Association of intrarenal blood flow with renal function and target organ damage in hypertensive patients with fibromuscular dysplasia: the ARCADIA-POL study.

INTRODUCTION Data on the assessment of intrarenal blood flow parameters in patients with renal fibromuscular dysplasia (FMD) are scarce. OBJECTIVES The aim of the study was to evaluate intrarenal blood flow parameters in patients with FMD and significant or nonsignificant renal artery stenosis (RAS). PATIENTS AND METHODS We evaluated intrarenal blood flow parameters by Doppler ultrasonography in 153 patients with renal FMD enrolled in the ARCADIA­POL study: 32 and 121 patients with and without significant RAS, respectively, compared with 60 matched patients with essential hypertension and 60 healthy controls. RESULTS Patients with FMD and significant RAS had a lower renal resistive index (RRI) compared with patients with FMD without significant RAS, patients with essential hypertension, and normotensive controls (mean [SD], 0.51 [0.08] vs 0.60 [0.07], 0.62 [0.06], and 0.61 [0.06], respectively; P <0.001). In patients with nonsignificant RAS, RRI correlated significantly with carotid intima-media thickness, 24­hour diastolic blood pressure, 24­hour pulse pressure, left ventricular diastolic function, known duration time of hypertension, and age. In patients with significant RAS, there was a significant correlation between RRI and known duration time of hypertension, left ventricular diastolic function, and age. In a separate, "per­kidney" analysis, renal arteries with FMD and significant RAS were characterized by lower RRI values, higher maximal blood flow velocity, higher renal aortic ratio, and longer acceleration time compared with renal arteries with FMD and nonsignificant RAS as well as renal arteries without FMD. CONCLUSIONS In contrast to atherosclerotic RAS, intrarenal blood flow in patients with FMD and RAS is preserved, confirming that renal vasculature is relatively intact in these patients.

A novel concept of immunological and allergy interactions in autism spectrum disorders: Molecular, anti-inflammatory effect of osthole.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by Diagnosis and Statistic Manual 5 (DSM-5) as persistent social interaction and communication deficient across multiple contexts. Various immunological findings have been reported in children with ASD, and co-existing allergic problems have been recorded in children diagnosed with ASD. Osthole, the effective component of Chinese traditional medicine, is reported to have anti-inflammatory effects. This study assessed the anti-inflammatory effect of osthole on the histamine-induced inflammatory responses in PBMC cells. METHODS: Peripheral blood mononuclear cells (PBMC's) from children with: (1) ASD group with co-existing allergies/asthma (n = 29); (2) ASD group without allergy/asthma (n = 29); (3) Allergy group (n = 30) and from typically developing age-matched control subjects (n = 28) were stimulated with either histamine, FXF, osthole or mixture of this substances. mRNA COX-2 gene expression, COX-2 production and inhibitory effect of tested substances on COX-2 were assessed after stimulation. RESULTS: Children with ASD may show either an innate proinflammatory response or increased activity of COX-2 which could display more impaired behavioral profile than children with non-inflamed. This study indicated that COX-2 may be involved in pathogenesis of ASD and/or allergy, and osthole could be used to decrease the effects of COX-2 in inflammation and ASD development. High incidence of allergy in ASD patients may indicate immune dysregulation that could be of relevance to the pathophysiology, symptomatology or neuroimmunology of ASD. CONCLUSIONS: This study shows that fexofenadine (FXF - antihistamine drug) and osthole exhibit selective COX-2 enzyme inhibitory activity. The selective COX-2 activity of osthole may explain further the anti-inflammatory properties of osthole in relieving congestion in allergic rhinitis, and as distinctive effects between FXF and osthole were observed, individual antihistamines may have different modes of action via the COX enzyme system.

A randomized comparison of modified subcutaneous "Z"-stitch versus manual compression to achieve hemostasis after large caliber femoral venous sheath removal.

OBJECTIVES: To compare subcutaneous "Z"-stitch versus manual compression in attaining hemostasis after large bore femoral venous access, and to assess its impact on venous patency. BACKGROUND: Structural interventions increasingly require large caliber venous access, for which convenient, safe, and effective method of postprocedural hemostasis is needed. "Z"-stitch has been introduced for this purpose in some centers but systematic data on its performance is limited. METHODS: This single center study randomized consecutive patients with femoral venous access sites requiring ≥10F sheaths to the "Z"-stitch or manual compression for hemostasis in a 2:1 fashion. There were three co-primary endpoints: time to hemostasis, time to ambulation, and a composite safety endpoint comprising vascular access site complications. Groin Doppler-Duplex was performed with the stitch in place and after its removal. RESULTS: 86 consecutive patients with 90 access sites were randomized. Mean age was 61.7 ± 19.1 years, 33.3% were men. Median sheath size was 14 F (range 10-22 F). Patients randomized to "Z"-stitch achieved hemostasis quicker [<1 min vs. 12.0 (IQR 10.0-15.0) min, P < 0.001] and ambulated sooner [7.0 (IQR 4.0-12.0) vs. 16.0 (IQR 11.8-20.3) hr post procedure, P < 0.001] when compared with manual compression alone. The "Z"-stitch reduced rates of access site complications (OR = 0.27, 95%CI 0.09-0.76, P = 0.01). All imaged veins were patent before and after stitch removal. CONCLUSIONS: The "Z"-stitch is a safe and effective method of achieving hemostasis after large bore femoral venous sheath removal and results in faster hemostasis, early patient ambulation and less access site complications, without compromising vein patency when compared with manual compression alone. © 2017 Wiley Periodicals, Inc.

