bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction risk chart for scleroderma digital ulcers: A composite predictive model based on capillaroscopic, demographic and clinico-serological parameters
Authors: Manfredi Andreina , Sebastiani Marco , Carraro Valeria , Iudici Michele , Bocci Mario , Vukatana Gentiana , Gerli Roberto , De Angelis Rossella , Del Medico Patrizia , Praino Emanuela , Lo Monaco Andrea , D'Amico Roberto , Del Giovane Cinzia , Mazzuca Salvatore , Colaci Michele , Giuggioli Dilia , Ferri Clodoveo
Published: December 2019

BACKGROUND: Digital ulcers (DU) affect 50% of systemic sclerosis (SSc) patients, representing a challenging clinical problem. Despite a high negative predictive value, capillaroscopic scores proposed to select patients at risk for DU show an inadequate positive predictive value, especially in patients without previous DU. AIM OF THIS STUDY: To increase the predictive value for DU development of capillaroscopy, through a predictive risk chart taking into account capillaroscopic, demographic, and clinico-serological parameters. PATIENTS AND METHODS: Two hundred and nineteen unselected SSc patients from 8 Italian Rheumatology Centers were consecutively enrolled during a 6-month period. Demographic, clinical, serological and instrumental data and capillaroscopy skin ulcers risk index (CSURI) were collected. RESULTS: A multivariate logistic regression analysis showed a significant positive association between DU appearance and male gender, DU history, altered CSURI, and ESR. A prediction risk chart of the development of DU within 6 months were built on the basis of the above parameters. According to the risk level, four risk classes were identified: low (≤19.3%); medium (>19.3%, ≤58.6%); high (>58.6%, ≤89.2%), and very high risk (>89.2%). CONCLUSIONS: The systematic evaluation of the above parameters can be helpful to identify patients at risk to develop DU optimizing preventive vasoactive therapy.
Muscle VO2 and forearm blood flow repeatability during venous and arterial occlusions in healthy and coronary heart disease subjects
Authors: Gayda Mathieu , Gremeaux Vincent , Drigny Joffrey , Juneau Martin , Nigam Anil
Published: December 2019

This study aims were: 1) to assess forearm blood flow (FBF) and muscle oxygen consumption (mVO2) repeatability assessed with near-infra red spectroscopy (NIRS) during venous occlusions (VO) in middle aged healthy subjects and patients with stable coronary heart disease (CHD), 2) to assess the agreement between mVO2 calculated from NIRS signals during VO and arterial occlusion (AO) in 18 middle aged healthy subjects and 12 patients with CHD. FBF and mVO2 were measured using NIRS during 2 successive VO (1-min duration), followed by a 5-min AO. Repeatability for FBF and mVO2 during VO was assessed with intra class correlation (ICC), coefficient of variation (CV %) and agreement between VO and AO mVO2 was assessed with a Bland and Altman analysis. FBF and mVO2 during VO were highly reproducible in healthy (FBF: ICC 0.73, CV% 9.75; mVO2: ICC 0.89, CV% 12.6) and CHD subjects (FBF: ICC 0.95, CV% 10.26; mVO2: ICC 0.98, CV% 7.92). VO and AO mVO2 were in agreement in healthy (mean bias: 0.002 mL O2.min−1.100g−1) and CHD subjects (mean bias: 0.014 mL O2.min−1.100g−1). FBF and mVO2 measured with NIRS during VO and/or AO are highly reproducible methods to assess microvascular function in healthy subjects and stable CHD patients.
Evidence that reduced nitric oxide signal contributes to cutaneous microvascular dysfunction in peripheral arterial disease
Authors: Hodges Gary J. , Nawaz Shah , Tew Garry A.
Published: December 2019

Peripheral arterial disease (PAD) is associated with cutaneous microvascular dysfunction and an increased risk of arterial ulceration in the affected lower-limb(s). The purpose of this study was to investigate the role of nitric oxide (NO) in cutaneous microvascular dysfunction in patients with PAD. Using laser-Doppler flowmetry, we measured skin blood flow (SkBF) in 5 patients with unilateral symptomatic PAD and 10 age-matched healthy controls at baseline and during 40 min of local skin heating to 42°C at 1) untreated lower-leg sites, and 2) lower-leg sites treated with 20 mM N(G)-nitro-L-arginine methyl ester (L-NAME) to inhibit NO synthase activity. SkBF was expressed as laser-Doppler flux (LDF) and normalized to maximal LDF (%LDF(max)) achieved through localized heating to 44°C and concomitant infusion of 56 mM sodium nitroprusside. Pharmacological agents and control treatments (lactated Ringer's) were administered using intradermal microdialysis. The plateau LDF response to local skin warming at the untreated skin sites was significantly (P < 0.05) lower in the diseased limb of the PAD patients (70.3 ± 13.6 %max) compared to the non-diseased contralateral limb (85.0 ± 10.2 %max) and the response observed for the control participants (89.0 ± 5.2 %max). The NO contribution to the plateau SkBF response tended to be lower in the diseased limb of the PAD patients (45.1 ± 16.4% versus 56.1 ± 10.7% [P = 0.12] and 55.4 ± 11.5% [P = 0.13], respectively). The results suggest that PAD impairs downstream cutaneous microvascular vasodilatory function and that the microvascular dysfunction is probably explained, at least in part, by a reduced NO signal.
Organotypical vascular model for characterization of radioprotective compounds: Studies on antioxidant 2,3-diaryl-substituted indole-based cyclooxygenase-2 inhibitors
Authors: Ullm Sandra , Laube Markus , Bechmann Nicole , Kniess Torsten , Pietzsch Jens
Published: December 2019

