bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Vasoreactivity to the Thromboxane A2 Mimic U-46619 of Collateral and Normal Peripheral Blood Vessels in in situ Perfused Rat Hindquarters
Authors: Verheyen A. , Lauwers F. , Vlaminckx E. , De Clerck F.
Published: April 2017

In situ perfusion of rat hindquarters was performed through both iliac arteries. Perfusion pressures were measured concomitantly in the normal vascular bed and in the ligation-induced collateral bed of the left and right hindleg, respectively. An increased vasoconstrictive response of the collateral versus normal blood vessels was found after bolus injections of increasing concentrations of the thromboxane A2 (TXA2) mimic U-46619. This increased reactivity was related to a difference in vascular structure and in receptor-mediated sensitivity. The vasoconstrictive effect of U-46619 was dose-dependently inhibited by the combined TXA2 synthetase inhibitor-TXA2/prostaglandin endoperoxide (PGH2) receptor antagonist ridogrel and the single TXA2/PGH2 receptor antagonist sulotroban. Selective blockade of α1- α2,-, β1- β2 and S2-receptors, cyclooxygenase inhibition, TXA2 synthesis inhibition, amine depletion and amine uptake blockade had no influence on the vasoconstrictive action of U-46619. Ca2+ entry blockade by flunarizine and nifedipine significantly reduced the vasoconstriction. This study shows that (1) rat peripheral collaterals in relation to normal arterial blood vessels are significantly more reactive to TXA2; (2) the vasoconstrictive effect of U-46619 is mediated predominantly by TXA2/PGH2 receptors; (3) the activation of these receptors elicits indirectly transmembrane Ca2+ entry to trigger vasoconstriction.
Endothelium-Dependent Contractions
Authors: Vanhoutte Paul M. , Lüscher Thomas F. , Gräser Thomas
Published: April 2017

The endothelial cells help to control the tone of the underlying vascular smooth muscle by releasing vasoactive factors. In physiological circumstances, the release of relaxing factors (nitric oxide and endothelium-derived hyperpolarizing factor) appears to predominate. However, in certain blood vessels (peripheral veins and large cerebral arteries), the normal endothelium has the propensity to release vasoconstrictor substances, among which are superoxide anion and thromboxane A2; the release of these endothelium-derived vasoconstrictors may contribute to the autoregulatory processes. In most blood vessels, anoxic conditions initiate the release of an unidentified endothelium-dependent contracting fractor. Cultured endothelial cells, and blood vessels maintained under culture conditions for prolonged periods of time, release the vasoconstrictor peptide endothelin. A characteristic of vascular diseases is that the ability of the endothelial cells to release relaxing factor(s) is reduced, while the generation of contracting factor is maintained or enhanced.
Cell Biology of Atrial Natriuretic Peptide
Authors: Huot Céline , Tremblay Johanne , Hamet Pavel
Published: April 2017

Atrial natriuretic peptide (ANP) exhibits a wide spectrum of cardiovascular, endocrine, metabolic and renal actions. cGMP is the major mediator of ANP at the cellular level and only tissues possessing paniculate guanylate cyclase appear to present ANP-induced actions. Three types of ANP receptors have recently been cloned. Two of them (A and B receptors) are homologous and contain guanylate cyclase catalytic domains. The C receptor could possibly regulate the metabolic fate of ANP. Data obtained by the radiation inactivation method suggest the presence of an inter- or intramolecular inhibitory component of nearly 90 kilodaltons that represses the catalytic activity of guanylate cyclase within its membrane environment. The mechanism of guanylate cyclase stimulation by ANP could involve this inhibitory component. Preliminary data suggest that the hyperresponsiveness of the particulate guanylate cyclase/cGMP system in hypertension occurs through modulation of the inhibitory component.
Alpha-Adrenoceptors in Vascular Smooth Muscle: All Is Not Well
Authors: Daniel E.E. , Shi A.G. , Wang Z.L. , Guan Y.Y. , Hoo K. , Cragoe E.J. , Kwan C.Y.
Published: April 2017

Studies of binding interactions and contractile responses of vascular muscles at α 1 and α2-adrenoceptors revealed the following. (1) Agonists at α1 and α2-adrenoceptors may achieve selectivity by virtue of different efficacies despite similar affinities at the two receptors as well as by differing affinities. This implies that their potencies in binding studies may not correlate with potencies in response and that an agonist may produce positive or negative interactions by occupying both α1- and α2-receptors. (2) Agonists at α2-adrenoceptors have the ability in some vascular muscles to release internal Ca2+ (implying an inositol triphosphate mechanism) as well as open Ca2+ channels. However, their contractile abilities are not closely related to function of Na+/H+ or Na+/Ca2+ exchange sites. Amiloride derivatives probably inhibit contractile effects of α-agonists and K+ elevation by an action at sites distal to the receptor or Ca channels. (3) The failure of α1-agonists to contract arteries in vitro is not related to the absence of these receptors but most likely to their uncoupling from contractile responses, possibly owing to changes related to the in vitro condition (loss of modulating endogenous substances present in vivo such as angiotensin II or endothelins or to changed physical conditions such as may alter function of stretch-activated channels).
Sodium Cotransport in Vascular Smooth Muscle Cells
Authors: O’Donnell Martha E. , Owen Nancy E.
Published: April 2017

