Acute effects of exercise with blood flow restriction on endothelial function in healthy young and older populations: a systematic review / Efeitos agudos do exercício com restrição do fluxo sanguíneo na função endotelial de jovens e idosos saudáveis: uma revisão sistemática

The objective of this review is to identify the acute effects of blood flow restriction (BFR) with vs without exercise on endothelial function in healthy individuals and the changes in endothelial function in young and older adults following different levels of exclusive BFR vs free flow. Systematic searches were performed in the following databases: PubMed, Web of Science, Scopus, and Cochrane Library, from inception to July 17, 2021. The studies included healthy individuals who underwent assessments of endothelial function before and after experimental protocols through endothelium-dependent flow-mediated dilatation. In total, 4890 studies were screened, and 6 studies of moderate-to-high methodological quality (Physiotherapy Evidence Database scores 6 ­ 10) including 82 subjects (aged 24 ­ 68 years) were eligible. Overall, flow-mediated dilatation increased in the non-cuffed arm immediately and 15 minutes after exercise, with no change in the cuffed arm (BFR of 60 ­ 80 mmHg). In protocols without exercise, cuff pressures of 25 ­ 30 mmHg applied for 30 minutes did not promote changes in the endothelial function, while those > 50 mmHg induced a dose-dependent attenuation of flow-mediated dilatation only in young individuals. A moderate level of BFR appears to have no effect on endothelial function after acute exercise. In non-exercise conditions, reductions in flow-mediated dilatation seem to result from increased retrograde shear provoked by cuff pressures ≥ 50 mmHg in young but not in older adults. An exercise-related increase in antegrade shear rate leads to a greater nitric oxide-mediated vasodilator response. However, BFR appears to attenuate this effect in young but not in older individuals. (AU)

O objetivo desta revisão foi identificar os efeitos agudos da restrição do fluxo sanguíneo (RFS) com vs. sem exercício na função endotelial de indivíduos saudáveis, bem como as alterações na função endotelial em jovens e idosos após diferentes níveis de RFS vs. fluxo livre. Pesquisas sistemáticas foram realizadas nas bases United States National Library of Medicine (PubMed), Web of Science, Scopus e Cochrane Library até 17 de julho de 2021. Os estudos incluíram indivíduos saudáveis que avaliaram a função endotelial antes e após protocolos experimentais, por meio da dilatação mediada por fluxo. Foi selecionado o total de 4.890 estudos, e foram elegíveis seis de moderada a alta qualidade metodológica (Physioterapy Evidence Database 6 ­ 10 pontos), incluindo 82 indivíduos (24 ­ 68 anos). No geral, a dilatação mediada por fluxo aumentou no braço sem manguito, imediatamente e 15 minutos após o exercício, sem alteração no braço com manguito (RFS de 60 ­ 80 mmHg). Em protocolos sem exercício, pressões do manguito de 25 ­ 30 mmHg aplicadas por 30 minutos não promoveram alterações na função endotelial, enquanto aquelas > 50 mmHg induziram uma atenuação dose-dependente da dilatação mediada por fluxo em indivíduos jovens. Um nível moderado de RFS parece não ter efeito na função endotelial após uma sessão de exercício. Em condições sem exercício, as reduções na dilatação mediada por fluxo parecem resultar do aumento do cisalhamento retrógrado provocado por pressões do manguito ≥ 50 mmHg em jovens, mas não em idosos. O aumento da taxa de cisalhamento anterógrado relacionada ao exercício leva a maior resposta vasodilatadora mediada pelo óxido nítrico. No entanto, a RFS parece atenuar esse efeito em jovens, mas não em . (AU)

Fluid shear stress regulates placental growth factor expression via heme oxygenase 1 and iron.

