isolated transplantations. Data from the Scientific Registry of Transplant Recipients (SRTR), including 152 primary cases of CLKT (1987–2011), shows that patient survival was 86.8, 82.1, and 78.9%, liver graft survival was 81.9, 76.5, and 72.6% and renal graft survival 83.4, 76.5, and 66.8% at 1, 2, and 10 years, respectively. Similar survival rates for isolated liver transplantations were 86.7, 81.2, and 77.4%, and for isolated kidney transplantations 98.2, 95.4, and 90%, respectively. In patients undergoing CLKT, PH1 as the underlying disease  was associated with reduced patient, liver, and kidney graft survival . The study also showed that during one decade, graft outcome after CLKT significantly improved (p = 0.04 for liver and p = 0.02 for kidney transplantation), however this did not translate into better patient survival (p = 0.2). The study demonstrated the center effect on overall patient survival, with inferior outcomes in children receiving CLKT in centers with minor experience (defined as 1–2 CLKTs performed) [p = 0.002), however (death-censored) graft survival was similar compared to isolated kidney recipients  [There are variable data on long-term outcomes of CLKT, depending on the series of patients and specific indications (when compared to outcomes of isolated organ transplantation). The major difference is also related to the primary parameter of outcome: - incidence of acute rejection, or - patient and graft survival. Overall, the incidence of acute rejection in CKLT is lower compared to isolated liver or kidney transplantation (reports from UNOS and CTS databases) , 14, whirformed) . Overallrformed) . The UNO• Indications for combined or sequential liver–kidney transplantation (CLKT/SLKT) include parallel or sequential failure of both organs, the need to replace the liver as the source of a specific missing enzyme in a patient with renal failure, and the need for renal transplantation in the recipient of liver graft due to renal failure.• The selection of optimal approach (CLKT vs. SLKT) is individual depending on specific clinical indications, current status of both organs, general condition of the recipient, and experience of the center.• In CLKT, the liver exerts a protective immunological effect upon the kidney, which translates to low acute rejection rates and good long-term graft survival, however this effect seems to be limited to non-sensitized patients.• In SLKT, there is no protective effect, as in most cases liver and kidney come from different donors, however the HLA matching between sequential organs (liver and kidney) is important for future outcome.• Overall outcome of CLKT/SLKT is good in terms of long-term graft survival, however it is not superior to an isolated liver or kidney transplantation setting in terms of patient survival, which is related to the complexity of transplantation procedures, especially in young children and the high risk during the early perioperative period.Qualification for organ transplantation in children with primary type 1 hyperoxaluria (PH1) is based on:Basic rule: ‘kidney first’ in all casesBasic rule ‘liver first’ in all casesEvaluation of GFR and adjusting strategy to the stage of CKDDegree of liver failure2.Transplanted liver protects renal graft against acute rejection:AlwaysWhen both grafts come from the same donor and the recipient is not hyperimmunizedWhen the liver comes from living-related donor and the kidney from a deceased donorIf the time interval between the sequential transplantations exceeds 1 year3.During CLKT:Liver is transplanted first and then the kidneyBiliary anastomosis is performed before kidney reperfusionKidney reperfusion should precede liver reperfusionOptimal cold ischemia time for both organs should be not longer than 16 h4.When patients with ARPKD receive an isolated renal transplant:Liver function improvesThere is no effect of this procedure on native liverLiver volume decreases due to better fluid turnoverThere is a risk of recurrent cholangitis in the native liver, exacerbated by post-transplant immunosuppression5.CLKT in atypical hemolytic uremic syndrome (aHUS):Is a single effective curative procedureIs still widely performed, as monoclonal anti-C5 is not effective in most cases of isolated kidney transplantationsIs indicated only when a living-related donor is availableIs not currently regarded as first-line option, as repeated administration of monoclonal anti-C5 is effective in isolated kidney transplantation for prevention against recurrence of aHUS6.Imediate post-CLKT extracorporeal removal of oxalate in patients with primary type 1 hyperoxaluria (PH1):Is unnecessary, as well functioning liver transplanted easily eliminates whole pool of oxalateIs indicated in cases of  delayed graft functionIs contraindicated in patients plasma oxalate concentration > 100 μmol/l and good urine outputShould never be done due to high risk of bleeding


Varicocele is known to be associated with infertility and sperm disorders. The exact cause of this ailment is not fully understood. There are limited numbers of studies where venous blood gases (VBGs) of varicocele veins were determined with conflicting results. Therefore, we have investigated the pattern of VBGs in both internal spermatic and external spermatic varicocele veins and correlation with semen quality parameters in infertile individuals who underwent left microsurgical varicocelectomy.n = 27) undergoing left microsurgical varicocelectomy at a tertiary care hospital, were included in the study. Before surgery, semen parameters and scrotal color Doppler ultrasonography was performed. During surgery, blood sample was drawn from varicocele veins  and a peripheral arm vein of the same patient as a control. The VBGs of all veins under study were estimated and compared with each other. The VBGs were also correlated with various semen quality parameters. Data, expressed as Mean ± SD, regarding VBGs in three veins were analyzed using one-way ANOVA. The correlation between VBGs and semen quality parameters was determined using Pearson’s correlation. Differences were considered significant at p < 0.05.Patients (p < 