Vascular smooth muscle cells possess a number of Na cotransport systems. Three of these cotransport systems, Na/Ca exchange, Na/H exchange and Na-K-Cl cotransport, have been the subject of an increasing number of investigations to determine the respective roles of these transporters in vascular smooth muscle cell function. Evidence has been obtained that the Na/Ca exchange system participates in regulation of intracellular Ca in vascular smooth muscle cells. The Na/H exchange system appears to function in concert with a Cl/HCO3 exchange system to regulate intracellular pH. The Na-K-Cl cotransport system is a major contributor to K flux across the plasma membrane of vascular smooth muscle cells and is regulated by a number of vasoactive agents, suggesting that this Na cotransport system is also an important component of vascular smooth muscle cell function. Cultured vascular smooth muscle cells derived from spontaneously hypertensive rats have been found to exhibit reduced Na-K-Cl cotransport activity compared to smooth muscle cells from normotensive controls. Thus, alteration of vascular smooth muscle Na-K-Cl cotransport activity may be related to changes in vascular tone. However, the precise function of Na-K-Cl cotransport in vascular smooth muscle cells remains to be clarified. Recent studies of Na-K-Cl cotransport in vascular endothelial cells provide evidence that the co-transporter is important for regulation of endothelial cell volume and suggest that this Na cotransport system may be vitally important for normal function of the vasculature.
Pressure and Flow: Are These the True Vascular Neuroeffectors?
Authors: Bevan John A.
Published: April 2017

Activity of the efferent nerve supply to the vasculature results in local increases or decreases in the tone of the vascular smooth muscle cells with corresponding changes in diameter. This results in changes in pressure and flow, both of which, because they too influence the vascular wall, extend the influence potentially to the entire bed. As the vascular bed is sensitive to pressure – an increase causing vasoconstriction – and to flow – an increase causing variable amounts of contraction and relaxation – the final results must reflect their interaction. Thus, the direct changes in artery tone brought about by neural activity are modified and diffused throughout the entire regional arterial system by the concomitant changes in the flow and pressure of the blood
Dynamics of Capillary Perfusion in the Brain
Authors: Göbel U. , Theilen H. , Schröck H. , Kuschinsky W.
Published: April 2017

The present study investigates the question of capillary recruitment and reserve capillaries in the brains of awake rats. Perfused capillaries were marked by intravenous globulin-coupled fluorescein isothiocyanate (FITC) and cerebral blood flow was measured autoradiographically. During hypercapnia, the density of perfused capillaries was unchanged compared to normocapnia, although blood flow was markedly increased. This shows the lack of capillary recruitment in the brain during the high flow that occurs during hypercapnia. In additional studies using fluorescent staining both of morphologically existing and of perfused capillaries, perfusion of all capillaries during normal, normocapnic conditions was found. These experiments show the lack of any capillary reserve in the rat brain.
Molecular Biology of the Vascular Renin-Angiotensin System
Authors: Samani N.J. , Swales J.D.
Published: April 2017

Considerable evidence has been accumulated for a renin-angiotensin system in the blood vessel wall with local generation of both angiotensin I and angiotensin II that plays an important role in blood pressure regulation. A major source for vascular renin is renal renin taken up by the arterial wall from the circulation. However, recent studies suggest that, in addition, local synthesis of components of the renin-angiotensin cascade also takes place in the vessel wall. The contribution that these locally derived components make to the functions of the vascular renin-angiotensin system remains to be elucidated. Studies, particularly in vitro, suggest that vascular pathways for angiotensin generation not involving renin or angiotensin-converting enzyme may also exist. As in the case of the locally derived components of the renin-angiotensin cascade, the role of these alternate pathways in the physiology of the vascular wall remain to be defined.
Role of the Local Renin-Angiotensin System in the Autoregulation of the Cerebral Circulation
Authors: Paulson O.B. , Waldemar G.
Published: April 2017

Inhibition of angiotensin-converting enzyme (ACE) shifts the limits of cerebral blood flow autoregulation toward lower blood pressure values. This effect seems to be mediated by blocking the formation of angiotensin II on the luminal side of the larger cerebral resistance vessels. Baseline cerebral blood flow (the flow within the autoregulatory limits) is not changed by acute or chronic ACE inhibition. An interaction between the vascular renin-angiotensin and the sympathetic nervous system is present. Activation of the latter inhibits the downwards shift of the upper limit of autoregulation following ACE inhibition.
Methodological Approaches Used for the Study of the Coronary Microcirculation in situ
Authors: Chilian William M. , DeFily David V.
Published: April 2017

Measurements of coronary microvascular parameters in situ are difficult because of the thickness of the heart muscle and cardiac contraction. Both of these problems hamper the visualization of the coronary microcirculation. We have refined methodological approaches that enable the study of the coronary microcirculation in situ. In the first approach, microvessels can be visualized in the beating heart using a preparation that compensates for cardiac motion by creating an illusion that the heart is motionless. This is accomplished by flashing a stroboscopic light source once per heart cycle at the same point in each cycle and synchronizing a ventilator with the cardiac cycle. Images of microvessels can be obtained using standard intravital video-microscopic techniques. To visualize the intramural and subendocardial microcirculation, studies are completed in isolated hearts. In this preparation, measurements of microvascular diameters and pressures can be performed in both the subepicardial and subendocardial microcirculations. This latter approach allows insight into transmural differences of coronary microvascular regulation.
Chronic Captopril Treatment Reverses the Enhanced Vascular Concentrations of 3-Methylhistidine in the Spontaneously Hypertensive Rat
Authors: Jonsson Julie R. , Frewin Derek B. , Head Richard J.
Published: April 2017