Increased fluid shear stress (FSS) is a key initiating stimulus for arteriogenesis, the outward remodeling of collateral arterioles in response to upstream occlusion. Placental growth factor (PLGF) is an important arteriogenic mediator. We previously showed that elevated FSS increases PLGF in a reactive oxygen species (ROS)-dependent fashion both in vitro and ex vivo. Heme oxygenase 1 (HO-1) is a cytoprotective enzyme that is upregulated by stress and has arteriogenic effects. In the current study, we used isolated murine mesentery arterioles and co-cultures of human coronary artery endothelial cells (EC) and smooth muscle cells (SMC) to test the hypothesis that HO-1 mediates the effects of FSS on PLGF. HO-1 mRNA was increased by conditions of increased flow and shear stress in both co-cultures and vessels. Both inhibition of HO-1 with zinc protoporphyrin and HO-1 knockdown abolished the effect of FSS on PLGF. Conversely, induction of HO-1 activity increased PLGF. To determine which HO-1 product upregulates PLGF, co-cultures were treated with a CO donor (CORM-A1), biliverdin, ferric ammonium citrate (FAC), or iron-nitrilotriacetic acid (iron-NTA). Of these FAC and iron-NTA induced an increase PLGF expression. This study demonstrates that FSS acts through iron to induce pro-arteriogenic PLGF, suggesting iron supplementation as a novel potential treatment for revascularization.

Menstrual phase does not influence ventilatory responses to group III/IV afferent signaling in eumenorrheic young females.

Estrogen can reduce sympathetic activity, but its effects on minute ventilation (VE) with group III/IV afferent activation remain unclear. This study examined the influence of estrogen on VE during lower-extremity exercise with group III/IV activation. Females completed two identical visits in follicular and ovulatory menstrual phases. Nine participants (age 25 ± 4 years) performed three minutes of baseline steady-state cycle ergometry and then group III/IV afferents were further activated with proximal thigh cuffs inflated to 20, 60, and 100 mmHg (randomized) for two minutes and five minutes of cycling between each occlusion. Metaboreflex was isolated by post-exercise circulatory occlusion. Ventilation was measured continuously and rating of perceived exertion (RPE) was recorded for each stage. During rest and exercise, VE (p < 0.001) and tidal volume (VT) (p = 0.033) were higher in the follicular than ovulatory phase. Minute ventilation, VT, and respiratory rate (RR) with ergoreflex and metaboreflex activation were similar across phases. With cuff occlusion of 100 mmHg, VE increased from baseline by 26.3 ± 7.0 L/min in the follicular phase (p < 0.001) and by 25.3±7.7 L/min in the ovulatory phase (p < 0.001), with no difference between phases (p> 0.05); RR and VT increased similarly with occlusion, also with no phase differences. In eumenorrheic females, menstrual phase influences ventilation but not ventilatory responses to group III/IV isolation.

Histopathological study of JNK in venous wall of patients with chronic venous insufficiency related to osteogenesis process.

Chronic venous insufficiency (CVI) is one of the most common vascular pathologies worldwide. One of the risk factors for the development of CVI is aging, which is why it is related to senile changes. The main trigger of the changes that occur in the venous walls in CVI is blood flow reflux, which produces increased hydrostatic pressure, leading to valve incompetence. The cellular response is one of the fundamental processes in vascular diseases, causing the activation of cell signalling pathways such as c-Jun N-terminal kinase (JNK). Metabolic changes and calcifications occur in vascular pathology as a result of pathophysiological processes. The aim of this study was to determine the expression of JNK in venous disease and its relationship with the role played by the molecules involved in the osteogenic processes in venous tissue calcification. This was a cross-sectional study that analyzed the greater saphenous vein wall in 110 patients with (R) and without venous reflux (NR), classified according to age. Histopathological techniques were used and protein expression was analysed using immunohistochemistry techniques for JNK and markers of osteogenesis (RUNX2, osteocalcin (OCN), osteopontin (OPN)). Significantly increased JNK, RUNX2, OCN, OPN and pigment epithelium-derived factor (PEDF) protein expression and the presence of osseous metaplasia and amorphous calcification were observed in younger patients (<50 years) with venous reflux. This study shows for the first time the existence of an osteogenesis process related to the expression of JNK in the venous wall.

Predictive factors of poor blood collecting flow during leukocyte apheresis for cellular therapy.