Vitamin D Receptor Gene Polymorphisms Associated with Childhood Autism.

BACKGROUND: Autism spectrum disorder (ASD) is a group of heterogeneous, behaviorally defined disorders whereby currently no biological markers are common to all affected individuals. A deregulated immune response may be contributing to the etiology of ASD. The active metabolite of vitamin D3 has an immunoregulatory role mediated by binding to the vitamin D receptor (VDR) in monocyte, macrophages, and lymphocytes. The effects of vitamin D and interaction with the VDR may be influenced by polymorphism in the VDR gene. METHODS: Genetic association of four different VDR polymorphisms (Apa-I, Bsm-I, Taq-I, Fok-I) associated with susceptibility to the development of autism in children was investigated. RESULTS: We uniquely found an association between the presence of the T allele at position Taq-I and presence of the a allele at position Apa-I of the VDR gene with decreased ASD incidence. There was also an association between female gender and the presence of the T allele. We found no statistical significant correlation between VDR single nucleotide polymorphisms (SNPs) and vitamin D3 concentration in serum of ASD children. CONCLUSION: Genetic polymorphism in two SNP in VDR may be correlated with development of ASD symptoms by influencing functionality of vitamin D3 metabolism, while vitamin D3 levels were not significantly different between ASD and non-ASD children.

Altered plasma fibrin clot properties in hypertensive patients with obstructive sleep apnoea are improved by continuous positive airway pressure treatment.

AIM: We investigated plasma fibrin clot properties in high-risk hypertensive patients with obstructive sleep apnoea (OSA) and assessed the impact of continuous positive airway pressure (CPAP) treatment on clot phenotype. METHODS: We studied 50 hypertensive patients with clinically significant OSA (age 50.0 ±â€Š8.8 years, 39 M, 11 F). In total, 38 hypertensive patients without OSA balanced for age, sex, blood pressure, cardiovascular risk factors, and metabolic status served as controls. Plasma fibrin clot properties, including clot permeability coefficient, clot lysis time (CLT), and turbidimetric parameters of clot formation were determined. Patients underwent transthoracic echocardiography, carotid ultrasonography, evaluation of endothelial function and calcium score index of coronary arteries, and Doppler imaging of renal arteries. RESULTS: Compared with controls, OSA patients were characterized by more compact fibrin structure (lower median clot permeability coefficient, 6.00 vs. 7.25 10 cm; P < 0.001), impaired fibrinolysis (longer median CLT, 108.00 vs. 92.50 min; P < 0.001), and by faster clot formation (shorter median lag phase, 40.50 vs. 42.50 s; P = 0.041), and higher median maximum clot absorbency indicating denser fibrin networks (0.87 vs. 0.81; P = 0.028). Clot permeability coefficient and CLT correlated with apnoea-hypopnoea index (r = -0.46; P < 0.001 and r = 0.44; P < 0.001, respectively) as well with mean (r = 0.31; P = 0.003; r = -0.36; P = 0.001, respectively) and minimal oxygen saturation (r = 0.46; P < 0.001; r = -0.49; P < 0.001, respectively). After 3 months of CPAP treatment we observed an increase in clot permeability coefficient (5.95 vs. 7.60 10 cm; P = 0,001), shortened CLT (107.00 vs. 87.00; P = 0.006), a longer lag phase of fibrin formation (40.00 vs. 43.50 s; P = 0.013), and a trend toward lower maximum clot absorbency (0.86 vs. 0.81; P = 0.058). CONCLUSION: In hypertensive patients at high cardiovascular risk, OSA was associated with unfavourable prothrombotic fibrin clot characteristics, including hypofibrinolysis, which significantly improve as early as after 3 months of CPAP treatment.

Morning blood pressure surge and markers of cardiovascular alterations in untreated middle-aged hypertensive subjects.