Radiotherapy of various cancers is closely associated with increased cardiovascular morbidity and mortality. Arachidonic acid metabolites are supposed to play a key role in radiation-induced vascular dysfunction. This study was designed to evaluate the effects of novel, antioxidative 2,3-diaryl-substituted indole-based selective cyclooxygenase-2 (COX-2) inhibitors (2,3-diaryl-indole coxibs) on radiation-induced formation of arachidonic acid metabolites via COX-2 and oxidant stress pathways in an organotypical vascular model of rat aortic rings. Acute and subacute effects of X-ray radiation (4 and 10 Gy; 1 and 3 days post irradiation) with or without the presence of 1 μM of the 2,3-diaryl-indole coxib 2-[4-(aminosulfonyl)phenyl]-3-(4-methoxyphenyl)-1H-indole (C1) or celecoxib as reference compared to sham-irradiated controls were assessed. The following parameters were measured: metabolic activity of the aortic rings; induction and regulation of COX-2 expression; release of prostaglandin E2 and F2α-isoprostane. Irradiation without presence of coxibs resulted in a dose-dependent augmentation of all parameters studied. When aortic rings were exposed to the 2,3-diaryl-indole coxib 1 h before irradiation, metabolic activity was restored and the release of both prostaglandin and isoprostane was inhibited. The latter indicates a direct interaction with oxidant stress pathways. By contrast, celecoxib exhibited only slight effects on the formation of isoprostane. The reduction of radiation-induced vascular dysfunction by antioxidative coxibs may widen the therapeutic window of COX-2 targeted treatment.
Impact of Di(2-ethylhexyl)phthalate on migration rate of human promyelocytic leukemia cells (HL-60)
Authors: Manz Patrick , Cadeddu Ron-Patrick , Wilk Matthias , Fritz Birgit , Haas Rainer , Wenzel Folker
Published: December 2019

INTRODUCTION: Softeners like phthalate esters are ubiquitous in the environment and have been detected in transfusion bags, though there is only a limited amount of studies on the effect of phthalates on blood cells. This study seeks to determine effects on cell migration of human promyelocytic leukemia cells (HL-60) incubated with di(2-ethylhexyl)phthalate (DEHP) at concentrations found in blood bags. MATERIAL AND METHODS: HL-60 cells were incubated with DEHP concentrations ranging from 0.1 μg/ml to 1000 μg/ml, diluted in DMSO, over 24 h, 48 h, and 72 h. Migration rate was analyzed along an SDF-1α gradient using Transwell migration inserts. RESULTS: Of the applied concentrations 100 μg/ml, 250 μg/ml, 500 μg/ml, and 1000 μg/ml showed a significant decrease in migration rates relative to DMSO control at all measuring points (p < 0.05), with relative migration rates between 37.87 % for 100 μg/ml and 25.34 % for 1000 μg/ml relative to DMSO after 24 h of stimulation and 19.73 % for 100 μg/ml and 14.69 % for 1000 μg/ml respectively after 72 h of incubation. CONCLUSION: Our results indicate HL-60 to be a suitable in vitro model for examining effects of DEHP on the migration of blood and nucleated cells at concentrations found in blood bags.
Study of skin vasomotion during phollicular and luteal phase in young healthy women
Authors: Rossi M. , Di Maria C. , Erba P. , Galetta F. , Carpi A. , Santoro G.
Published: December 2019

The aim of this study was to evaluate if changes in female sex hormones associated to follicular phase (FP) and luteal phase (LP) may affect skin vasomotion in women with evidence of ovulatory cycle. Nine healthy non-smoker women aged 25±4 years, with regular menstrual cycle of 28±2 days and evidence of ovulation (indicated by a mid-luteal serum progesterone concentration > 5 ng/ml) (group-1) and six healthy non-smoker healthy women aged 24±2 years with evidence of an-ovulatory cycle (group-2) were enrolled in the study. At the times 1 (7th–10th day from the beginning of the last menstrual cycle) and at the time 2 (18th–22th day from the beginning of the last menstrual cycle) forearm skin vasomotion was investigated by means of spectral Fourier analysis of the skin laser Doppler flowmetry (LDF) tracing registered under basal conditions and following acetylcholine (ACh) iontophoresis. The power spectral density (PSD) of the 0.01–0.02, 0.02–0.06 and 0.06–0.2 Hz LDF tracing frequency intervals (related to endothelial-, sympathetic- and myogenic-dependent vasomotion, respectively) was measured in PU2 (LDF perfusion unit)/Hz (1 PU = 10 mV). At the same times skin blood flux response (percentage change from baseline) to ACh and to sodium nitroprusside (SNP) iontophoresis was also investigated. Basal and ACh-stimulated skin vasomotion did not significantly differ between time 1 and time 2 in PSD of the three frequency intervals investigated in both groups, as well as between the two groups at each time of investigation. Similarly, no significant changes were observed in skin vasodilator response to ACh and SNP iontophoresis between time 1 and 2 in each group. These results suggest that the female sex hormone changes associated to the FP and LP in young women with ovulatory cycle do not affect basal and ACh stimulated skin vasomotion as well as the endothelial- and non-endothelial-dependent skin vasoreactivity.
Evaluation of the sublingual microcirculation in cardiogenic shock
Authors: Jung Christian , Ferrari Markus , Rödiger Christoph , Fritzenwanger Michael , Goebel Bjoern , Lauten Alexander , Pfeifer Ruediger , Figulla Hans R.
Published: December 2019

Objectives: Orthogonal polarized spectral imaging- and sidestream darkfield-technique have enabled visual evaluation of the microcirculation. Different investigators described microcirculatory alterations, especially in surgical patients suffering from septic shock. We investigated the sublingual microcirculation in non-surgical patients admitted to our medical, intensive care unit (ICU).

Methods: In 24 severely ill (APACHE-II Score: 27.8±11.3), intubated patients admitted to our ICU the sublingual microcirculation was recorded with a handheld intravital microscope. Sublingual vessels were categorized according to their size (small: 10–25 μm; medium: 26–50 μm; large: 51–100 μm) and the flow in semiquantitative categories (0: no flow; 1: intermittent flow; 2: sluggish flow; 3: continuous flow).