Leukocyte apheresis is necessary in various cellular therapies. However, maintenance of a stable flow rate during leukocyte apheresis is often difficult, even in patients or donors without major problems. Despite this, predictive methods and evidence regarding the reality of the situation are limited. We conducted a retrospective analysis involving adult patients who required leukocyte apheresis for the treatment of neoplasms using WT1-pulsed dendritic cell vaccine. Monocytes were separated from apheresis products to obtain dendritic cells. All the patients were pre-evaluated based on laboratory and chest X-ray findings and subjected to an identical apheresis procedure. The occurrence of poor blood collecting flow during leukocyte apheresis was monitored, and the frequency, clinical information, and associated risk factors were analyzed. Among 160 cases, poor blood collecting flow was observed in 53 cases (33.1%) in a median time of 54 min (range, 2-127 min) post-initiation of leukocyte apheresis. Owing to difficulty in obtaining higher collecting flow, a longer procedure time was required, and in some cases, the scheduled apheresis cycles could not be completed. Consequently, the number of harvested monocytes was low. Multivariable analysis indicated that female patients have an increased risk of poor inlet flow rate. Furthermore, prolonged QT dispersion (QTD) calculated using Bazett's formula was found to be a risk factor. Although the patients did not present any major problems during leukocyte apheresis, poor blood collecting flow was observed in some cases. Sex and pre-evaluated QTD might be useful predictors for these cases; however, further prospective evaluation is necessary.

Dynamic blood flow phantom for in vivo liquid biopsy standardization.

In vivo liquid biopsy, especially using the photoacoustic (PA) method, demonstrated high clinical potential for early diagnosis of deadly diseases such as cancer, infections, and cardiovascular disorders through the detection of rare circulating tumor cells (CTCs), bacteria, and clots in the blood background. However, little progress has been made in terms of standardization of these techniques, which is crucial to validate their high sensitivity, accuracy, and reproducibility. In the present study, we addressed this important demand by introducing a dynamic blood vessel phantom with flowing mimic normal and abnormal cells. The light transparent silica microspheres were used as white blood cells and platelets phantoms, while hollow polymeric capsules, filled with hemoglobin and melanin, reproduced red blood cells and melanoma CTCs, respectively. These phantoms were successfully used for calibration of the PA flow cytometry platform with high-speed signal processing. The results suggest that these dynamic cell flow phantoms with appropriate biochemical, optical, thermal, and acoustic properties can be promising for the establishment of standardization tool for calibration of PA, fluorescent, Raman, and other detection methods of in vivo flow cytometry and liquid biopsy.

Abnormal morphology biases hematocrit distribution in tumor vasculature and contributes to heterogeneity in tissue oxygenation.

Oxygen heterogeneity in solid tumors is recognized as a limiting factor for therapeutic efficacy. This heterogeneity arises from the abnormal vascular structure of the tumor, but the precise mechanisms linking abnormal structure and compromised oxygen transport are only partially understood. In this paper, we investigate the role that red blood cell (RBC) transport plays in establishing oxygen heterogeneity in tumor tissue. We focus on heterogeneity driven by network effects, which are challenging to observe experimentally due to the reduced fields of view typically considered. Motivated by our findings of abnormal vascular patterns linked to deviations from current RBC transport theory, we calculated average vessel lengths [Formula: see text] and diameters [Formula: see text] from tumor allografts of three cancer cell lines and observed a substantial reduction in the ratio [Formula: see text] compared to physiological conditions. Mathematical modeling reveals that small values of the ratio λ (i.e., [Formula: see text]) can bias hematocrit distribution in tumor vascular networks and drive heterogeneous oxygenation of tumor tissue. Finally, we show an increase in the value of λ in tumor vascular networks following treatment with the antiangiogenic cancer agent DC101. Based on our findings, we propose λ as an effective way of monitoring the efficacy of antiangiogenic agents and as a proxy measure of perfusion and oxygenation in tumor tissue undergoing antiangiogenic treatment.

Effects of blood flow restriction on muscle size and gene expression in muscle during immobilization: A pilot study.

