Relative impact of respiratory muscle activity on tidal flow and end expiratory volume in healthy neonates

INTRODUCTION: It has been suggested that infants dynamically regulate their tidal flow and end-expiratory volume level. The interaction between muscle activity, flow and lung volume in spontaneously sleeping neonates is poorly studied, since it requires the assessment of transcutaneous electromyography of respiratory muscles (rEMG) in matched comparison to lung function measurements. METHODS: After determining feasibility and repeatability of rEMG in 20 spontaneously sleeping healthy neonates, we measured the relative impact of intercostal and diaphragmatic EMG activity in direct comparison to the resulting tidal flow and FRC. RESULTS: We found good feasibility, repeatability and correlation of timing indices between rEMG activity and flow. The rEMG amplitude was significantly dependent on the resistive load of the face mask. Diaphragm and intercostal muscle activity commenced prior to the onset of flow and remained active during the expiratory cycle. The relative contribution of intercostal and diaphragmatic activity to flow was variable and changed dynamically. CONCLUSION: Using matched rEMG, air flow and lung volume measurements, we have found good feasibility and repeatability of intercostal and diaphragm rEMG measurements and provide the first quantitative measures of the temporal relationship between muscle activity and flow in spontaneously sleeping healthy neonates. Lung mechanical function is dynamically regulated and adapts on a breath to breath basis. So, non-invasive rEMG measurements alone or in combination with lung function might provide a more comprehensive picture of pulmonary mechanics in future studies. The data describing the timing of EMG and flow may be important for future studies of EMG triggered mechanical ventilation.

Risk-conscious Reconstruction in Pakistan-administered Kashmir. A Case Study of the Chakhama Valley

The Chakhama Valley, a remote area in Pakistan-administered Kashmir, was badly damaged by the 7.6-magnitude earthquake that struck India and Pakistan on 8 October 2005. More than 5% of the population lost their lives, and about 90% of the existing housing was irreparably damaged or completely destroyed. In early 2006, the Aga Khan Development Network (AKDN) initiated a multisector, community-driven reconstruction program in the Chakhama Valley on the premise that the scale of the disaster required a response that would address all aspects of people's lives. One important aspect covered the promotion of disaster risk management for sustainable recovery in a safe environment. Accordingly, prevailing hazards (rockfalls, landslides, and debris flow, in addition to earthquake hazards) and existing risks were thoroughly assessed, and the information was incorporated into the main planning processes. Hazard maps, detailed site investigations, and proposals for precautionary measures assisted engineers in supporting the reconstruction of private homes in safe locations to render investments disaster resilient. The information was also used for community-based land use decisions and disaster mitigation and preparedness. The work revealed three main problems: (1) thorough assessment of hazards and incorporation of this assessment into planning processes is time consuming and often little understood by the population directly affected, but it pays off in the long run; (2) relocating people out of dangerous places is a highly sensitive issue that requires the support of clear and forceful government policies; and (3) the involvement of local communities is essential for the success of mitigation and preparedness.

Investigation of hemodynamics in an in vitro system simulating left ventricular support through the right subclavian artery using 4-dimensional flow magnetic resonance imaging.