Results: Patients with cardiogenic shock (n=7) had lower microflow compared with patients without cardiogenic shock (small p<0.001, medium p<0.001, large p=0.003). Several other diseases, including diabetes and arterial hypertension, age, gender, had no influence. In general, patients with a flow less than 3 in the small vessels showed higher arterial blood lactate levels (p=0.043) compared to continuous flow.

Conclusions: A consequence of cardiogenic shock is the impairment of microcirculation with organ hypoperfusion. We observed that cardiac output is correlated to disturbance in microflow in the smallest vessels. On-line evaluation of microcirculation in vivo may be a valid tool for optimizing therapeutic measures in high risk patients.

Additional online material may be found at: http://www.kim1.uniklinik-jena.de/Microcirculation.html.
New perfusion imaging of tissue transplants with Contrast Harmonic Ultrasound Imaging (CHI) and Magnetic Resonance Imaging (MRI) in comparison with laser-induced Indocyanine Green (ICG) fluorescence angiography
Authors: Jung E.M. , Prantl L. , Schreyer A.G. , Schreyer C.I. , Rennert J. , Walter M. , Jung W. , Hoffstetter P. , Herold T. , Zorger N. , Feuerbach S. , Fellner C.
Published: December 2019

Purpose: Evaluation of post-surgery tissue perfusion of free flaps of the lower leg with contrast enhanced harmonic imaging (CHI), laser-induced indocyanine green (ICG) fluorescence angiography and magnetic resonance imaging (MRI).

Materials and methods: 10 patients with free flaps of the lower limb were evaluated with CHI, ICG-fluorescence angiography and perfusion weighted MRI. Perfusion weighted MRI was performed after intravenous bolus injection of 25 ml Gd-DTPA. The ICG fluorescence was detected by a near-infrared-laser device (λem = 780 nm). Ultrasound was carried out by an experienced examiner with a linear probe after intravenous bolus injection of 2.4 ml SonoVue®. For MRI time intensity curves as well as color-coded blood volume maps of the whole free flap were qualitatively evaluated. For CHI and ICG time intensity curves in selected regions of interest were analyzed. A score from 1–5 (1 = low, 5 = excellent) was used for analysis of perfusion images by three independent readers.

Results: In 3 cases (radialis, parascapular and lateral thigh flap) CHI, MRI and ICG perfusion imaging showed an excellent (score 4–5) contrast enhancement of the cutaneous and subcutaneous part of the free flaps. In 2 cases of osteocutaneous flaps perfusion in central and distal parts of the free flaps was reduced (score 2). Correlation between CHI, MRI and ICG was 0.69–0.83 for the distal parts of the free flaps and 0.74–0.87 for the center of the flaps (Spearman test). Perfusion in the center of the free flaps was significantly different for MRI and ICG and also for MRI and CHI (p<0.05, Wilcoxon test).

Conclusion: These first results introduce CHI and MRI perfusion imaging as a promising post-surgery monitoring in patients with free flaps.
Improving the spatial accuracy in functional magnetic resonance imaging (fMRI) based on the blood oxygenation level dependent (BOLD) effect: Benefits from parallel imaging and a 32-channel head array coil at 1.5 Tesla
Authors: Fellner C. , Doenitz C. , Finkenzeller T. , Jung E.M. , Rennert J. , Schlaier J.
Published: December 2019

Geometric distortions and low spatial resolution are current limitations in functional magnetic resonance imaging (fMRI). The aim of this study was to evaluate if application of parallel imaging or significant reduction of voxel size in combination with a new 32-channel head array coil can reduce those drawbacks at 1.5 T for a simple hand motor task. Therefore, maximum t-values (tmax) in different regions of activation, time-dependent signal-to-noise ratios (SNR(t)) as well as distortions within the precentral gyrus were evaluated. Comparing fMRI with and without parallel imaging in 17 healthy subjects revealed significantly reduced geometric distortions in anterior–posterior direction. Using parallel imaging, tmax only showed a mild reduction (7–11%) although SNR(t) was significantly diminished (25%). In 7 healthy subjects high-resolution (2 × 2 × 2 mm3) fMRI was compared with standard fMRI (3 × 3 × 3 mm3) in a 32-channel coil and with high-resolution fMRI in a 12-channel coil. The new coil yielded a clear improvement for tmax (21–32%) and SNR(t) (51%) in comparison with the 12-channel coil. Geometric distortions were smaller due to the smaller voxel size. Therefore, the reduction in tmax (8–16%) and SNR(t) (52%) in the high-resolution experiment seems to be tolerable with this coil. In conclusion, parallel imaging is an alternative to reduce geometric distortions in fMRI at 1.5 T. Using a 32-channel coil, reduction of the voxel size might be the preferable way to improve spatial accuracy.
Contrast-enhanced ultrasound in diagnosing liver malignancy
Authors: Zuber-Jerger I. , Schacherer D. , Woenckhaus M. , Jung E.M. , Schölmerich J. , Klebl F.
Published: December 2019

Purpose: The use of contrast enhancers has widened the possibilities of sonographic imaging, and allows the differentiation of characteristic enhancement patterns leading to diagnosis in focal liver lesions. The aim of our study was to evaluate contrast ultrasound signs in diagnosing malignant liver lesions.

Methods: 86 patients with 100 solid liver lesions were enrolled. A baseline gray-scale sonogram was obtained with a multifrequency 4 C convex array probe, followed by contrast-enhanced sonography with a low mechanical index (<0.2) over 300 seconds. Final diagnosis was confirmed by histology or in case of haemangioma by CT/NMR and quantitative contrast harmonic imaging (CHI) with perfusion analysis (qontrast).