PURPOSE: Muscle mass is known to rapidly decrease with muscle disuse. Previous reports suggest that repetitive blood flow restriction (BFR) mitigates the reduction of muscle mass with disuse. However, the effects of BFR on muscle atrophy and gene expression levels in muscle during cast immobilization have not been clarified. METHODS: To investigate the effect of BFR on muscle atrophy and gene expression levels during cast immobilization in humans, we recruited 10 healthy males who were randomly divided into the control and BFR treatment groups. All subjects were immobilized with a cast for 14 days. BFR treatment was conducted only in the BFR group. We evaluated cross sectional area (CSA) of thigh muscles by magnetic resonance imaging before and 14 days after cast immobilization. A percutaneous biopsy of the vastus lateralis muscle (VL) was performed before and 1, 7, and 14 days after cast immobilization. Expression of genes related to muscle atrophy and synthesis were evaluated using real-time PCR. RESULTS: The CSA of the VL and the thigh flexor muscles were significantly decreased in both groups; however, percent decrease in CSA was significantly smaller in the BFR group compared with the control group. In two-way repeated ANOVA analysis, the time × treatment interaction in gene expression of the muscle-specific ubiquitin ligases muscle ring finger 1 (MuRF1) was significant, and elevated MURF1 expression level by cast immobilization was seemed to be suppressed by the BFR treatment. CONCLUSION: BFR treatment may prevent reduced VL and thigh flexor muscles and increased MuRF1 expression level during cast immobilization. Further study is required to confirm these results.

Enhancement of the blood-circulation time and performance of nanomedicines via the forced clearance of erythrocytes.

The rapid elimination of nanoparticles from the bloodstream by the mononuclear phagocyte system limits the activity of many nanoparticle formulations. Here, we show that inducing a slight and transient depletion of erythrocytes in mice (~5% decrease in haematocrit) by administrating a low dose (1.25 mg kg-1) of allogeneic anti-erythrocyte antibodies increases the circulation half-life of a range of short-circulating and long-circulating nanoparticle formulations by up to 32-fold. Treatment of the animals with anti-erythrocyte antibodies significantly improved the targeting of CD4+ cells in vivo with fluorescent anti-CD4-antibody-conjugated nanoparticles, the magnetically guided delivery of ferrofluid nanoparticles to subcutaneous tumour allografts and xenografts, and the treatment of subcutaneous tumour allografts with magnetically guided liposomes loaded with doxorubicin and magnetite or with clinically approved 'stealthy' doxorubicin liposomes. The transient and partial blocking of the mononuclear phagocyte system may enhance the performance of a wide variety of nanoparticle drugs.

Identifying prostate cancer and its clinical risk in asymptomatic men using machine learning of high dimensional peripheral blood flow cytometric natural killer cell subset phenotyping data.

We demonstrate that prostate cancer can be identified by flow cytometric profiling of blood immune cell subsets. Herein, we profiled natural killer (NK) cell subsets in the blood of 72 asymptomatic men with Prostate-Specific Antigen (PSA) levels < 20 ng ml-1, of whom 31 had benign disease (no cancer) and 41 had prostate cancer. Statistical and computational methods identified a panel of eight phenotypic features ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text]) that, when incorporated into an Ensemble machine learning prediction model, distinguished between the presence of benign prostate disease and prostate cancer. The machine learning model was then adapted to predict the D'Amico Risk Classification using data from 54 patients with prostate cancer and was shown to accurately differentiate between the presence of low-/intermediate-risk disease and high-risk disease without the need for additional clinical data. This simple blood test has the potential to transform prostate cancer diagnostics.