Morphometric studies conducted on the blood vessels of the spontaneously hypertensive rat have provided evidence that medial hypertrophy is a key characteristic of the vascular change which occurs in hypertension. In the present study, we determined whether 3-methylhistidine (3MH), a post-translationally modified amino acid which is found uniquely in the actin and myosin of muscle, could provide a biochemical marker of such change. Our results indicated that the concentrations of 3MH were selectively elevated in the blood vessels from the spontaneously hypertensive rat, when compared with concentrations in vascular tissues from the Wistar-Kyoto rat. The concentrations of 3MH in non-vascular tissues were similar in the two strains. Chronic captopril treatment prevented the development of hypertension in the spontaneously hypertensive rat and was associated with a reduction of the vascular concentrations of 3MH. We therefore conclude that blood vessel concentrations of 3MH are a useful biochemical index of the changes in vascular smooth muscle contractile protein which occur during the development of hypertension in the spontaneously hypertensive rat.
Functional and Morphologic Endothelial Damage in Rabbit External Jugular Veins Stored in Heparinized Normal Saline
Authors: Schwartz Lewis B. , Radic Zeljko S. , O’Donohoe Martin K. , McCann Richard L. , Mikat Eileen M. , Hagen Per-Otto
Published: April 2017

Previous studies have demonstrated that vein storage in normal saline leads to significant mechanical morphological, and biochemical aberrations. However, little information is available regarding the functional damage that occurs. The purpose of this study was to evaluate the effect of saline storage on venous smooth muscle and endothelial function. Segments of ten external jugular veins from male New Zealand White rabbits were placed nondistended in either modified Krebs solution at 37 °C (Krebs-stored, KS) or heparinized normal saline at room temperature (saline-stored, SS) for 1 h. Segments 4 mm in length were then simultaneously studied in vitro under isometric tension. There was no difference in maximum tension or sensitivity to either bradykinin or histamine. Acetylcholine-induced relaxation in KS segments was not significantly different from relaxation in a historical cohort of nonstored segments (nonstored 87.4 ± 1.0% vs. KS 84.5 ± 2.0%; p = NS). However, there were significant attenuations in SS segment endothelium-dependent relaxation in response to both acetylcholine (KS 84.5 ± 2.0% vs. SS 76.4 ± 2.7%, p < 0.02) and aden-osine diphosphate (KS 47.9 ± 2.9% vs. SS 40.6 ± 3.7%, p < 0.002). Relaxant responses to sodium nitroprusside (endothelium-independent) were not significantly different in the two groups (KS 94.6 ± 1.6% vs. SS 95.7 ± 2.2%; p = NS). Electron microscopic evaluation of SS segments revealed endothelial cell disruption with cellular edema and loss of intact junctions. These results demonstrate that rabbit external jugular vein storage in normal saline at room temperature for 1 h (1) is associated with significant morphologic damage, (2) impairs endothelial-dependent relaxation, and (3) appears to have no effect on smooth muscle cell function. Additionally, KS-stored (37 °C) veins exhibit a level of endothelium-dependent relaxation that is equivalent to nonstored controls.
Disturbed Wnt Signalling due to a Mutation in CCDC88C Causes an Autosomal Recessive Non-Syndromic Hydrocephalus with Medial Diverticulum
Authors: Ekici A.B. , Hilfinger D. , Jatzwauk M. , Thiel C.T. , Wenzel D. , Lorenz I. , Boltshauser E. , Goecke T.W. , Staatz G. , Morris-Rosendahl D.J. , Sticht H. , Hehr U. , Reis A. , Rauch A.
Published: April 2017

The etiology of non-syndromic hydrocephalus is poorly understood. Via positional cloning in a consanguineous family with autosomal recessive hydrocephalus we have now identified a homozygous splice site mutation in the CCDC88C gene as a novel cause of a complex hydrocephalic brain malformation. The only living patient showed normal psychomotor development at the age of 3 years and 3 months and her deceased aunt, who was assumed to suffer from the same condition, had mild mental retardation. The mutation in the affected patients, a homozygous substitution in the donor splice site of intron 29, resulted in a shorter transcript due to exclusion of exon 29 and loss of functional protein, as shown by Western blotting (p.S1591HfsX7). In normal human tissue panels, we found CCDC88C ubiquitously expressed, but most prominently in the fetal brain, especially in pons and cerebellum, while expression in the adult brain appeared to be restricted to cortex and medulla oblongata. CCDC88C encodes DAPLE (HkRP2), a Hook-related protein with a binding domain for the central Wnt signalling pathway protein Dishevelled. Targeted quantitative RT-PCR and expression profiling of 84 genes from the Wnt signalling pathway in peripheral blood from the index patient and her healthy mother revealed increased mRNA levels of CCDC88C indicating transcriptional upregulation. Due to loss of CCDC88C function β-catenin (CTNNB1) and the downstream target LEF1 showed increased mRNA levels in the patient, but many genes from the Wnt pathway and transcriptional target genes showed reduced expression, which might be explained by a complex negative feedback loop. We have thus identified a further essential component of the Wnt signalling pathway in human brain development.
Transcutaneous Cervical and Transabdominal Ultrasonography as a Diagnostic Tool in Gastroesophageal Reflux in Childhood
Authors: Karabulut Bilge , Bostanci Ilknur , Kacar Mahmut , Karaca Gokhan , Kosar Pinar
Published: April 2017