Results: 55 malignant (6 HCC, 46 secondary malignant lesions – 3 of them lymphoma, 3 cholangiocarcinoma), and 45 benign lesions (8 FNH, 1 von Meyenburg complex, 1 granuloma, 3 adenoma, 21 hemangioma, 2 focal fat storage imbalances, 7 abscesses, one scar, and in one case normal liver) were found.

51/55 malignant (all but one filia and three HCC), but also 17/45 benign lesions showed hypoperfusion in the late phase. The ultrasound pattern in the arterial phase differed in malignant lesions: 22 lesions were initially hypervascular, 20 had rim enhancement and in 13 lesions there was a non-specific vascularisation.

In all but one malignant lesion a diminishing of contrast agent in the late phase compared to the arterial phase with respect to the surrounding liver tissue was observed. Only three benign lesions with this later sign were falsely diagnosed as malignant: one adenoma, one epitheloid granuloma, and a scar. Quantitative perfusion pattern was analyzed exemplary.

Diminishing of contrast agent in the late phase compared to the arterial phase with respect to the surrounding liver tissue as a sign for malignancy had a positive predictive value of 95%, a sensitivity of 98%, a negative predictive value of 98%, and a specificity of 93%.

Conclusions: Diminishing of contrast agent in the late phase compared to the arterial phase with respect to the surrounding liver tissue is a helpful sign in contrast enhanced ultrasound to diagnose malignancies.
Alteration of serum thrombopoietin levels in patients with chronic hepatitis C under interferon therapy
Authors: Wenzel Folker , Gruber Wolfgang , Giers Günther
Published: December 2019

Thrombocytopenia is commonly observed during interferon-α (IFN-α) therapy in patients with chronic hepatitis C. Since thrombopoietin (TPO) is the main regulator of thrombopoiesis, thrombocytopenia may partially be due to a reduced TPO generation. Because of the developments of the second generation of TPO mimetic drugs patients with reduced TPO levels should be identified possibly having a benefit by medicinal stimulation of thrombopoiesis. Therefore, platelet count and serum TPO concentration of patients receiving an interferon-α therapy were determined.

Twelve patients treated with IFN-α (daily 10×106 IU s.c. for four weeks) in cause of chronic hepatitis C were examined during the first month of therapy. Serum TPO concentration significantly decreased from 80.8±48.0 to 34.6±24.5 pg/ml (p<0.05, Mann–Whitney test), and platelet count declined from 214,417±48,292 to 151,333±44,726 platelets/μl. During the following three weeks platelet count remained at a low level, while serum TPO increased to normal range.

In conclusion, an interferon treatment causes reduced serum TPO level during the first week of therapy accompanied by decreased platelet count. The reduction in TPO synthesis contributes to the development of thrombocytopenia in patients during interferon therapy.
Improved viscosity modeling in patients with type 2 diabetes mellitus by accounting for enhanced red blood cell aggregation tendency
Authors: Mutsaerts Henri J.M.M. , Out Mattijs , Goedhart Peter T. , Ince Can , Hardeman Max R. , Romijn Johannes A. , Rabelink Ton J. , Reiber Johan H.C. , Box Frieke M.A.
Published: December 2019

Aims: Distorted wall shear stress (WSS) in patients with type 2 diabetes mellitus (T2DM) may be partly explained by an altered red blood cell aggregation tendency (RAT) on viscosity at low shear rate (SR). The present study evaluates viscosity modeling by implementation of hematocrit and RAT in patients with and without T2DM (non-T2DM). Methods: A Couette viscometer and LORCA aggregometer provided viscosity and RAT on 6 shear rates in 55 patients (46–78 yrs, 66% male, T2DM: n = 28), following informed consent. Using a K-fold cross-validation, two linear mixed models predicted by SR and Hct and by SR, Hct and RAT were compared. Results: In non-T2DM modeling was improved in relatively low RATs (48%, p = 1.0 × 10−11) and became worse in relatively high RATs (−18%, p = 0.019). In T2DM the opposite was observed, as modeling became worse in relatively low RATs (−16%, p = 0.001) but was improved in relatively high RATs (22%, p = 0.022). Conclusions: In addition to confirming previous research, major differences in modeling improvement between T2DM and non-T2DM were found. Especially patients with T2DM, a high RAT and often high viscosity at low SR benefit from a more accurate viscosity modeling. Further studies should evaluate how these findings affect WSS in these patients.
Effect of mechanical ventilation on microvascular perfusion in critical care patients
Authors: Lauten Alexander , Ferrari Markus , Pfeifer Ruediger , Goebel Bjoern , Rademacher Wilma , Krizanic Florian , Roediger Christoph , Figulla Hans R. , Jung Christian
Published: December 2019

Purpose: Microvascular perfusion, pivotal for adequate tissue oxygenation is potentially linked to outcome in critical care therapy. Mechanical ventilation (MV) and positive end-expiratory pressure (PEEP) as standard concepts of respiratory management are known to have deleterious effects on regional organ perfusion especially in the splanchnic area. As these effects have been attributed to different physiologic mechanisms, the purpose of this study was to investigate the effect of positive pressure ventilation on extra-abdominal tissue perfusion in non-surgical intensive care patients. Methods: Sublingual microcirculation was evaluated in 46 severely ill patients (group 1: n=26 requiring MV and PEEP; group 2: n=20 spontaneous breathing) admitted to the intensive care unit using sidestream darkfield intravitalmicroscopy. According to current guidelines, sublingual vessels were categorized by means of size and flow in semi-quantitative categories determining microvascular flow index (MFI). Total microvascular flow index (TMFI) was calculated for each patient as mean value of flow in all vessel categories. Results: No significant difference was observed between both groups in microvascular flow index in each vessel category and in total microvascular flow index. Patients requiring mechanical ventilation presented with more comorbidities and higher acuity of illness scores resulting in a higher ICU mortality, which however was not accompanied by microcirculatory differences at the time of measurement. Conclusion: Mechanical ventilation and PEEP have no general deleterious effects on microvascular perfusion of the sublingual mucosa. However, further clinical studies are required to investigate potential effects of higher levels of ventilation pressure or PEEP on microvascular perfusion.
Comparison of time-resolved CT-angiography, contrast-enhanced ultrasound and digital subtraction angiography in a patient with a small type II endoleak after endovascular aneurysm repair
Authors: Sommer Wieland H. , Hoffmann Ralf. T. , Becker Christoph R. , Reiser Maximilian F. , Clevert Dirk A.
Published: December 2019