OBJECTIVES Left ventricular assist devices are an important treatment option for patients with heart failure alter the hemodynamics in the heart and great vessels. Because in vivo magnetic resonance studies of patients with ventricular assist devices are not possible, in vitro models represent an important tool to investigate flow alterations caused by these systems. By using an in vitro magnetic resonance-compatible model that mimics physiologic conditions as close as possible, this work investigated the flow characteristics using 4-dimensional flow-sensitive magnetic resonance imaging of a left ventricular assist device with outflow via the right subclavian artery as commonly used in cardiothoracic surgery in the recent past. METHODS An in vitro model was developed consisting of an aorta with its supra-aortic branches connected to a left ventricular assist device simulating the pulsatile flow of the native failing heart. A second left ventricular assist device supplied the aorta with continuous flow via the right subclavian artery. Four-dimensional flow-sensitive magnetic resonance imaging was performed for different flow rates of the left ventricular assist device simulating the native heart and the left ventricular assist device providing the continuous flow. Flow characteristics were qualitatively and quantitatively evaluated in the entire vessel system. RESULTS Flow characteristics inside the aorta and its upper branching vessels revealed that the right subclavian artery and the right carotid artery were solely supported by the continuous-flow left ventricular assist device for all flow rates. The flow rates in the brain-supplying arteries are only marginally affected by different operating conditions. The qualitative analysis revealed only minor effects on the flow characteristics, such as weakly pronounced vortex flow caused by the retrograde flow via the brachiocephalic artery. CONCLUSIONS The results indicate that, despite the massive alterations in natural hemodynamics due to the retrograde flow via the right subclavian and brachiocephalic arteries, there are no drastic consequences on the flow in the brain-feeding arteries and the flow characteristics in the ascending and descending aortas. It may be beneficial to adjust the operating condition of the left ventricular assist device to the residual function of the failing heart.

Influence of two types of self-retaining retractors on multifidus muscle blood flow during dorsolateral thoracolumbar hemilaminectomy in dogs

OBJECTIVES To assess the influence of the use of Gelpi and Grevel retractors on multifidus muscle blood flow during hemilaminectomy, using a dorsolateral approach, for acute disc extrusion in dogs as measured by laser speckle contrast imaging (LSCI). METHODS Blood flow in the multifidus muscles was measured intra-operatively using LSCI prior to insertion of the retractors, immediately after hemilaminectomy and removal of the retractors, and after 10 minutes of lavage of the surgical site. Plasma creatine kinase levels were measured preoperatively and 12-24 hours postoperatively. RESULTS Muscular blood flow was significantly decreased following retraction and remained lower than initial values 10 minutes after lavage in all dogs. The decrease in blood flow was significantly greater with Gelpi retractors (n = 8) than with Grevel retractors (n = 10). No significant relation was found between the duration of retraction and postoperative changes in creatine kinase levels or blood flow. CLINICAL SIGNIFICANCE Findings in this study demonstrate a drop in blood flow within the multifidus muscles using the dorsolateral approach regardless of retractor type used. Gelpi retractors seem to have greater influence on muscular blood flow than Grevel retractors. Further studies are warranted to confirm this second finding.

Genomics of Rapid Incipient Speciation in Sympatric Threespine Stickleback

Ecological speciation is the process by which reproductively isolated populations emerge as a consequence of divergent natural or ecologically-mediated sexual selection. Most genomic studies of ecological speciation have investigated allopatric populations, making it difficult to infer reproductive isolation. The few studies on sympatric ecotypes have focused on advanced stages of the speciation process after thousands of generations of divergence. As a consequence, we still do not know what genomic signatures of the early onset of ecological speciation look like. Here, we examined genomic differentiation among migratory lake and resident stream ecotypes of threespine stickleback reproducing in sympatry in one stream, and in parapatry in another stream. Importantly, these ecotypes started diverging less than 150 years ago. We obtained 34,756 SNPs with restriction-site associated DNA sequencing and identified genomic islands of differentiation using a Hidden Markov Model approach. Consistent with incipient ecological speciation, we found significant genomic differentiation between ecotypes both in sympatry and parapatry. Of 19 islands of differentiation resisting gene flow in sympatry, all were also differentiated in parapatry and were thus likely driven by divergent selection among habitats. These islands clustered in quantitative trait loci controlling divergent traits among the ecotypes, many of them concentrated in one region with low to intermediate recombination. Our findings suggest that adaptive genomic differentiation at many genetic loci can arise and persist in sympatry at the very early stage of ecotype divergence, and that the genomic architecture of adaptation may facilitate this.

Impact of Taylor-Aris diffusivity on analyte and system zone dispersion in CZE assessed by computer simulation and experimental validation.