Background/Aim: The aim of this study is to investigate if there is a diagnostic expressive difference in the angle of His, upper and lower esophageal diameter (UED and LED), wall thickness of cervical esophagus (WTCE) measured by cervical and transabdominal ultrasonography (USG) between children with (+) and without gastroesophageal reflux (GER–). Methods: 50 children were separated into 2 groups. Group 1 was the control group (n = 30) consisting of children who had no symptoms of GER and had no GER detected in USG. Group 2 was the study group (n = 20) consisting of children with complaints related to GER, and who were GER+ by USG and esophageal pH monitoring. The USG examinations were completed after having observed 3 episodes of reflux or after 30 min if no reflux was detected. The angle of His, UED, LED and WTCE were measured. In 24-hour esophageal pH monitoring, acid contact to the proximal or distal probe greater than 5.0% of the total time below pH 4 was accepted as pathologic reflux. Results: The age range of the 50 children (30 boys) was 4–13 years. Between the 2 groups there were no differences with regard to age and gender. Values of UED, LED and WTCE were statistically higher in group 2 compared with group 1. The angle of His was higher in the control group, but this was not statistically significant. Conclusion: Our study is the first in the literature that shows that measuring UED, LED and WTCE by USG, which is a noninvasive, readily available repeatable, cheap and fast technique, has a high diagnostic value in children with suspected GER.
Abnormal T2-Weighted MRI Signal Surrounding Leads in a Subset of Deep Brain Stimulation Patients
Authors: Englot Dario J. , Glastonbury Christine M. , Larson Paul S.
Published: April 2017

Background: Deep brain stimulation (DBS) surgery is a common treatment option for numerous neurological disorders. However, it is not without potential complications, such as hemorrhage and infection. Interestingly, we have observed several instances of abnormal T2-weighted signal hyperintensity surrounding DBS leads on postoperative MRI that are not associated with hemorrhage or infection. Methods: To better characterize the incidence and timing associated with this finding, we retrospectively reviewed postoperative imaging for all DBS implants performed over 9 years at one institution. Results and Conclusions: Fifteen instances of T2 signal hyperintensity surrounding DBS leads on postoperative MRI scans were observed across 239 implants (6.3% incidence) in 133 patients. The signal characteristics were most consistent with vasogenic edema, possibly representing an inflammatory response. The finding was typically unilateral, even in patients with simultaneous bilateral lead implants. Most affected patients were asymptomatic, although 3 were symptomatic and 1 experienced marked gait instability that was treated with steroids. T2 signal abnormality was seen more commonly in scans obtained 3 or more days after surgery than in those collected immediately postoperatively. No differences in age, anatomical target, diagnosis, or number of microelectrode passes were noted between patients with or without T2 signal. Further research will be needed to explain this curious neuroimaging finding, and to rule out cause for clinical concern.
Post-Interventional Microembolism: Cortical Border Zone Is a Preferential Site for Ischemia
Authors: Park Kwang-Yeol , Chung Pil-Wook , Kim Yong Bum , Moon Heui-Soo , Suh Bum-Chun , Yoon Won Tae
Published: April 2017

Background: Previous diffusion-weighted MRI (DWI) studies have indicated that 10–40% of patients have silent embolism during neurointerventional procedures. However, lesion patterns of the embolisms have not been adequately investigated. Methods: DWI was taken within 7 days before and 48 h after cerebral angioplasty and stent procedures. New lesions on the follow-up DWI were analyzed in the non-treated arterial territories. Based on the arterial territories, supratentorial lesions were classified into cortical lesions and subcortical lesions. Cortical lesions were subdivided into cortical border zone and cortical proper lesions. Subcortical lesions were divided into deep perforator and internal border zone lesions. Infratentorial lesions were divided into brainstem and cerebellar lesions. Results: 72 patients were included in this study. There were 223 new DWI lesions (1–23 lesions) in the non-treated arterial territories of 37 patients. There were 154 cortical lesions, 45 cerebellar lesions, 21 subcortical lesions and 3 brainstem lesions. Analysis of the distribution pattern of cortical lesions showed that 88 of 154 lesions were located at the cortical border zone. Of the subcortical lesions, 13 of 21 lesions were located at the internal border zone area, within the corona radiata and centrum ovale. Only 4 lesions were located at the deep perforator territory. Infratentorial lesions were mostly located at the cerebellar hemisphere (45/48). Most lesions were tiny infarcts (<5 mm diameter); 7 of 223 lesions were >10 mm in diameter. Conclusions: Interventional-angiography-related microembolisms mostly lodge in the cerebral cortical border zone area and cerebellar hemisphere. Microembolisms to the deep perforating artery territory are distinctly rare.
Incidence and Risk Factors for Acute Kidney Injury in HIV Infection
Authors: Li Yongmei , Shlipak Michael G. , Grunfeld Carl , Choi Andy I.
Published: April 2017

Background/Aims: Although HIV-infected persons are at higher risk for acute kidney injury (AKI) during hospitalization compared with their uninfected counterparts, risk factors for AKI are not well-defined. We aimed to describe the evolving incidence of AKI among HIV-infected individuals and to identify important AKI risk factors. Methods: We conducted a prospective cohort study of 56,823 HIV-infected persons in the Department of Veterans Affairs Clinical Case Registry. Outcomes were: AKI (acute in-hospital serum creatinine increase of ≥0.3 mg/dl, or a relative increase by 50% or greater), and dialysis-requiring AKI. We used proportional hazards regressions to identify risk factors. Results: From its peak in 1995 at 62 per 1,000 person-years, the incidence of AKI declined after the introduction of highly active antiretroviral therapy (HAART) in 1996 to a low point of 25 per 1,000 person-years in 2006. Incidence of dialysis-requiring AKI declined in the early 1990s, but doubled between 2000 and 2006. Using multivariate proportional hazard regression, we identified the following strong risk factors for AKI: chronic kidney disease (eGFR <60 ml/min/1.73 m2) (5.38, 95% CI: 5.11–5.67), proteinuria (1.78, 1.70–1.87), low serum albumin (<3.7 mg/dl) (5.24, 4.82–5.71), low body mass index (<18.5 kg/m2) (1.69, 1.54–1.86), cardiovascular disease (1.77, 1.66–1.89), low CD4 count (<200 cells/mm3) (2.54, 2.33–2.77), and high viral load (≥100,000 copies/ml) (2.51, 2.28–2.75). In addition, there was substantial heterogeneity in the strengths of risk factors for dialysis-requiring AKI before and after the introduction of HAART. Conclusions: Although AKI incidence has decreased during the HAART era, it remains common in HIV-infected persons and appears attributable to both kidney- and HIV-related factors.
Comparison of Volume Status in Asymptomatic Haemodialysis and Peritoneal Dialysis Outpatients
Authors: Papakrivopoulou Eugenia , Booth John , Pinney Jennifer , Davenport Andrew
Published: April 2017