We report discordant imaging findings of a small persistent type II endoleak in a 72-year-old man who had undergone endovascular aneurysm repair (EVAR) of an abdominal aortic aneurysm. Although the aneurysm was growing in size digital subtraction angiography could not detect an endoleak, but time-resolved CT-angiography and contrast enhanced ultrasound did detect a small type II endoleak.
Influence of bleeding on haemorheology and haemostasis in surgery
Authors: Stephan B. , Schenk J.F. , Pindur G. , Meiss C. , Borchers H. , Nemeh A. , Weinrich M. , Wagner B.
Published: December 2019

Changes in haemorheology and haemostasis may contribute to bleeding or thrombosis, which is of concern particularly in surgery. Blood loss itself has a major influence on both parameters being closely involved in the clinical outcome. In order to analyze the underlying interrelations, a prospective study with 122 patients (64 females, 58 males) aged between 18 and 83 years (mean: 51.8 years) was conducted. All patients were electively submitted to orthopaedic surgery. Haemorheological parameters included measurements of plasma viscosity, red body cell (RBC) and platelet aggregation index preoperatively, as well as by day 1 and day 7 after surgery. Additionally hematological and haemostaseological parameters including leukocyte and platelet counts, haematocrit and fibrinogen were investigated. Bleeding was defined as high (>500 ml) or low blood loss (≤500 ml) according to the drainage volume. High but not low blood loss was associated with an increase of RBC aggregation by day 1 and 7 after surgery. Plasma viscosity decreased significantly by day 1, returning to normal 7 days after surgery. Platelet count decreased significantly, concurrent with the haematocrit, by day 1 postoperatively, whereas by day 7 a significant increase was observed, being more distinct in high blood loss. Platelet aggregation index did not change under the influence of blood loss. Plasma fibrinogen, clearly corresponding to the extend of blood loss, showed a continuous postoperative increase, which was significantly higher at day 7. Leukocytes increased moderately but significantly in particular in high blood loss. In conclusion, the postoperative decrease of plasma viscosity and of platelet counts, concurrent with the haematocrit, provides evidence of being clearly dependent on blood loss which is regarded as a dilution effect corresponding with the haemorrhagic risk. The increase of RBC aggregation at the early postoperative stage is solely observed in high blood loss and is esteemed as a result of volume therapy. The marked increase of platelet counts and plasma fibrinogen at the late postoperative stage, being more pronounced in high blood loss, might contribute to an elevated prothrombotic risk and is ascribed to an inflammatory response to surgery. In summary, it is concluded, that bleeding tendency corresponding with haemorheologic parameters is enhanced in the early, whereas the prothrombotic risk, well correlating with haemostaseologic parameters, is elevated in the later stage after surgery.
Quantitation of angiogenesis in vitro induced~by VEGF-A and FGF-2 in two different human endothelial cultures – an all-in-one assay
Authors: Bahramsoltani Mahtab , Spiegelaere Ward De , Janczyk Pawel , Hiebl Bernhard , Cornillie Pieter , Plendl Johanna
Published: December 2019

Angiogenic therapy is considered to be a promising tool for treatment of ischemic diseases. Many in vivo and in vitro assays have been developed to identify potential proangiogenic drugs and to investigate their mode of action. However, until now no validated system exists that would allow quantitation of angiogenesis in vitro in only one assay. Here, a previously established all-in-one in vitro assay based on staging of the angiogenic cascade was validated by quantitation of the effects of the known proangiogenic factors VEGF-A and FGF-2. Both growth factors were applied separately or in combination to human endothelial cell cultures derived from the heart and the foreskin, and angiogenesis was quantitated over 30 days of culture. Additionally, gene expression of VEGFR-1, VEGFR-2 and FGFR-1 at 3, 10, 20 or 40 days of cultivation was quantitated by RT-qPCR. In both cultures, VEGF-A as well as FGF-2 induced a run through all defined stages of angiogenesis in vitro. Application of VEGF-A only led to formation of irregular globular endothelial structures, while FGF-2 resulted in development of regular capillary-like structures. Quantitation of the angiogenic effects of VEGF-A and transcripts of VEGFR-1 and VEGFR-2 showed that a high VEGFR-1/VEGFR-2 ratio evoked deceleration of angiogenesis.
CD14+ CD163+ IL-10+ monocytes/macrophages: Pro-angiogenic and non pro-inflammatory isolation, enrichment and long-term secretion profile
Authors: Mayer A. , Lee S. , Jung F. , Grütz G. , Lendlein A. , Hiebl B.
Published: December 2019