The purpose of the study was to evaluate the degree of morning blood pressure surge (MBPS) and its relationship with markers of cardiovascular alterations in untreated middle-aged hypertensives. We studied 241 patients (mean age, 36.6 ± 10.7 years). Subjects with higher sleep-through MBPS (st-MBPS) were older (P = .003), had higher carotid intima-media thickness (cIMT) (P = .05) and lower E/A ratio (P = .01) than those with lower MBPS. Subjects with higher prewakening MBPS (pw-MBPS) had significantly higher deceleration time (P = .01) compared with those with lower pw-MBPS. St-MBPS correlated significantly with age, cIMT values, 24-hour systolic and diastolic BP, and systolic BP night-time fall. The significant correlations between pw-MBPS and cIMT values, deceleration time, 24-hour diastolic BP and systolic BP night-time fall were observed. A relationship between MBPS and cardiovascular alterations was observed both in dippers and nondippers, although in non-dippers, it was less pronounced. The results may imply a possible link between MBPS and markers of cardiovascular alterations in untreated hypertensive subjects.

Influence of candidate polymorphisms on the dipeptidyl peptidase IV and µ-opioid receptor genes expression in aspect of the ß-casomorphin-7 modulation functions in autism.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with population prevalence of approximately 60-70 per 10,000. Data shows that both opioid system function enhancement and opiate administration can result in autistic-like symptoms. Cow milk opioid peptides, including ß-casomorphin-7 (BCM7, Tyr-Pro-Phe-Pro-Gly-Pro-Ile), affect the µ-opioid receptor (MOR) and are subjected to degradation resulting from the proline dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5) enzyme activity. The presence of MOR and DPPIV activity are crucial factors determining biological activity of BCM7 in the human body. Our study examined the effect of ß-casomorphin-7 on the MOR and DPPIV genes expression according to specific point mutations in these genes. In addition, we investigated frequency of A118G SNP in the MOR gene and rs7608798 of the DPPIV (A/G) gene in healthy and autistic children. Our research indicated correlation in DPPIV gene expression under the influence of BCM7 and hydrolyzed milk between healthy and ASD-affected children with genotype GG (P<0.0001). We also observed increased MOR gene expression in healthy children with genotype AG at polymorphic site A118G under influence of BCM7 and hydrolyzed milk. The G allele frequency was 0.09 in MOR gene and 0.68 in the DPPIV gene. But our results suggest no association between presence of the alleles G and A at position rs7608798 in DPPIV gene nor alleles A and G at position A118G of the MOR and increased incidence of ASD. Our studies emphasize the compulsion for genetic analysis in correlation with genetic factors affecting development and enhancement of autism symptoms.

Relationship between hemodynamic parameters of renal artery stenosis and the changes of kidney function after renal artery stenting in patients with hypertension and preserved renal function.

INTRODUCTION: The role of physiological assessment of renal artery stenosis (RAS) using renal fractional flow reserve (rFFR) and resting translesional pressures ratio (Pd/Pa ratio) in the prediction of benefit from revascularization is still unknown. OBJECTIVES: The aim of the study was to assess the relationship between hemodynamic data and the change in kidney function after renal artery stenting in secondary hypertension. PATIENTS AND METHODS: 34 hypertensive patients (50% males, median age 65 years) with at least 60% RAS, underwent stenting and were followed up for 6 months. Pd/Pa ratio (ratio of mean distal to lesion to proximal pressure) and hyperemic rFFR (after papaverine) were measured before the procedure. At baseline and after 6 months, the glomerular filtration rate (eGFR), serum cystatin C and albuminuria were determined. In receiver operating characteristic curves, two previously established cut-off values with the highest accuracy of identifying severe RAS were used: 0.93 for the Pd/Pa ratio and 0.8 for the rFFR. RESULTS: No significant difference in eGFR was found between patients with decreased and normal Pd/Pa ratio (1.4 vs 7.9 ml/min, p = ns). Similarly, minor changes in eGFR were observed in patients with decreased vs normal rFFR (2.4 vs 4.1 ml/min, p = ns). In patients with decreased Pd/Pa ratio, albuminuria remained stable (change 1.4 mg/24 h) compared with an increase of 12.6 mg/24 h in the subgroup with Pd/Pa ≥ 0.93(p < 0.05). However, after exclusion of two outliers with significant baseline proteinuria (425 and 1095 mg/24 h, respectively), the difference in albuminuria change according to the baseline Pd/Pa ratio was no longer maintained. CONCLUSIONS: Hemodynamic parameters of RAS do not distinguish the patients who may benefit from renal artery stenting in terms of kidney function improvement in short-term follow-up.

