Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle

Neuronal activity within the central nervous system (CNS) strictly depends on homeostasis and therefore does not tolerate uncontrolled entry of blood components. It has been generally believed that under normal conditions, the endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid barrier (BCSFB) prevent immune cell entry into the CNS. This view has recently changed when it was realized that activated T cells are able to breach the BBB and the BCSFB to perform immune surveillance of the CNS. Here we propose that the immune privilege of the CNS is established by the specific morphological architecture of its borders resembling that of a medieval castle. The BBB and the BCSFB serve as the outer walls of the castle, which can be breached by activated immune cells serving as messengers for outside dangers. Having crossed the BBB or the BCSFB they reach the castle moat, namely the cerebrospinal fluid (CSF)-drained leptomeningeal and perivascular spaces of the CNS. Next to the CNS parenchyma, the castle moat is bordered by a second wall, the glia limitans, composed of astrocytic foot processes and a parenchymal basement membrane. Inside the castle, that is the CNS parenchyma proper, the royal family of sensitive neurons resides with their servants, the glial cells. Within the CSF-drained castle moat, macrophages serve as guards collecting all the information from within the castle, which they can present to the immune-surveying T cells. If in their communication with the castle moat macrophages, T cells recognize their specific antigen and see that the royal family is in danger, they will become activated and by opening doors in the outer wall of the castle allow the entry of additional immune cells into the castle moat. From there, immune cells may breach the inner castle wall with the aim to defend the castle inhabitants by eliminating the invading enemy. If the immune response by unknown mechanisms turns against self, that is the castle inhabitants, this may allow for continuous entry of immune cells into the castle and lead to the death of the castle inhabitants, and finally members of the royal family, the neurons. This review will summarize the molecular traffic signals known to allow immune cells to breach the outer and inner walls of the CNS castle moat and will highlight the importance of the CSF-drained castle moat in maintaining immune surveillance and in mounting immune responses in the CNS.

The relapse risk of AML patients undergoing autologous transplantation correlates with the stem cell mobilizing potential

Autologous stem cell transplantation (ASCT) is widely used to consolidate first remission in AML. We determined the significance of circulating CD34+ cells at the day of blood stem cell collection in 78 AML patients. Patients mobilizing more than 60,000 CD34+ cells/ml had shorter overall survival (OS; P=0.0274), shorter time to progression (TTP; P=0.0014), and a higher relapse rate (P=0.0177). High levels of CD34+ cells were an independent marker for shorter OS and TTP in a multivariate analysis. These data suggest that ASCT is associated with unfavorable outcome in AML patients with high levels of mobilized peripheral CD34+ cells.

Standard vs. point-of-care measurement of fibrinogen: potential impact on clinical decisions

Intraoperative major bleeding is a common complication during surgery and can lead to the transfusion of blood products and/or procoagulant drugs. This is a therapeutic challenge, and adherence to guidelines is desirable to preserve blood product resources. The intraoperative administration of fibrinogen concentrate, a pro-coagulant drug, in bleeding patients might reduce the use and therefore the risks associated with blood products.

Impact of salt on cardiac differential gene expression and coronary lesion in normotensive mineralocorticoid-treated mice

We previously reported that excess of deoxycorticosterone-acetate (DOCA)/salt-induced cardiac hypertrophy in the absence of hypertension in one-renin gene mice. This model allows us to study molecular mechanisms of high-salt intake in the development of cardiovascular remodeling, independently of blood pressure in a high mineralocorticoid state. In this study, we compared the effect of 5-wk low- and high-salt intake on cardiovascular remodeling and cardiac differential gene expression in mice receiving the same amount of DOCA. Differential gene and protein expression was measured by high-density cDNA microarray assays, real-time PCR and Western blot analysis in DOCA-high salt (HS) vs. DOCA-low salt (LS) mice. DOCA-HS mice developed cardiac hypertrophy, coronary perivascular fibrosis, and left ventricular dysfunction. Differential gene and protein expression demonstrated that high-salt intake upregulated a subset of genes encoding for proteins involved in inflammation and extracellular matrix remodeling (e.g., Col3a1, Col1a2, Hmox1, and Lcn2). A major subset of downregulated genes encoded for transcription factors, including myeloid differentiation primary response (MyD) genes. Our data provide some evidence that vascular remodeling, fibrosis, and inflammation are important consequences of a high-salt intake in DOCA mice. Our study suggests that among the different pathogenic factors of cardiac and vascular remodeling, such as hypertension and mineralocorticoid excess and sodium intake, the latter is critical for the development of the profibrotic and proinflammatory phenotype observed in the heart of normotensive DOCA-treated mice.