The establishment of a stable endothelial layer on a biomaterial suture is a well known strategy to achieve hemocompatibility. The endothelialisation is supported by factors as e.g. vascular endothelial growth factor (VEGF), which can be secreted by monocytes/macrophages (mo/mΦ) in an angiogenic milieu. In order to avoid detrimental inflammation triggered by these mo/mΦ, we established a protocol for the generation of alternatively activated macrophages and studied their response towards VEGF-A165. We could generate sufficient amounts of these CD14+ CD163+ IL-10+ mo/mΦ from buffy coats(8.6 ± 4.7 × 105 cells/mlbuffy coat). Furthermore, we achieved a VEGF-A165 secretion in the nanogram range. The VEGF-A165 secretion increased 2.1-fold within 14 days from 7.6 ± 2.2 to 16.1 ± 2.5ng/ml when the cells were grown with a VEGF-A165 supplemented (10ng/ml) cell culture medium. Within this time period the secretion levels of other pro-angiogenic growth factors (bFGF, PDGF-BB) and immunomodulatory cytokines (IL-10, IL-12, IL-1ra, TNFα, IFNγ) reached only the picogram range. These results suggest that angiogenically stimulated CD14+ CD163+ IL-10+ mo/mΦ might be useful as a cellular cytokine delivery system supporting endothelialisation of biomaterials without inducing pro-inflammatory effects.
Embedding of radiographic media molecules in the membrane of erythrocytes
Authors: Franke R.P. , Minkow A. , Hiebl B. , Fuhrmann R. , Mrowietz C. , Jung F.
Published: December 2019

The incubation of erythrocytes (RBC) or endothelial cells (HUVEC) in radiographic contrast media (RCM) could induce morphological alterations of or at the cell membranes, e.g. the generation of echinocytes or the formation of stress fibres coinciding with a massive buckling of HUVEC into the vascular lumen, as was demonstrated in several examinations in the recent years. The apposition or embedding of RCM at or in the cell membranes was discussed as possible causative mechanisms because the embedding of molecules into the internal leaflet of the cell membrane bilayer is expected to bulge the cell membrane to the outside, thus inducing e.g. the generation of echinocytes. The examination presented here is based therefore on high resolution scanning electron microscopy (SEM) analyses if iodine as marker element of RCM molecules can be found near the inside of or in RBC membranes (co-localisation study). Morphological analyses exploited secondary electron images (SE) while the analysis of elements exploited either back scattered electrons (BSE) or energy dispersive X-ray analysis (EDX) or the areal display of elements in high lateral resolution in the Bit-map modus. Even at the highest convenient magnification (1:40,000) it was impossible to detect RBC membrane associated iodine (I) after RBC incubation in RCM (Iodixanol, Iopromide) in vitro. Neither in the birds view on the samples nor looking from the side on the freeze fractured samples carrying the RBC was it possible to detect either the signal cohorts typical of I in the sum spectra or the main Lα1-peak in trace analysis.
Erythrocytapheresis and sublingual micro-vascular flow in severe malaria
Authors: Siegenthaler Nils , Giraud Raphael , Bendjelid Karim
Published: December 2019

The authors describe clinical cases of two patients admitted to intensive care unit following severe Plasmodium falciparum malaria. Patients' sublingual microcirculation was monitored by on-line Sidestream dark-field imaging before and after treatment with erythrocytapheresis. Before treatment, microcirculatory flow alterations were obvious. Therapy produced a rapid decrease in infected red blood cells with a significant improvement in microcirculatory flows, capillary perfusion and patients' outcome. The present cases emphasize the relevance of microcirculation monitoring in patients with capillary perfusion alterations resulting from severe malaria. As far as we know, this is the first observations of an improvement of capillary perfusion after erythrocytapheresis.
Calculated effect of fluid retention upon velocity of blood flow and turbulence: Implications for atherosclerosis
Authors: Blankfield Robert P.
Published: December 2019

Fluid retention increases intravascular volume and pressure. The calculations in this paper demonstrate that fluid retention increases the likelihood that blood will flow in a turbulent manner, in part due to an increase in stroke volume, regardless of whether or not blood pressure is increased. Increased turbulence will promote endothelial dysfunction, thereby contributing to the development of atherosclerotic cardiovascular disease. Accordingly, fluid retention is predictably detrimental to the cardiovascular system. The reason that some medications, such as cyclo-oxygenase-2 inhibitors, nonselective nonsteroidal anti-inflammatory drugs, estrogens, progestins, and rosiglitazone, are associated with an increased risk of myocardial infarcts and strokes may be that they cause fluid retention. Increased stroke volume and/or edema formation may indicate that a medication increases the risk of adverse cardiovascular events. For drugs that increase the risk of adverse cardiovascular events, it may be possible to reduce or neutralize the increased risk by simultaneously administering a diuretic.
Impaired microvascular endothelial function in relatively young obese humans is associated with altered metabolic and inflammatory markers
Authors: Al-Tahami Belqes Abdullah , Bee Yvonne-Tee Get , Ismail Abdul Aziz Al-Safi , Rasool Aida Hanum Ghulam
Published: December 2019

Introduction: This study aims to assess microvascular endothelial function in obese compared to age matched lean controls. Serum lipid profile, fasting glucose, high sensitivity C-reactive protein (hs-CRP) and adiponectin levels were also determined. Methods: This cross-sectional study involved 36 healthy lean and 36 obese subjects. Microvascular endothelial function was assessed using Laser Doppler fluximetry and iontophoresis with acetylcholine and sodium nitroprusside. Results: Mean age of subjects was 26.54 ± 0.60 years. Obese subjects had higher systolic (118.8 ± 1.5 vs 105.7 ± 2.0mmHg, p < 0.001) and diastolic blood pressure (71.61 ± 1.35 vs 64.53 ± 1.40mmHg, p = 0.001), higher triglyceride (1.35 ± 0.13 vs 0.79 ± 0.05 mmol/l, p < 0.001), lower high density lipoprotein cholesterol (HDL-C) (1.43 ± 0.04 vs 1.62 ± 0.05 mmol/l, p = 0.003), higher hs-CRP (11.58 ± 1.88 vs 1.88 ± 0.35 mg/l, p < 0.001), and lower adiponectin levels (8.80 ± 0.43 vs 25.93 ± 0.40 μg/ml, p < 0.001) compared to lean subjects. Endothelial dependent vasodilatation was lower in obese compared to lean subjects (40.53 ± 6.59 vs 71.03 ± 7.13 AU, p = 0.001). Conclusion: Microvascular endothelial function is reduced in obese compared to age matched controls. This is associated with higher BP, triglyceride and lower HDL-C and adiponectin levels in obese group.
Eadie-Hofstee analysis of red blood cell deformability
Authors: Stadnick H. , Onell R. , Acker J.P. , Holovati J.L.
Published: December 2019