Application of pressure-driven laminar flow has an impact on zone and boundary dispersion in open tubular CE. The GENTRANS dynamic simulator for electrophoresis was extended with Taylor-Aris diffusivity which accounts for dispersion due to the parabolic flow profile associated with pressure-driven flow. Effective diffusivity of analyte and system zones as functions of the capillary diameter and the amount of flow in comparison to molecular diffusion alone were studied for configurations with concomitant action of imposed hydrodynamic flow and electroosmosis. For selected examples under realistic experimental conditions, simulation data are compared with those monitored experimentally using modular CE setups featuring both capacitively coupled contactless conductivity and UV absorbance detection along a 50 μm id fused-silica capillary of 90 cm total length. The data presented indicate that inclusion of flow profile based Taylor-Aris diffusivity provides realistic simulation data for analyte and system peaks, particularly those monitored in CE with conductivity detection.

Effects of Interspecific Gene Flow on the Phenotypic Variance-Covariance Matrix in Lake Victoria Cichlids

Quantitative genetics theory predicts adaptive evolution to be constrained along evolutionary lines of least resistance. In theory, hybridization and subsequent interspecific gene flow may however rapidly change the evolutionary constraints of a population and eventually change its evolutionary potential, but empirical evidence is still scarce. Using closely related species pairs of Lake Victoria cichlids sampled from four different islands with different levels of interspecific gene flow, we tested for potential effects of introgressive hybridization on phenotypic evolution in wild populations. We found that these effects differed among our study species. Constraints measured as the eccentricity of phenotypic variance-covariance matrices declined significantly with increasing gene flow in the less abundant species for matrices that have a diverged line of least resistance. In contrast we find no such decline for the more abundant species. Overall our results suggest that hybridization can change the underlying phenotypic variance-covariance matrix, potentially increasing the adaptive potential of such populations.

MODELING THE DYNAMICS OF AIRWAY CONSTRICTION: EFFECTS OF AGONIST TRANSPORT AND BINDING

Recent advances have revealed that during exogenous airway challenge, airway diameters can not be adequately predicted by their initial diameters. Furthermore, airway diameters can also vary greatly in time on scales shorter than a breath. In order to better understand these phenomena, we developed a multiscale model which allows us to simulate aerosol challenge in the airways during ventilation. The model incorporates agonist-receptor binding kinetics to govern the temporal response of airway smooth muscle (ASM) contraction on individual airway segments, which together with airway wall mechanics, determines local airway caliber. Global agonist transport and deposition is coupled with pressure-driven flow, linking local airway constrictions with global flow dynamics. During the course of challenge, airway constriction alters the flow pattern, redistributing agonist to less constricted regions. This results in a negative feedback which may be a protective property of the normal lung. As a consequence, repetitive challenge can cause spatial constriction patterns to evolve in time, resulting in a loss of predictability of airway diameters. Additionally, the model offers new insight into several phenomena including the intra- and inter-breath dynamics of airway constriction throughout the tree structure.

Hemodynamic parameters change earlier than tissue oxygen tension in hemorrhage

BACKGROUND: Untreated hypovolemia results in impaired outcome. This study tests our hypothesis whether general hemodynamic parameters detect acute blood loss earlier than monitoring parameters of regional tissue beds. MATERIALS AND METHODS: Eight pigs (23-25 kg) were anesthetized and mechanically ventilated. A pulmonary artery catheter and an arterial catheter were inserted. Tissue oxygen tension was measured with Clark-type electrodes in the jejunal and colonic wall, in the liver, and subcutaneously. Jejunal microcirculation was assessed by laser Doppler flowmetry (LDF). Intravascular volume was optimized using difference in pulse pressure (dPP) to keep dPP below 13%. Sixty minutes after preparation, baseline measurements were taken. At first, 5% of total blood volume was withdrawn, followed by another 5% increment, and then in 10% increments until death. RESULTS: After withdrawal of 5% of estimated blood volume, dPP increased from 6.1% +/- 3.0% to 20.8% +/- 2.7% (P < 0.01). Mean arterial pressure (MAP), mean pulmonary artery pressure (PAP) and pulmonary artery occlusion pressure (PAOP) decreased with a blood loss of 10% (P < 0.01). Cardiac output (CO) changed after a blood loss of 20% (P < 0.05). Tissue oxygen tension in central organs, and blood flow in the jejunal muscularis decreased (P < 0.05) after a blood loss of 20%. Tissue oxygen tension in the skin, and jejunal mucosa blood flow decreased (P < 0.05) after a blood loss of 40% and 50%, respectively. CONCLUSIONS: In this hemorrhagic pig model systemic hemodynamic parameters were more sensitive to detect acute hypovolemia than tissue oxygen tension measurements or jejunal LDF measurements. Acute blood loss was detected first by dPP.