With an estimated 1.8 million new cases in 2018 alone, prostate cancer is the fourth most common cancer in the world. Catching the disease early increases the chances of survival, but this cancer remains difficult to detect. The best diagnostic test currently available measures the blood level of a protein called the prostate-specific antigen (PSA for short). Heightened amounts of PSA may mean that the patient has cancer, but 15% of individuals with prostate cancer have normal levels of the protein, and many healthy people can have high amounts of PSA. This blood test is therefore not widely accepted as a reliable diagnostic tool. Other methods exist to detect prostate cancer, yet their results are limited. A small piece of the prostate can be taken for analysis, but results from this invasive procedure are often incorrect. Scans can help to spot a tumor, but they are not accurate enough to be conclusive on their own. New tests are therefore urgently needed. Prostate cancer is often associated with changes in the immune system that can be detected through a blood test. In particular, the appearance of a type of white blood (immune) cells called natural killer cells may be altered. Yet, it was unclear whether measurements based on these cells could help to detect prostate cancer and assess the severity of the disease. Here, Hood, Cosma et al. collected and examined the natural killer cells of 72 participants with slightly elevated PSA levels and no other symptoms. Amongst these, 31 individuals had prostate cancer and 41 were healthy. These biological data were then used to produce computer models that could detect the presence of the disease, as well as assess its severity. The algorithms were developed using machine learning, where previous patient information is used to make prediction on new data. This work resulted in a new detection tool which was 12.5% more accurate than the PSA test in detecting prostate cancer; and in a detection tool that was 99% accurate in predicting the risk of the disease (in terms of clinical significance) in individuals with prostate cancer. Although these new approaches first need to be validated in the clinic before being deployed, they could ultimately improve the detection and diagnosis of prostate cancer, saving lives and reducing the need for further tests.

Influence of tube voltage, tube current and newer iterative reconstruction algorithms in CT perfusion imaging in rabbit liver VX2 tumors.

PURPOSE: We aimed to explore the influence of tube voltage, current and iterative reconstruction (IR) in computed tomography perfusion imaging (CTPI) and to compare CTPI parameters with microvessel density (MVD). METHODS: Hepatic CTPI with three CTPI protocols (protocol A, tube voltage/current 80 kV/40 mAs; protocol B, tube voltage/current 80 kV/80 mAs; protocol C: tube voltage/current 100 kV/80 mAs) were performed in 25 rabbit liver VX2 tumor models, and filtered back projection (FBP) and IR were used for reconstruction of raw data. Hepatic arterial perfusion (HAP), hepatic portal perfusion (HPP), total perfusion (TP), hepatic arterial perfusion index (HPI), blood flow (BF) and blood volume (BV) of VX2 tumor and normal hepatic parenchyma were measured. Image noise, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were quantified and radiation dose was recorded. MVD was counted using CD34 stain and compared with CTPI parameters. RESULTS: The highest radiation dose was found in protocol C, followed by protocols B and A. IR lowered image noise and improved SNR and CNR in all three protocols. There was no statistical difference between HAP, HPP, TP, HPI, BF and BV of VX2 tumor and normal hepatic parenchyma among the three protocols (P > 0.05) with FBP or IR reconstruction, and no statistical difference between IR and FBP reconstruction (P > 0.05) in either protocol. MVD had a positive linear correlation with HAP, TP, BF, with best correlation observed with HAP; MVD of VX2 tumor showed no or poor correlation with HPI and BV. CONCLUSION: CTPI parameters are not affected by tube voltage, current or reconstruction algorithm; HAP can best reflect MVD, but no correlation exists between BV and MVD.

The acute and chronic effects of resistance training with blood flow restriction on hormonal responses in untrained young men: A comparison of frequency.

The present study aimed to determine the effect of low-intensity training with blood flow restriction (BFR) on the response rate of anabolic hormones. Forty healthy and untrained young men, aged 18 to 25 years old, were randomly divided into five groups: one session of BFR training (BFR1), two sessions of BFR training (BFR2), one session of resistance training without BFR (WBFR1), two sessions of resistance training without BFR (WBFR2), and the control group (without training). BFR groups had three sets of 20 repetitions with 20-30% 1RM, and none-BFR groups had three sets of 10 repetitions with 70-80% 1RM for six weeks. Both BFR1 and WBFR1 groups trained 3day a week (1 session in a day and three sessions a week), BFR2 and WBFR2 groups trained three days a week (but two sessions a day and six sessions in a week) and Control group did not perform any training. The mean changes in growth hormone(GH), testosterone(TS), and vascular endothelial growth factor (VEGF) hormones were determined by ELISA technique before, after a first training session and after six weeks of the training program. To the analysis of data, two way repeated measures ANOVA at a significant level of P<0.05  also were used. The results showed a significant increase in GH levels in each of the four training groups as compared with the pre-test and the control group after a first training session and after six weeks of the training program (P<0.05). There was no significant increase in TS levels in each of the four training groups, as compared with the pre-test and the control group in both acute and chronic TS response (P>0.05). Only the WBFR1 group did not significantly increase in VEGF levels after the first training session (P>0.05). In chronic VEGF response, there were no significant changes observed in all training groups as compared with the control group(P>0.05). Despite the effectiveness of low-intensity BFR training, such as high-intensity resistance training on hormonal responses, two sessions per day training with the same volume does not necessarily result in larger responses in all hormones than one session per day training.