Effect of acceleration forces during transport through a pneumatic tube system on ROTEM® analysis

ROTEM® is considered a helpful point-of-care device to monitor blood coagulation in emergency situations. Centrally performed analysis is desirable but rapid transport of blood samples is an important prerequisite. The effect of acceleration forces on sample transport through a pneumatic tube system on ROTEM® should be tested at each institution to exclude a pre-analytical influence. The aims of the present work were: (i) to investigate the effect of pneumatic tube transport on ROTEM® parameters; (ii) to compare blood sample transport via pneumatic tube vs. manual transportation; and (iii) to determine the effect of acceleration forces on ROTEM® parameters.

CD62L (L-Selectin) Shedding for Assessment of Perioperative Immune Sensitivity in Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass

To investigate the suitability of blood granulocyte and monocyte sensitivity, as measured by the quantity of different agonists required to induce CD62L shedding, for assessment of perioperative immune changes in patients undergoing cardiac surgery with cardiopulmonary bypass.

Point-of-care prothrombin time testing in paediatric intensive care: an observational study of the ease of use of two devices

Two major difficulties arise when taking blood samples in children: the challenge of venous access and the comparatively large amount of blood required.

The Rapid TEG α-Angle may be a sensitive predictor of transfusion in moderately injured blunt trauma patients

Background. To guide the administration of blood products, coagulation screening of trauma patients should be fast and accurate. The purpose of this study was to identify the correlation between CCT and TEG in trauma, to determine which CCT or TEG parameter is most sensitive in predicting transfusion in trauma, and to define TEG cut-off points for trauma care. Methods. A six-month, prospective observational study of 76 adult patients with suspected multiple injuries was conducted at a Level 1 trauma centre of a university hospital. Physicians blinded to TEG results made the decision to transfuse based on clinical evaluation. Results. The study results showed that conventional coagulation tests correlate moderately with Rapid TEG parameters (R: 0.44–0.61). Kaolin and Rapid TEG were more sensitive than CCTs, and the Rapid TEG α-Angle was identified as the single parameter with the greatest sensitivity (84%) and validity (77%) at a cut-off of 74.7 degrees. When the Rapid TEG α-Angle was combined with heart rate >75 bpm, or haematocrit < 41%, sensitivity (84%, 88%) and specificity (75%, 73%) were improved. Conclusion. Cutoff points for transfusion can be determined with the Rapid TEG α-Angle and can provide better sensitivity than CCTs, but a larger study population is needed to reproduce this finding.

Anticancer drug vinblastine sulphate induces transient morphological changes on the olfactory mucosa of the rabbit

Vinblastine sulphate (VBS) is an anticancer drug that acts by disrupting microtubule dynamics of highly mitotic tissue cells. The consequences of VBS on the olfactory mucosa (OM), a tissue with high mitotic numbers, are not clearly understood. We used qualitative and quantitative methods to determine the structural changes that may be produced on the rabbit OM by VBS. Following a single dose (0.31 mg/kg) of this drug, the structure of the mucosa was greatly altered on the first 3-5 days. The alteration was characterized by disarrangement of the normal layering of nuclei of the epithelia, degeneration of axonal bundles, occurrence of blood vessels within the bundles, localized death of cells of Bowman's glands and glandular degeneration. Surprisingly on or after day 7 and progressively to day 15 post-exposure, the OM was observed to regenerate and acquire normal morphology, and the vessels disappeared from the bundles. Relative to control values, bundle diameters, olfactory cell densities and cilia numbers decreased to as low as 53.1, 75.2 and 71.4%, respectively, on day 5. Volume density for the bundles, which was 28.6% in controls, decreased to a lowest value of 16.8% on day 5. In contrast, the volume density for the blood vessels was significantly lower in controls (19.9%) than in treated animals at day 2 (25.8%), day 3 (34.3%) and day 5 (31.5%). These findings suggest that the changes induced on the rabbit OM by VBS are transient and that regenerative recovery leads to the restoration of the normal structure of the mucosa.