Eosinophilic vasculitis: an inhabitual and resistant manifestation of a vasculitis

A 55-year-old woman was referred because of diffuse pruritic erythematous lesions and an ischemic process of the third finger of her right hand. She was known to have anaemia secondary to hypermenorrhea. She presented six months before admission with a cutaneous infiltration on the left cubital cavity after a paravenous leakage of intravenous iron substitution. She then reported a progressive pruritic erythematous swelling of her left arm and lower extremities and trunk. Skin biopsy of a lesion on the right leg revealed a fibrillar, small-vessel vasculitis containing many eosinophils.Two months later she reported Raynaud symptoms in both hands, with a persistent violaceous coloration of the skin and cold sensation of her third digit of the right hand. A round 1.5 cm well-delimited swelling on the medial site of the left elbow was noted. The third digit of her right hand was cold and of violet colour. Eosinophilia (19 % of total leucocytes) was present. Doppler-duplex arterial examination of the upper extremities showed an occlusion of the cubital artery down to the palmar arcade on the right arm. Selective angiography of the right subclavian and brachial arteries showed diffuse alteration of the blood flow in the cubital artery and hand, with fine collateral circulation in the carpal region. Neither secondary causes of hypereosinophilia nor a myeloproliferative process was found. Considering the skin biopsy results and having excluded other causes of eosinophilia, we assumed the diagnosis of an eosinophilic vasculitis. Treatment with tacrolimus and high dose steroids was started, the latter tapered within 12 months and then stopped, but a dramatic flare-up of the vasculitis with Raynaud phenomenon occurred. A new immunosuppressive approach with steroids and methotrexate was then introduced. This case of aggressive eosinophilic vasculitis is difficult to classify into the usual forms of vasculitis and constitutes a therapeutic challenge given the resistance to current immunosuppressive regimens.

Comparison of immortalized bEnd5 and primary mouse brain microvascular endothelial cells as in vitro blood-brain barrier models for the study of T cell extravasation

Important insights into the molecular mechanism of T cell extravasation across the blood-brain barrier (BBB) have already been obtained using immortalized mouse brain endothelioma cell lines (bEnd). However, compared with bEnd, primary brain endothelial cells have been shown to establish better barrier characteristics, including complex tight junctions and low permeability. In this study, we asked whether bEnd5 and primary mouse brain microvascular endothelial cells (pMBMECs) were equally suited as in vitro models with which to study the cellular and molecular mechanisms of T cell extravasation across the BBB. We found that both in vitro BBB models equally supported both T cell adhesion under static and physiologic flow conditions, and T cell crawling on the endothelial surface against the direction of flow. In contrast, distances of T cell crawling on pMBMECs were strikingly longer than on bEnd5, whereas diapedesis of T cells across pMBMECs was dramatically reduced compared with bEnd5. Thus, both in vitro BBB models are suited to study T cell adhesion. However, because pMBMECs better reflect endothelial BBB specialization in vivo, we propose that more reliable information about the cellular and molecular mechanisms of T cell diapedesis across the BBB can be attained using pMBMECs.