Background: The majority of haemodialysis (HD) patients gain weight between dialysis sessions and thereby become volume overloaded, whereas peritoneal dialysis (PD) is a more continuous technique. Cardiovascular mortality and hypertension is increased with both treatment modalities. We therefore wished to compare volume status in PD and HD to determine whether PD patients are chronically volume overloaded, as a risk factor for cardiovascular mortality. Study Design, Setting and Participants:We retrospectively audited 72 healthy HD patients and 115 healthy PD patients attending a university hospital dialysis centre for routine outpatient treatment, who had multi-frequency bioimpedance measurements of extracellular water to total body water (ECW/TBW). Results: The groups were well matched for age, sex, weight and ethnicity, PD patients had greater urine output [1,075 (485–1,613) vs. 42.5 (0–1,020) ml/day, p < 0.001], but there was no difference in antihypertensive prescription (63.5 vs. 76.4%), mean arterial blood pressure (post-dialysis 101.6 ± 1.5 mm Hg vs. pre-dialysis 102 ± 2.4 mm Hg), although post-dialysis arterial blood pressure was lower than in PD patients (96.4 ± 3.1 mm Hg, p < 0.05). The ratio of ECW/TBW fell after HD (pre-dialysis 0.394 ± 0.001 vs. post-dialysis 0.389 ± 0.004, p < 0.001) and was similar in the PD group to the group before HD (0.393 ± 0.001), and greater than that in the group after HD (p < 0.001). ECW/TBW was greater than the normal reference range in 30% PD patients, 28% patients before HD and 20% patients after HD. Conclusions: Overhydration is common in healthy stable PD outpatients, and ECW volumes in PD patients are not dissimilar to those of pre-dialysis HD patients. The role of chronic volume overload as a risk factor for cardiovascular disease needs further investigation.
Methyl Sulfone Manifests Anticancer Activity in a Metastatic Murine Breast Cancer Cell Line and in Human Breast Cancer Tissue - Part 2: Human Breast Cancer Tissue
Authors: Caron Joan McIntyre , Monteagudo Luke , Sanders Melinda , Bannon Marissa , Deckers Peter J.
Published: April 2017

Background: Methyl sulfone is a small molecule that reverses cancerous phenotypes of a melanoma cell line. Here, we sought to determine whether methyl sulfone was effective against human breast cancer tissue. Methods: We studied normal and cancerous breast tissue obtained from 17 patients. Results: Methyl sulfone introduced structural order, with cancer tissue taking on the morphology of normal in vivo breast tissue; this structural order was sustainable over long-term culture. Methyl sulfone promoted proper wound healing, including migration of cells into wounded areas and establishment of stable contact inhibition once wounds were covered. Methyl sulfone decreased expression of two breast stem cell marker proteins, HCAM and OCT3/4, which are associated with aberrantly rapid migration of metastatic cells. Finally, normal and cancerous primary breast cells remained viable and healthy in methyl sulfone culture for at least 90 days. Conclusion: Methyl sulfone reintroduced a normal structural phenotype to human breast cancer tissues.
Involvement of Heat Shock Proteins in Candida albicans Biofilm Formation
Authors: Becherelli Marco , Tao Jianshi , Ryder Neil S.
Published: April 2017

Biofilm growth represents one of the most challenging problems associated with Candida infections, largely due to the natural resistance of biofilm to the common antifungal drugs. As elevated expression of heat shock proteins (HSP) promotes Candida yeast-hyphae switch, which is an essential step in biofilm formation, we investigated the expression of hsp genes during Candida albicans biofilm development. By measuring mRNA levels using qRT-PCR, we found that all three hsp genes that we monitored are overexpressed in the initial stage of C. albicans biofilm formation. To corroborate this finding, we examined the effect of 17-DMAG, a specific Hsp90 inhibitor, on the formation of C. albicans biofilm. Our results indicate the requirement of HSP during the early phase of Candida biofilm development.
Protective Effect of Metformin on Myocardial Injury in Metabolic Syndrome Patients following Percutaneous Coronary Intervention
Authors: Li Jing , Xu Jin-peng , Zhao Xing-zhou , Sun Xue-jiang , Xu Zhan-wen , Song Shu-jiang
Published: April 2017