0.01) in the internal spermatic vein compared with the external spermatic and the peripheral veins. Partial pressure of oxygen (pO2) and oxygen saturation (sO2) were higher (p < 0.01) in the internal spermatic vein compared with the peripheral vein. However, concentration of bicarbonate (HCO3) was lower (p < 0.01) in both veins compared with the peripheral vein. Partial pressure of carbon dioxide (pCO2) was also lower (p < 0.01) in the varicocele veins compared with the control vein.The pH was found to be higher (3 and pCO2 levels compared with the control peripheral veins. External spermatic veins had lower pCO2 and HCO3 but other VBGs were similar to the peripheral veins. The shift of VBGs of internal spermatic vein toward arterial blood pattern may be a missing link to understand the pathophysiology of varicocele.The internal spermatic veins had higher pH and oxygen tension, but lower HCO Varicocele is known to be associated with infertility and sperm disorders. Most researchers believe that renospermatic reflux is the main mechanism behind all mal-effects of varicocele –6. ThereTwenty-seven consecutive patients diagnosed with infertility and varicocele, undergoing microsurgical varicocelectomy under spinal anaesthesia, were included in the study after informed written consent. The calculated sample size was 23 using the following equation:α + Zβ)/C]2 + 3. The values for α (two tailed), β and r were 0.050, 0.300 and 0.500 respectively.N = [ as suggested by the World Health Organization .Scrotal CDUS was performed  using 10 mHz linear probe . Briefly2), partial pressure of carbon dioxide (pCO2), oxygen saturation (sO2), and bicarbonate (HCO3) values were determined.During surgery just before ligation of varicocele veins, 2.0 mL blood was drawn with a 27G needle inserted towards the direction of testes, in a heparinized syringe, from 1 to 2 internal spermatic veins and from external spermatic vein if found dilated (> 2.5 mm diameter). Peripheral blood sample from same individual was also drawn simultaneously from the wrist vein as a control. The patients did not receive oxygen inhalation at the time of blood sampling as well as for the previous 15 min at minimum. All patients maintained 97% or more oxygen saturation at room air. The blood samples were taken free of air, sealed, and blood gas analysis was performed immediately with a blood-gas analyser . The pH, partial pressure of oxygen . Tukey’s post hoc test was carried out to identify individual differences. The Pearson correlation test was employed to determine correlations between different variables. Level of significance was set at Out of twenty-seven patients, twenty-three (85.18%) had G2 varicocele and 4 (14.8%) had G3 varicocele. Age of the patients ranged from 20 to 43 (29.38 ± 7.94) years. Ten (37.04%) patients were 20–30 years old, 13 (48.15%) were between 31 to 40 years and 4 (14.81%) patients were 41–43 years old. Most of them (81.48%) were non-smokers.6 per mL, 16.89 ± 14.4%, 17.59 ± 13.49%, 58.11 ± 27.43%, and 7.11 ± 7.00% respectively  with PSV of subcapsular artery of left testes, testicular volume  and transverse diameter of testes. . Sperm count had significant negative correlation  with RI of left intraparenchymal artery, whereas progressive motility of sperms had negative correlation  with RI of left intraparenchymal artery as well as RI of left subcapsular artery   in the internal spermatic vein compared with the external spermatic and the peripheral veins. The pO2 and sO2 were elevated (p < 0.01) in the internal spermatic vein compared with the peripheral vein. Serum HCO3 concentration was lower (p < 0.01) in both internal and external spermatic veins compared with the peripheral vein. The pCO2 was also lower (p < 0.01) in both varicocele veins compared with the peripheral veins (Table Table 2, and pO2 levels but lower HCO3 and pCO2 levels in comparison to the peripheral vein. On the other hand, the external spermatic varicocele veins revealed different VBGs profile that was similar to the peripheral veins, except lower HCO3 and pCO2 levels. Previously, between 1968 and 1989, there were only three studies that addressed the composition of venous blood in varicocele veins [The current study demonstrates unique characteristics of the VBGs of internal spermatic varicocele veins, which are different from the peripheral veins. The internal spermatic veins have higher pH, sOle veins –16. Howe2 and pO2 levels were significantly higher in the internal spermatic varicocele vein compared with the peripheral vein. Nevertheless, further anatomical documentation of an arterial venous shunt mechanism is still required. Donhue and Brown reported in 1969 that the internal spermatic veins of varicocele patients had higher oxygen tension when the blood was drawn from the vein by inserting cannula in the direction of kidney. Anyhow this was not seen when the cannula was directed towards the testes. The authors proposed that the reflux of renal blood might be responsible for this mechanism [Our results have shown a clear shift of VBGs profile of the internal spermatic veins toward an arterial pattern. The exact mechanism is not clear, but renospermatic backflow, low oxygen consumption due to lower testicular function, or the presence of arterio-venous communications may be a possible clue to this change. There are a few human and multiple animal studies that demonstrate the presence of an arterio-venous shunt in the spermatic cord and testes –12. Baseechanism . In our echanism . There iechanism  and haveIn order to understand the significance of these findings, we determined the correlation of VBGs with testicular blood flow and semen parameters but no significant correlation was found.3 and pCO2 compared with the peripheral veins. The clinical importance of VBGs is difficult to ignore and the above-mentioned variation in blood gases may be a missing link or this may be another possible cause of higher intravenous pressure in these veins, to understand the pathophysiology of varicocele [Internal spermatic varicocele veins have significantly higher oxygen content and pH but lower HCOricocele . Further