Intussusceptive angiogenesis: pillars against the blood flow

Adaptation of vascular networks to functional demands needs vessel growth, vessel regression and vascular remodelling. Biomechanical forces resulting from blood flow play a key role in these processes. It is well-known that metabolic stimuli, mechanical forces and flow patterns can affect gene expression and remodelling of vascular networks in different ways. For instance, in the sprouting type of angiogenesis related to hypoxia, there is no blood flow in the rising capillary sprout. In contrast, it has been shown that an increase of wall shear stress initiates the splitting type of angiogenesis in skeletal muscle. Otherwise, during development, both sprouting and intussusception act in parallel in building the vascular network, although with differences in spatiotemporal distribution. Thereby, in addition to regulatory molecules, flow dynamics support the patterning and remodelling of the rising vascular tree. Herewith, we present an overview of angiogenic processes with respect to intussusceptive angiogenesis as related to local haemodynamics.

Variation in stress reactivity affects cage-induced stereotypies in female CD-1 (ICR) mice

Stereotypies in captive animals typically occur under conditions that are stressful for the animals, and there is some anecdotal evidence that stress levels during early stereotypy development predict later stereotypy levels. Based on this and on the involvement of stress in the behavioural sensitization to psychostimulant drugs, it has been hypothesized that stereotypy development might be causally related to stress. To address this question further, we used mice of the commercial outbred stock CD-1 (ICR) and mice of two lines derived from the outbred CD-1 (ICR) strain by selective breeding for high (HR) and low (LR) stress reactivity, respectively, and examined whether genetically driven variation in stress reactivity is associated with variation in the expression of cage-induced stereotypies. From 21 days of age, 10 females of each line were housed in pairs under standard laboratory conditions until they were video recorded for stereotypic behaviour and tested for corticosterone responses in a stress reactivity test (SRT) at 12 weeks of age. As expected, HR females showed a significantly stronger corticosterone response in the SRT than LR females, while ICR females were intermediate. Unexpectedly, however, both HR and LR females showed very low levels of stereotypic behaviour, while ICR females developed the high levels of stereotypies typical for this strain of mouse. Consequently, there was no significant relationship between measures of acute corticosterone reactivity and stereotypy performance, but a trend for reduced recovery of the corticosterone response in the ICR line suggests that variation in recovery rather than the acute response might predict stereotypy levels in these mice. (C) 2011 Elsevier B.V. All rights reserved.

Outcome and patterns of failure after postoperative intensity modulated radiotherapy for locally advanced or high-risk oral cavity squamous cell carcinoma

Background To determine the outcome and patterns of failure in oral cavity cancer (OCC) patients after postoperative intensity modulated radiotherapy (IMRT) with concomitant systemic therapy. Methods All patients with locally advanced (AJCC stage III/IV) or high-risk OCC (AJCC stage II) who underwent postoperative IMRT at our institution between December 2006 and July 2010 were retrospectively analyzed. The primary endpoint was locoregional recurrence-free survival (LRRFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), acute and late toxicities. Results Overall 53 patients were analyzed. Twenty-three patients (43%) underwent concomitant chemotherapy with cisplatin, two patients with carboplatin (4%) and four patients were treated with the monoclonal antibody cetuximab (8%). At a median follow-up of 2.3 (range, 1.1–4.6) years the 3-year LRRFS, DMFS and OS estimates were 79%, 90%, and 73% respectively. Twelve patients experienced a locoregional recurrence. Eight patients, 5 of which had both a flap reconstruction and extracapsular extension (ECE), showed an unusual multifocal pattern of recurrence. Ten locoregional recurrences occurred marginally or outside of the high-risk target volumes. Acute toxicity grades of 2 (27%) and 3 (66%) and late toxicity grades of 2 (34%) and 3 (11%) were observed. Conclusion LRRFS after postoperative IMRT is satisfying and toxicity is acceptable. The majority of locoregional recurrences occurred marginally or outside of the high-risk target volumes. Improvement of high-risk target volume definition especially in patients with flap reconstruction and ECE might transfer into better locoregional control.