In recent years, linear data transformation has become an accepted method to simplify the analysis of red blood cell (RBC) deformability curves obtained by ektacytometry. In this study, we introduce the Eadie-Hofstee transformation as an alternative linearization method for the analysis of RBC deformability. RBCs were treated with hydrogen peroxide (H2O2), tert-butyl-hydroperoxide (t-BuOOH), or methyl β-cyclodextrin (MβCD) and analyzed via ektacytometry (LORCA). RBC hemopathological clinical isolates (hereditary spherocytosis and α-thalassemia) were also analyzed by LORCA. Following ektacytometry, Eadie-Hofstee linearization was performed to obtain the maximum deformability (EImax) and shear stress at half maximal deformation (KEI) parameters. Significant changes in deformability parameters were observed with all agents tested. For H2O2 and t-BuOOH, the KEI values increased significantly accompanied by marginal changes in EImax, while treatment with MβCD resulted in a dose dependant decrease in EImax. Contrasting deformability profiles were also observed in the two hematological disorders tested. In this study we have demonstrated the ability of Eadie-Hofstee linearization to detect and resolve changes in RBC deformability induced in vitro as well as deformability changes associated with in vivo hematological disorders. This technique shows promise in basic research, blood bank and clinical hematology settings.
Erythrocyte aggregation in patients with systemic lupus erythematosus
Authors: Spengler M.I. , Svetaz M.J. , Leroux M.B. , Bertoluzzo S.M. , Carrara P. , Van Isseldyk F. , Petrelli D. , Parente F.M. , Bosch P.
Published: December 2019

Systemic Lupus Erythematosus (SLE) is an autoimmune, chronic inflammatory, non-organ specific disease. SLE patients present a high prevalence of thrombotic and arteriosclerotic disease. The aim of the present work was to study the erythrocyte aggregation kinetics, and the effect of plasma factors, namely, immunoglobulin and fibrinogen concentration, as well as cell factors such as deformability and erythrocyte membrane lipid fluidity on the erythrocyte aggregation, in SLE patients and healthy controls. The results show that SLE patients red blood cells aggregate at higher rate and the aggregates size are also greater than controls due to an increase of immunoglobulin and plasma fibrinogen. The negative correlation between aggregation parameters and rigidity index could point out that the altered deformability diminishes the erythrocyte aggregation. Correlation between rigidity index and anisotropy suggests that the decrease of membrane lipid fluidity might be a cause of deformability decrease. The erythrocyte aggregation increase in these patients could induce a decreased flow that might contribute to the thromboembolic process present in SLE patients.
Hemorheological profile in primary Sjögren's syndrome: A case-control study
Authors: Vayá Amparo , Suescun Marta , Micó Luisa , Todolí Jose , Ricart Jose M.
Published: December 2019

Rheological blood behavior in primary Sjögren's syndrome (SS) has been scarcely investigated. We evaluated the rheological profile (blood viscosity, plasma viscosity, erythrocyte deformability, erythrocyte aggregation, erythrocyte aggregation time and erythrocyte disaggregation threshold) along with fibrinogen, high-sensitive C reactive protein, plasma lipids, immunoglobulins, total proteins and erythrocyte sedimentation rate in 22 patients with primary SS (2 males, 20 females, aged 58 ± 9 years) and in 22 healthy volunteers (3 males, 19 females, aged 57 ± 5 years). Patients showed statistically higher plasma viscosity, erythrocyte sedimentation rate and G immunoglobulin (IgG) levels and lower total cholesterol than controls (p = 0.006, p = 0.023, p = 0.034, p = 0.036, respectively). Three patients with extraglandular involvement showed the highest plasma viscosity values: 1.98 cP, 1.70 cP and 1.65 cP, respectively. No differences were observed for the other rheological parameters analyzed. In a multivariate regression analysis, only fibrinogen, triglycerides and IgG were independent determinants for plasma viscosity values (beta coefficient: 0.335; p = 0.001; beta coefficient: 0.242; p = 0.019; beta coefficient: 0.660; p < 0.001, respectively). Our results indicate that patients with primary SS show increased plasma viscosity, mostly related with IgG levels without other alterations in the rheological profile. Further research with a larger sample size achieved by multicenter studies would be desirable.
Contrast-enhanced ultrasound of hepatocellular carcinoma: Correlation of washout time and angiogenesis
Authors: Xia Y. , Jiang Y.X. , Dai Q. , Xiao Y. , Lv K. , Wang L.
Published: December 2019

Background: The use of the pure blood pool ultrasound contrast agent SonoVue (Bracco, Italy) with specific ultrasound imaging software has enabled the dynamic visualization of tumor microcirculation. Aim: The present study was designed to investigate the washout time of hepatocellular carcinoma (HCC) and correlate it with angiogenesis parameters. Methods: Thirty-one surgically confirmed HCC cases were prospectively evaluated with contrast-enhanced ultrasound (CEUS), and parameters such as wash-in time, peak enhancement time and washout time were determined offline. We also calculated microvessel density and the percentage of microvessel area (MVA) and compared CEUS parameters between a well differentiated group and a poorly to moderately differentiated group. The Spearman rank order correlation method was used to analyze the relationship between washout time and angiogenesis parameters. Results: The washout time was longer in well differentiated HCC patients compared to those with poorly to moderately differentiated HCC (p < 0.05). In addition, the washout time of HCC was positively correlated with the percentage of MVA (r = 0.510). Conclusions: Given that the percentage of MVA was positively correlated with tumor blood volume, washout time may be associated with HCC blood volume.
Minimal model-derived insulin sensitivity, insulin secretion and glucose tolerance: relationships with blood rheology
Authors: Brun Jean-Frédéric , Varlet-Marie Emmanuelle , Raynaud de Mauverger Eric , Mercier Jacques
Published: December 2019