Objectives: The present study tested the hypothesis that pretreatment with metformin decreases postprocedural myocardial injury and improves clinical outcomes in metabolic syndrome patients following percutaneous coronary intervention (PCI). Methods: We enrolled 152 metabolic syndrome patients with no prior history of metformin treatment. Patients scheduled for elective coronary intervention were randomized to the metformin or control group 7 days before the procedure. Creatine kinase-MB (CK-MB) and troponin I levels were measured at baseline and 8 and 24 h after the procedure, and clinical outcomes were monitored for 1 year. Results: Post-PCI myocardial injury as indicated by CK-MB elevation (14.5 vs. 32.9%, p = 0.008) and troponin I elevation (14.5 vs. 34.2%, p = 0.005) was significantly lower in the metformin group than in the control group. Postprocedural peak values of CK-MB (2.70 ± 4.30 vs. 6.29 ± 8.03 ng/ml, p < 0.001) and troponin I (0.02 ± 0.05 vs. 0.07 ± 0.10 ng/ml, p = 0.001) were also significantly lower in the metformin group than in the control group. At 1 year, the composite endpoint of death from any cause, post-PCI myocardial infarction (MI), MI after PCI hospitalization or ischemia-driven target lesion revascularization occurred in 7.9% of metformin-treated patients and 28.9% of controls (hazard ratio 0.25, 95% CI 0.10-0.62, log rank p = 0.001). Conclusions: A 7-day metformin pretreatment regimen (250 mg 3 times a day) significantly reduces postprocedural myocardial injury and improves 1-year clinical outcomes in metabolic syndrome patients undergoing PCI.
Proflie of Human β-Defensins 1,2 and Proinflammatory Cytokines (TNF-α, IL-6) in Patients with Chronic Kidney Disease
Authors: Oh Dong-Jin , Kim Hye Ryoun , Lee Mi-Kyung , Woo Yo Seop
Published: April 2017

Background/Aim: Our aim was to determine whether altered human β-defensin (HBD), pro-inflammatory cytokines including interleukin (IL)-6 and tumor necrotic factor (TNF)-α could increase the risk of developing and exacerbation of chronic kidney disease (CKD), especially for patients with diabetic nephropathy (DN). Methods: Serum samples were obtained from 338 CKD patients and 88 sex, age-matched healthy controls. The concentrations of HBD-1 were assayed using an RIA kit. Serum levels of HBD-2, IL-6 and TNF-α were assayed using an ELISA kit. Results: Serum levels of HBD-1, IL-6 and TNF-α were significantly higher in CKD patients compared to healthy controls (P<0.05). HBD-1 levels were inversely related to estimated glomerular filtration rate (eGFR), which was the coefficient factor (β = -0.357, P = 0.035) explaining the variability in HBD-1 in CKD. Diabetic nephropathy (DN) patients at stage 3-5 had significantly higher serum HBD-1 levels than non DN patients (P=0.00). Conclusion: Our data support the view that there is increased inflammation in CKD and DN. The inverse correlation between eGFR and serum HBD-1 which we observed is suggestive of a relationship between innate immunity and renal function and should be further investigated.
Renalase Gene Polymorphism in Patients with Hypertension and Concomitant Coronary Heart Disease
Authors: Li Xiaogang , Jiang Weihong , Li Luhong , Huang Ruixia , Yang Qiong , Yang Yan , Hong Yuan , Tang Xiaohong
Published: April 2017

Background/Aims: This study aimed to investigate renalase gene polymorphism in patients with hypertension and concomitant coronary heart disease (CHD) and to evaluate the risk for CHD in hypertensive patients from the view of genetics. Methods: NCBI and HapMap genome database were employed to screen the Single nucleotide polymorphisms (SNP). These SNPs were detected in hypertensive and CHD patients (n=791), hypertensive patients (n=802) and healthy controls (n=812), and the genotypes were recorded. Haploview 4.2 software was used to determine the genotypes, allele frequency, haplotypes, linkage disequilibrium and Hardy-Weinberg (HWE) equilibrium, and odds ratio (OR) was calculated with non-conditioned logistic regression analysis. Results: The frequency of allele A of rs2576178 in patients with hypertensive and CHD was markedly higher than that in hypertensive patients (p=0.001, OR=1.625,95% CI 1.221-2.160). The frequency of allele C of rs2296545 in hypertensive patients was significantly higher than that in healthy controls (P=0.009, OR=1.436, 95% CI 1.095-1.883). Conclusion: The allele A of rs2576178 may be a predisposing factor of CHD in hypertensive patients, and hypertensive patients with AA genotype are susceptible to develop CHD. The allele C of rs2296545 may be a predisposing factor of hypertension and patients with CC genotype are susceptible to develop hypertension.
Calcitriol Supplementation Improves Endothelium-Dependent Vasodilation in Rat Hypertensive Renal Injury
Authors: Takenaka Tsuneo , Inoue Tsutomu , Ohno Yoichi , Miyazaki Takashi , Nishiyama Akira , Ishii Naohito , Suzuki Hiromichi
Published: April 2017

Background/Aims: Vitamin D increases renal expression of klotho in normotensive rats. Klotho reduces oxidative stress. Methods: In this study, we aimed to determine if vitamin D would suppress oxidative stress using 4 groups of hypertensive rats: uninephrectomized, stroke-prone, spontaneously hypertensive rats fed a high-salt (6%) diet (controls; C); those treated with irbesartan (I); those treated with calcitriol (V); and those treated with both irbesartan and calcitriol (I+V). Results: Systolic blood pressure was higher in the C group than in the I and I+V groups. Albuminuria was attenuated in groups I, V, and I+V. Renal angiotensin II (AngII) concentration was lower in groups I and I+V than in group C, and plasma AngII levels of groups I and V were higher and lower than those in group C, respectively. Compared with group C, renal klotho expression, 8-epi-prostaglandin F2α excretion, and acetylcholine-induced decrease in blood pressure improved in the V and I+V groups. Conclusions: The data indicate that irbesartan effectively decreases blood pressure and renal AngII levels, and improves albuminuria. Our findings indicate that vitamin D enhances klotho expression, suppressing oxidative stress and albuminuria without substantial changes in renal AngII levels. These results suggest that the amelioration of endothelium function by vitamin D involves free klotho.
Energy and Oxygen Metabolism Disorder During Septic Acute Kidney Injury
Authors: Yang Rong-li , Wang Xiao-ting , Liu Da-wei , Liu Si-bo
Published: April 2017