ß-casomorphin-7 alters µ-opioid receptor and dipeptidyl peptidase IV genes expression in children with atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with heterogeneous clinical phenotypes reflecting genetic predisposition and exposure to environmental factors. Reactions to food may play a significant role especially in young children. Milk proteins are particularly strong allergens and are additional source of bioactive peptides including ß-casomorphin-7 (BCM7, Tyr-Pro-Phe-Pro-Gly-Pro-Ile). BCM7 exerts its influence on nervous, digestive, and immune functions via the µ-opioid receptor (MOR). Proline dipeptidyl peptidase IV (DPPIV; EC 3.4.14.5) appears to be the primary degrading enzyme of BCM7. Moreover, DPPIV is known to restrict activity of proinflammatory peptides. BCM7 is considered to modulate an immune response by affecting MOR and DPPIV genes expression. In this study, we determined the MOR and DPPIV genes expression in children diagnosed with a severe form of AD. 40 healthy children and 62 children diagnosed with severe AD (AD score ≥60) were included in the study. Peripheral blood mononuclear cells (PBMCs) from the studied subjects were incubated with the peptide extracts of raw and hydrolysed cow milk with defined ß-casein genotypes (A1A1, A2A2 and A1A2) and MOR and DPPIV genes expression was determined with real-time PCR. Incubation PBMCs with peptide extracts from cow milk caused an increase of the MOR gene expression (p<0.05; p<0.001) in AD children with a simultaneous decrease in the DPPIV gene expression (p<0.001). The obtained results supplement the knowledge on the BCM7 participation in AD etiology and provide an important diagnostic tool.

Relationship between obstructive sleep apnea and markers of cardiovascular alterations in never-treated hypertensive patients.

We addressed a question if there is a relationship between severity of newly diagnosed obstructive sleep apnea (OSA) and markers of cardiovascular alterations in middle-aged untreated hypertensive patients. In 121 consecutive patients with never-treated essential hypertension (mean age 35.9±10.1 years; 97 men and 24 women) evaluation of office and ambulatory blood pressure (BP) measurements, metabolic syndrome (MS) components and markers of alterations in cardiovascular system including left ventricular structure and function, carotid artery wall intima-media thickness (cIMT) and urinary albumin excretion (UAE) was performed. OSA was classified as mild (apnea/hypopnea index (AHI) 5-15 events h(-1)) or moderate-to-severe (AHI >15 events h(-1)). Mild and moderate-to-severe OSA were diagnosed in 30% and 20% of patients, respectively. No differences in nighttime BP levels and decline between patients with and without OSA were observed. The patients with moderate-to-severe OSA were characterized by higher cIMT (0.74±0.16 vs. 0.60±0.15 mm; P=0.001), UAE (14.5±6.9 vs. 10.0±8.0 mg 24 h(-1); P=0.014), relative wall thickness (0.42±0.05 vs. 0.39±0.05; P=0.023) and by a higher degree of diastolic dysfunction (E'-wave velocity 11.4±3.2 vs. 15.5±3.8 m s(-1); P<0.001) as compared with the patients without OSA. In multivariate analysis, AHI independently of BP and MS components correlated with UAE, relative wall thickness and E'-wave velocity. In the middle-aged never-treated hypertensive patients, moderate-to-severe OSA correlates with markers of cardiovascular alterations independently of BP levels and MS components.

Relationship between renal resistive index and early target organ damage in patients with never-treated essential hypertension.

The aim of our study was to evaluate renal resistive index (RI) value in never treated hypertensive patients in relation to ambulatory blood pressure measurement (ABPM) values and early target organ damage. The study included 318 subjects: 223 patients with never treated essential hypertension (mean age 37.1 years) and 95 normotensive healthy subjects (mean age 37.9 years). ABPM, echocardiography and carotid and renal arteries duplex color Doppler examinations were performed. RI values in patients with never treated essential hypertension were no different from the normotensive control group (0.59 +/- 0.05 vs 0.59 +/- 0.05; NS). In the untreated patients RI correlated significantly with 24-h pulse pressure (r=0.234; p<0.01) and ambulatory arterial stiffness index (AASI) values (r=0.274; p<0.001), intima-media thickness (IMT) (r=0.249; p<0.001), E'/A' (rho= -0.279; p<0.001) and relative wall thickness (RWT; r=0.185; p<0.01). In the multivariate stepwise analysis, RI values correlated independently with carotid IMT (beta=0.272; p=0.020) and 24-h AASI values (beta=0.305; p=0.009). In normotensive healthy controls, significant independent correlation between RI and carotid IMT and 24-h AASI values were also found. Our study may indicate limited value of RI in differentiating patients with uncomplicated hypertension with healthy controls. Renal resistive values were independently correlated with carotid IMT and AASI. These may suggest that renal vascular resistance is related to two markers for cardiovascular events both in the hypertensive and normotensive subjects.