Flow-induced Reorganization of Laminin-integrin Networks Within the Endothelial Basement Membrane Uncovered by Proteomics.

The vessel wall is continuously exposed to hemodynamic forces generated by blood flow. Endothelial mechanosensors perceive and translate mechanical signals via cellular signaling pathways into biological processes that control endothelial development, phenotype and function. To assess the hemodynamic effects on the endothelium on a system-wide level, we applied a quantitative mass spectrometry approach combined with cell surface chemical footprinting. SILAC-labeled endothelial cells were subjected to flow-induced shear stress for 0, 24 or 48 h, followed by chemical labeling of surface proteins using a non-membrane permeable biotin label, and analysis of the whole proteome and the cell surface proteome by LC-MS/MS analysis. These studies revealed that of the >5000 quantified proteins 104 were altered, which were highly enriched for extracellular matrix proteins and proteins involved in cell-matrix adhesion. Cell surface proteomics indicated that LAMA4 was proteolytically processed upon flow-exposure, which corresponded to the decreased LAMA4 mass observed on immunoblot. Immunofluorescence microscopy studies highlighted that the endothelial basement membrane was drastically remodeled upon flow exposure. We observed a network-like pattern of LAMA4 and LAMA5, which corresponded to the localization of laminin-adhesion molecules ITGA6 and ITGB4. Furthermore, the adaptation to flow-exposure did not affect the inflammatory response to tumor necrosis factor α, indicating that inflammation and flow trigger fundamentally distinct endothelial signaling pathways with limited reciprocity and synergy. Taken together, this study uncovers the blood flow-induced remodeling of the basement membrane and stresses the importance of the subendothelial basement membrane in vascular homeostasis.

Syncytiotrophoblast extracellular microvesicle profiles in maternal circulation for noninvasive diagnosis of preeclampsia.

Preeclampsia is the most common placental pathology in pregnant females, with increased morbidity and mortality incurred on the mother and the fetus. There is a need for improved biomarkers for diagnosis and monitoring of this condition. Placental syncytiotrophoblasts at the maternal-fetal interface release nanoparticles, including extracellular microvesicles, into the maternal blood during pregnancy. Syncytiotrophoblast extracellular microvesicles (STEVs) are being studied for their diagnostic potential and for their potential physiologic role in preeclampsia. We hypothesized that STEV profiles in maternal circulation would be altered under conditions of preeclampsia compared to normal pregnancy. Extracellular vesicles (EVs) released by BeWo cells in vitro showed high expression of syncytin-1, but no plac1 expression, demonstrating that trophoblast cell EVs express syncytin-1 on their surface. Placental alkaline phosphatase also showed high expression on BeWo EVs, but due to concern for cross reactivity to highly prevalent isoforms of intestinal and bone alkaline phosphatase, we utilized syncytin-1 as a marker for STEVs. In vivo, syncytin-1 protein expression was confirmed in maternal plasma EVs from Control and Preeclampsia subjects by Western blot, and overall, lower expression was noted in samples from patients with preeclampsia (n = 8). By nanoparticle analysis, EV profiles from Control and Preeclampsia groups showed similar total plasma EV quantities (p = 0.313) and size distribution (p = 0.415), but STEV quantitative signal, marked by syncytin-1 specific EVs, was significantly decreased in the Preeclampsia group (p = 2.8 × 10-11). Receiver operating characteristic curve demonstrated that STEV signal threshold cut-off of <0.316 was 95.2% sensitive and 95.6% specific for diagnosis of preeclampsia in this cohort (area under curve = 0.975 ± 0.020). In conclusion, we report that the syncytin-1 expressing EV profiles in maternal plasma might serve as a placental tissue specific biomarker for preeclampsia.