Background/Aims: Acute kidney injury (AKI) during septic shock, which is one of the most common clinical syndromes in the intensive care unit (ICU), has a high mortality rate and poor prognosis, partly because of a poor understanding of the pathogenesis of renal dysfunction during septic shock. Although ischemic injury of the kidney has been reported to result from adenosine triphosphate (ATP) depletion, increasing evidence has demonstrated that AKI occurs in the absence of renal hypoperfusion and even occurs during normal or increased renal blood flow (RBF); nevertheless, whether energy metabolism disorder is involved in septic AKI and whether it changes according to renal hemodynamics have not been established. Moreover, tubular cell apoptosis, which is closely related to ATP depletion, rather than necrosis, has been shown to be the major form of cell injury during AKI. Methods: We used canine endotoxin shock models to investigate the hemodynamics, renal energy metabolism, renal oxygen metabolism, and pathological changes during septic AKI and to explore the underlying mechanisms of septic AKI. Results: The present results revealed that the nicotinamide adenine dinucleotide (NAD+) pool and the ATP/adenosine diphosphate (ADP) ratio were significantly decreased during the early phase of septic AKI, which is accompanied by a decreased renal oxygen extraction ratio (O2ER%) and decreased renal oxygen consumption (VO2). Furthermore, significant apoptosis was observed following renal dysfunction. RBF and renal oxygen delivery were not significantly altered. Conclusion: These results suggest that imbalanced energy metabolism, rather than tubular cell apoptosis, may be the initiator of renal dysfunction during septic shock.
Analysis of the Intestinal Microbiome of a Recovered Clostridium difficile Patient after Fecal Transplantation
Authors: Broecker Felix , Kube Michael , Klumpp Jochen , Schuppler Markus , Biedermann Luc , Hecht Jochen , Hombach Michael , Keller Peter M. , Rogler Gerhard , Moelling Karin
Published: April 2017

Background:Clostridium difficile infections upon antibiotic disruption of the gut microbiota are potentially lethal. Fecal microbiota transplantation (FMT) is a promising treatment option for recurrent C. difficile-associated disease (CDAD). Here, we present a patient with recurrent CDAD that received FMT, leading to full recovery for what has now been 3 years. We performed metagenomic sequencing on stool samples to assess if there are indications for recolonization with C. difficile and changes in the gut microbiota after FMT. Methods: DNA from the stool of the donor and recipient was subjected to illumina sequencing. Obtained read sets were assembled to contiguous sequences and open reading frames were predicted. Deduced proteins were taxonomically assigned. Results: We detected complex and apparently healthy microbiomes in the donor's and recipient's intestines after FMT, but no indications for C. difficile colonization. Conclusions: Metagenomic analysis proved suitable to analyze the intestinal microbiome after FMT. Discussion of our evaluation procedure and data management may be helpful for future studies. We demonstrated restoration of a healthy and diverse gut microbiome with chimeric composition from donor and recipient, and long-lasting clearance of C. difficile. The procedure is simple, cheap, caused no side effects, and was stable over 3 years.
Characterization of a Fluorescent Probe for Imaging Nitric Oxide
Authors: Ghebremariam Yohannes T. , Huang Ngan F. , Kambhampati Thiruvengadam Swetha , Volz Katharina S. , Joshi Gururaj G. , Anslyn Eric V. , Cooke John P.
Published: April 2017

Background: Nitric oxide (NO), a potent vasodilator and anti-atherogenic molecule, is synthesized in various cell types, including vascular endothelial cells (ECs). The biological importance of NO enforces the need to develop and characterize specific and sensitive probes. To date, several fluorophores, chromophores and colorimetric techniques have been developed to detect NO or its metabolites (NO2 and NO3) in biological fluids, viable cells or cell lysates. Methods: Recently, a novel probe (NO550) has been developed and reported to detect NO in solutions and in primary astrocytes and neuronal cells with a fluorescence signal arising from a nonfluorescent background. Results: Here, we report further characterization of this probe by optimizing conditions for the detection and imaging of NO products in primary vascular ECs, fibroblasts, and embryonic stem cell- and induced pluripotent stem cell-derived ECs in the absence and presence of pharmacological agents that modulate NO levels. In addition, we studied the stability of this probe in cells over time and evaluated its compartmentalization in reference to organelle-labeling dyes. Finally, we synthesized an inherently fluorescent diazo ring compound (AZO550) that is expected to form when the nonfluorescent NO550 reacts with cellular NO, and compared its cellular distribution with that of NO550. Conclusion: NO550 is a promising agent for imaging NO at baseline and in response to pharmacological agents that modulate its levels.
The Immunology of Bipolar Disorder
Authors: Barbosa Izabela Guimarães , Machado-Vieira Rodrigo , Soares Jair C. , Teixeira Antonio L.
Published: April 2017