Intussusceptive angiogenesis: a biologically relevant form of angiogenesis

Angiogenesis, i.e. the development and growth of blood vessels, is a major topic of research as it plays an important role in normal development and in various pathologies. Recent evidence revealed the existence of different mechanisms of blood vessel growth, including sprouting and intussusceptive angiogenesis, vascular mimicry, and blood vessel cooption. The latter two have only been observed in tumor growth, but sprouting and intussusceptive angiogenesis also occur in healthy, physiologically growing tissues. Despite this variety of angiogenic mechanisms, most of the current research is focused on the mechanism of sprouting angiogenesis because this mechanism was first described and because most existing experimental models are related to sprouting angiogenesis. Consequently, the mechanism of intussusceptive angiogenesis is often overlooked in angiogenesis research. Here, the mechanism of intussusceptive angiogenesis is reviewed and the current techniques and models for investigating intussusceptive angiogenesis are summarized. In addition, other mechanisms of vascular growth are briefly reviewed.

Pleasant Events, Activity Restriction, and Blood Pressure in Dementia Caregivers

Objective: A combination of high engagement in pleasurable activities and low perceived activity restriction is potentially protective for a number of health and quality of life outcomes. This study tests the newly proposed Pleasant Events and Activity Restriction (PEAR) model to explain level of blood pressure (BP) in a sample of elderly dementia caregivers. Methods: This cross-sectional study included 66 caregivers, ≥55 years of age, providing in-home care to a relative with dementia. Planned comparisons were made to assess group differences in BP between caregivers reporting high engagement in pleasant events plus low perceived activity restriction (HPLR; n = 22) to those with low pleasure plus high restriction (LPHR; n = 23) or those with either high pleasure plus high restriction or low pleasure plus low restriction (HPHR/LPLR; n = 21). Results: After adjustments for age, sex, body mass index, use of antihypertensive medication, physical activity, and number of health problems, HPLR participants (86.78 mm|Hg) had significantly lower mean arterial pressure compared with LPHR participants (94.70 mm|Hg) (p = .01, Cohen's d = 0.89) and HPHR/LPLR participants (94.84 mm|Hg) (p = .023, d = 0.91). Similar results were found in post hoc comparisons of both systolic and diastolic BP. Conclusions: This study extends support for the PEAR model to physical health outcomes. Differences in BP between the HPLR group and other groups were of large magnitude and thus clinically meaningful. The findings may inform intervention studies aimed at investigating whether increasing pleasant events and lowering perceived activity restriction may lower BP. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

[Childhood's determinants for high blood pressure in adulthood]

Hypertension has been estimated to affect 20 - 25% of the adult population and represents an important risk factor for cardiovascular disease like coronary heart disease, stroke and peripheral artery occlusive disease. In addition, hypertension supports the development and progression of chronic kidney insufficiency. The interaction of multiple genetic and environmental factors are felt to influence the level of blood pressure. Epidemiological data in the sixties and seventies demonstrated a correlation between cardiovascular disease and infant mortality in the same population. In the late eighties Barker and coworkers described a strong correlation between low birth weight and increased risk for the development of cardiovascular complications. It has been supposed that factors influencing the intrauterine growth and development can lead to adult cardiovascular diseases, known as the concept of "fetal programming". Beside the effect of fetal programming, multiple (preventable and non-preventable) factors determine the blood pressure level in childhood, which will define adult blood pressure level through the blood pressure tracking from childhood to adulthood. Hence, the prevention of cardiovascular disease in adulthood begins in childhood through identification of preventable risk factors as for example obesity and passive smoking and recognition of risk groups like small for gestational age or preterm children.