Blood Flow Limits Endothelial Cell Extrusion in the Zebrafish Dorsal Aorta.

Blood flow modulates endothelial cell (EC) response during angiogenesis. Shear stress is known to control gene expression related to the endothelial-mesenchymal transition and endothelial-hematopoietic transition. However, the impact of blood flow on the cellular processes associated with EC extrusion is less well understood. To address this question, we dynamically record EC movements and use 3D quantitative methods to segregate the contributions of various cellular processes to the cellular trajectories in the zebrafish dorsal aorta. We find that ECs spread toward the cell extrusion area following the tissue deformation direction dictated by flow-derived mechanical forces. Cell extrusion increases when blood flow is impaired. Similarly, the mechanosensor polycystic kidney disease 2 (pkd2) limits cell extrusion, suggesting that ECs actively sense mechanical forces in the process. These findings identify pkd2 and flow as critical regulators of EC extrusion and suggest that mechanical forces coordinate this process by maintaining ECs within the endothelium.

Finger and thumb replantation: From biomechanics to practical surgical applications.

Finger and thumb amputations, which are always dramatic injuries with major functional and psychological repercussions, remain a surgical challenge. This review on digit replantation develops the underlying biomechanical and surgical aspects as well as practical indications. The different stages from trauma to postoperative monitoring are described. We describe the steps to follow from theory to practice in order to optimize the surgical acts that must as effective possible in terms of management and decision-making efficiency. Indications recognized as standards such as thumb amputation, multi-digit amputations and distal amputations are detailed, as well as the more controversial ring finger replantations. The challenge of successful finger and thumb replantation lies in searching for the best functional and cosmetic outcome and not performing irrelevant microsurgical manipulations.

Perfusion Assessment and Treatment in the Diabetic Patient.

The accurate assessment of peripheral perfusion is a critical step in caring for a diabetic patient with active ulceration. This article guides the provider through diagnostic and therapeutic options. The perfusion assessment begins with a physical examination and augmented using noninvasive tests. Although some of these tests can be performed at the bedside, often a dedicated vascular laboratory is required. Additional cross-sectional imaging studies or formal angiography should be performed as well. These tools aid in the creation of the best therapeutic plan, which aims to restore perfusion and allow for rapid wound healing via open or endovascular means.

Circulating Osteogenic Progenitor Cells in Mild, Moderate, and Severe Aortic Valve Stenosis.

The aim of this study was to characterize endothelial progenitor cells with osteoblastic phenotype (EPC-OCNs) and their role in individuals with varying degrees of aortic stenosis (AS). Peripheral blood mononuclear cells retrieved from blood samples of individuals with mild (n=40), moderate (n=35), or severe (n=103) AS from September 16, 2008, through March 30, 2015, were analyzed by flow cytometry for the EPC surface markers CD34, CD133, and kinase insert domain receptor (KDR) and the osteoblastic cell surface marker OCN. Levels of EPC-OCNs were correlated with AS severity and calcifications. Patients with severe AS had significantly elevated numbers of total circulating EPC-OCNs, including the EPC-OCN subtypes CD133+/OCN+, CD34+/CD133+/OCN+, and CD133+/KDR+/OCN+, compared with those with mild AS. Individuals with moderate AS also had significantly increased numbers of the circulating progenitor cell CD133+/OCN+ compared with patients with mild AS. There was a significant association between total circulating EPC-OCN levels and aortic valve (AV) calcification, AV mean gradient, and AV area measured by echocardiography. In summary, this study found the presence of circulating EPC-OCNs in patients with progressive AV stenosis. These findings might support the potential role for EPC-OCNs in the progression of AV stenosis and calcification.