Bipolar disorder (BD) is a psychiatric condition associated with elevated frequency of clinical comorbidities and cognitive impairment. The neurobiology of BD is not completely understood. Recent evidence has implicated immune dysfunction in its physiopathology. Here, we review several data supporting the presence of immunological dysfunction in BD: (i) increased frequency of autoimmune diseases; (ii) distinct immune cell profile; (iii) release of/altered cytokines by stimulated mononuclear cells; (iv) elevated levels of circulating immune markers, and (v) inflammatory changes in the central nervous system. We also discuss the interplay between immunological dysfunction and neuroprogression in BD.
Neuroimmunoendocrine Interactions in Post-Traumatic Stress Disorder: Focus on Long-Term Implications of Childhood Maltreatment
Authors: Wieck Andréa , Grassi-Oliveira Rodrigo , Hartmann do Prado Carine , Teixeira Antonio L. , Bauer Moisés E.
Published: April 2017

Childhood maltreatment has been linked to enhanced vulnerability to psychiatric pathologies in adult life, including post-traumatic stress disorder (PTSD). Previous works have reported cogent neuroendocrine and immune changes related to adult traumatic events (war survivors, refugees, etc.), but little information is known regarding the impact of early-life stress (ELS) in adult physiology. Here, we review the neuroendocrine and immunological changes commonly observed in PTSD, focusing on the long-term implications of ELS. Childhood maltreatment may lead to altered glucocorticoid (GC) secretion, resulting in hypo- or hypercortisolemia, and reciprocal changes in peripheral leukocyte sensitivity to GC. It is believed that these neuroendocrine changes are correlated with the immune imbalance phenomenon (low-grade inflammation), characterized by increased plasma levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and C-reactive protein. Changes in peripheral lymphocyte subsets are also documented, such as a reduction in regulatory T cells and an expansion of activated T cells. The excess of circulating cytokines may thus interfere with key brain neurotransmitter pathways involved in depression and enhanced risk to cardiovascular, respiratory, gastrointestinal, inflammatory and autoimmune diseases. Recent gene-environment and epigenetic findings have indicated potential molecular mechanisms linking ELS, neuroendocrine and immunity in PTSD.
Minimalinvasive Chirurgie bei Malignomen des Gastrointestinaltrakts: Magen - Pro-Position
Authors: Wullstein Christoph
Published: April 2017

Hintergrund: Wenngleich einige Studien Vorteile für laparoskopische Magenresektionen zeigen, ist die Diskussion um die laparoskopische Magenresektion beim Karzinom kontrovers. Methode: Literaturübersicht. Ergebnisse: Laparoskopische Magenresektionen beim Karzinom sind technisch sicher durchführbar und führen zu Vorteilen in der kurzfristigen Rekonvaleszenz nach der Operation im Hinblick auf geringere Schmerzen, kürzere postoperative Darmatonie, schnelleren Kostaufbau, verbesserte Lebensqualität in den ersten 3 Monaten postoperativ, eine schnellere Wiederaufnahme normaler Aktivitäten und eine kürzere Krankenhausverweildauer. Der Blutverlust ist geringer als nach offener Operation, die Operationsdauer ist länger. Einige Studien und Metaanalysen zeigen eine reduzierte Morbidität nach laparoskopischer Resektion. Die Letalität des Eingriffs unterscheidet sich nicht. Die Anzahl der bei der Operation entfernten Lymphknoten ist in vielen Studien vergleichbar, in wenigen Studien bei laparoskopischer Resektion geringer als nach offenen Operationen. Das Langzeitüberleben unterscheidet sich in den publizierten Studien nicht von dem nach konventioneller Operation. Schlussfolgerungen: Laparoskopische Magenresektionen beim Karzinom erscheinen sicher, zeigen zahlreiche Vorteile in der Rekonvaleszenz nach der Operation und sind in den Langzeitüberlebensraten vergleichbar. Möglichen Hinweisen auf eine eventuell reduzierte Anzahl an bei der Operation entnommenen Lymphknoten muss durch eine entsprechende Operationstechnik begegnet werden, die durch eine prospektive Qualitätssicherung abgesichert werden sollte.
Obesity-Related Adipokines Predict Patient-Reported Shoulder Pain
Authors: Gandhi Rajiv , Perruccio Anthony V. , Rizek Randy , Dessouki Omar , Evans Heather M.K. , Mahomed Nizar N.
Published: April 2017

Background/Aims: Increasingly, an inflammatory modulating effect of adipokines within synovial joints is being recognized. To date, there has been no work examining a potential association between the presence of adipokines in the shoulder and patient-reported outcomes. This study undertakes an investigation assessing these potential links. Methods: 50 osteoarthritis patients scheduled for shoulder surgery completed a pre-surgery questionnaire capturing demographic information including validated, patient-reported function (Disabilities of the Arm, Shoulder, and Hand questionnaire) and pain (Short Form McGill Pain Questionnaire) measures. Synovial fluid (SF) samples were analyzed for leptin, adiponectin, and resistin levels using Milliplex MAP assays. Linear regression modeling was used to assess the association between adipokine levels and patient-reported outcomes, adjusted for age, sex, BMI, and disease severity. Results: 54% of the cohort was female (n = 27). The mean age (SD) of the sample was 62.9 (9.9) years and the mean BMI (SD) was 28.1 (5.4) kg/m2. From regression analyses, greater SF leptin and adiponectin levels, but not regarding resistin, were found to be associated with greater pain (p < 0.05). Adipokine levels were not associated with functional outcome scores. Conclusions: The identified association between shoulder-derived SF leptin and adiponectin and shoulder pain is likely explained by the pro-inflammatory characteristics of the adipokines and represents potentially important therapeutic targets.