Sonographic Assessment of the Umbilical Cord

The umbilical cord is not an inert structure, suspended between the fetus and placenta, but it plays an active role and it is involved in several processes afflicting the feto-placental unit. Its study has to be regarding not only its morphology and morphometry, and the impendance of blood flow by Doppler waveform analysis, but it includes also an analysis of the coiling type and the amount of the Wharton Jelly. The umbilical cord has been considered like an important and huge source of informations, useful to assess the well-being of the fetus and the outcome of pregnancy. The standardization of ultrasound techniques is the first step to speak the same language and make the study of this structure a fundamental part of well-being fetus assessment. This article is carefully focused on morphologic, morphometric and functional ultrasound examination of umbilical cord and suggests that any anomaly detected should provide an indication for an intense fetal follow-up, useful for early helpful therapy, preventing serious complication for the pregnancy.

Vascular endothelial cell-specific phosphotyrosine phosphatase (VE-PTP) activity is required for blood vessel development

VE-PTP, a receptor-type phosphotyrosine phosphatase, associates with the tyrosine kinase receptor Tie-2 and VE-cadherin and enhances the adhesive function of the latter. Here, VE-PTP was found to be restricted to endothelial cells, with a preference for arterial endothelium. Mutant mice expressing a truncated, secreted form of VE-PTP lacking the cytoplasmic and transmembrane domains and the most membrane-proximal extracellular fibronectin type III repeat, showed severe vascular malformations causing lethality at 10 days of gestation. Although blood vessels were initially formed, the intraembryonic vascular system soon deteriorated. Blood vessels in the yolk sac developed into dramatically enlarged cavities. In explant cultures of mutant allantoides, endothelial cells were found next to vessel structures growing as cell layers. No signs for enhanced endothelial apoptosis or proliferation were observed. Thus, the activity of VE-PTP is not required for the initial formation of blood vessels, yet it is essential for their maintenance and remodeling.

Influence of water immersion, water gymnastics and swimming on cardiac output in patients with heart failure

Background Whole-body water immersion leads to a significant shift of blood from the periphery into the intra-thoracic circulation, followed by an increase in central venous pressure and heart volume. In patients with severely reduced left ventricular function, this hydrostatically in-duced volume shift might overstrain the cardiovascular adaptive mechanisms and lead to cardiac decompensation. The aim of this study is to assess the hemodynamic response to water immer-sion, gymnastics and swimming in patients with heart failure (CHF). Methods We examined 10 patients with compensated CHF (62.9 +/- 6.3 years, EF 31.5 +/- 4.1%, peak VO2 19.4 +/- 2.8 ml/kg/min.), 10 patients with coronary artery disease (CAD) but preserved left ventricular function (57.2 +/- 5.6 years, EF 63.9 +/- 5.5%, peak VO2 28.0 +/- 6.3 ml/kg/min.) and 10 healthy subjects (32.8 +/- 7.2 years, peak VO2 45.6 +/- 6.0 ml/kg/min.). Hemodynamic response to thermo-neutral (32 degrees C) water immersion and exercise was measured using a non-invasive foreign gas rebreathing method during stepwise water immersion, water gymnastics and swimming. Results Water immersion up to the chest increased cardiac index by 19% in healthy subjects, by 21% in CAD patients and 16% in CHF patients. While some CHF patients showed a decrease of stroke volume during immersion, all subjects were able to increase cardiac index (by 87% in healthy subjects, 77% in CAD patients and 53% in CHF patients). Oxygen uptake during swim-ming was 9.7 +/- 3.3 ml/kg/min. in CHF patients, 12.4 +/- 3.5 ml/kg/min. in CAD patients and 13.9 +/- 4.0 ml/kg/min. in healthy subjects. Conclusions Patients with severely reduced left ventricular function but stable clinical conditions and a minimal peak VO2 of at least 15 ml/kg/min. during a symptom-limited exercise stress test tolerate water immersion and swimming in thermo-neutral water well. Although cardiac in-dex and oxygen uptake are lower compared with CAD patients with preserved left ventricular function and healthy controls, these patients are able to increase cardiac index adequately during water immersion and swimming.