Insulin resistance is associated with a mild hyperviscosity syndrome, which is more closely related to insulin resistance than to the clinical scoring of the metabolic syndrome. In studies using the intravenous glucose tolerance test with minimal model analysis we reported that low insulin sensitivity (SI) is associated with increased erythrocyte aggregability (EA). Actually, this issue is confusing because insulin resistance is often associated with compensatory hyperinsulinemia (insulin being a hormone with reported hemorheologic effects) and that a decline in insulin secretion has marked metabolic effects that modify blood rheology. From the intravenous glucose tolerance test (IVGTT) the minimal model allows the calculation of SI, insulin response, and an overall glucose tolerance parameter termed “disposition index” (DI) that measures whether insulin response is adequate or not for the level of insulin sensitivity. In this study we assessed SI, insulin response, and DI during an IVGTT in 335 subjects of both genders (age 8–77 yr; BMI 14–67 kg/m2). SI was only correlated (negatively) with EA (Myrenne M r = −0.285; p = 0.0001; M1 r = −0.240 p = 0.003). Fasting insulin was also correlated (positively) with EA (Myrenne M r = 0.233, 0.00880; M1 r = 0.320 p = 0.0003; SEFAM TA r = −0.342 p = 0.04; SEFAM S60 r = 0.419 p = 0.01) and SEFAM RBC disaggregation thresholds (γS = r = 0.372 p = 0.025; γD = r = 0.504 p = 0.002). Fasting DI (SI × fasting insulin) is negatively correlated to M (r = −0.274; p = 0.002) and M1 (r = −0.225; p = 0.01) but also positively to whole blood viscosity (r = 0.168; p = 0.01) and hematocrit (r = 0.142; p = 0.05). Stimulatory DI (SI × insulin peak) fails to be correlated with any parameter of EA but is negatively correlated to whole blood viscosity (r = −0.150; p = 0.02) and plasma viscosity (r = −0.163; p = 0.01). This study confirms that red cell aggregability is associated with insulin resistance and hyperinsulinemia, but plasma viscosity seems to be more related to overall glucose tolerance than to either SI or insulinemia.
Lack of association between systolic blood pressure and blood viscosity in normotensive healthy subjects
Authors: Irace Concetta , Carallo Claudio , Scavelli Faustina , Loprete Antonio , Merante Valentina , Gnasso Agostino
Published: December 2019

Objective: A direct relationship between blood pressure and viscosity has frequently been reported, although clear data are not available. To better understand the relationship between these two variables, we evaluated blood viscosity and blood pressure in a group of healthy subjects without cardiovascular risk factors. Methods: Healthy subjects were selected from participants in a campaign of prevention of cardiovascular disease (n = 103). They underwent blood sampling for measurement of plasma and blood viscosity, haematocrit, blood lipids and glucose. The quantity and distribution of body fat was assessed by body mass index and waist/hip ratio, respectively. Results: Systolic blood pressure (SBP) correlated significantly with age (r = 0.222) and waist/hip ratio (r = 0.374). Diastolic blood pressure (DBP) correlated significantly with waist/hip ratio (r = 0.216), haematocrit (r = 0.333) and blood viscosity (r = 0.258). Multiple linear regression analyses demonstrated that the only variable significantly associated with SBP was age, while haematocrit was the only variable significantly associated with DBP. Blood viscosity was closely related to waist/hip ratio. Conclusion: These findings show that SBP, in healthy subjects, is not influenced by haematocrit and blood viscosity. In contrast, DBP is related to the values of haematocrit. Among classical cardiovascular risk factors, waist/hip ratio is closely related to blood viscosity.
Rheological alterations and thrombotic events in patients with systemic lupus erythematosus
Authors: Vayá Amparo , Calvo Javier , Alcalá Carmen , Micó Luisa , Todolí Jose , Ricart Jose M.
Published: December 2019

Systemic lupus erythematosus (SLE) is characterised by increased venous and arterial thrombotic risk. Nevertheless, how hemorheological alterations contribute to thrombotic risk remains a question of debate. We aimed to determine the rheological profile in 105 patients with SLE (24 with a thrombotic event) and 105 healthy controls. We determined blood viscosity and erythrocyte aggregation along with plasma lipids and fibrinogen. Although SLE patients showed lower blood viscosity at 230 s−1 at a native hematocrit when compared with controls (p < 0.001), differences disappeared after adjusting the hematocrit to 45% (p = 0.095). When comparing SLE patients with and without thrombotic events, no differences in any rheological parameter were found (p > 0.05), except in fibrinogen which was higher in patients with thrombosis (p = 0.013). No differences in the rheological parameters were observed when venous and arterial thrombotic events were compared, although a tendency for higher fibrinogen was observed in patients with venous thrombosis (p = 0.053). Only hematocrit, fibrinogen and triglycerides were independent predictors of native blood viscosity in the multivariate regression analysis, even after adjusting for continuous variables and for tobacco and hypertension: beta coefficient: 0.727 p < 0.001; beta coefficient: 0.152 p = 0.003 and beta coefficient: 0.133 p = 0.015, respectively. The logistic regression analysis revealed that neither increased native blood viscosity (BVn > 4.33) nor increased erythrocyte aggregation (EA1 > 7.85) increased thrombotic risk: OR 0.636, CI 0.313–3.12, p = 0.578 and OR 2.01, CI 0.77–5.20, p = 0.152, respectively. However, hyperfibrinogenemia (Fbg > 342 mg/dL) increased thrombotic risk by around three times: OR 3.44 CI 1.32–8.96, p = 0.011. Our results suggest that the role of blood viscosity and erythrocyte aggregation in thrombotic risk in SLE patients fails to demonstrate any association.