Mechanical power of ventilation and driving pressure: two undervalued parameters for pre extracorporeal membrane oxygenation ventilation and during daily management?

The current ARDS guidelines highly recommend lung protective ventilation which include plateau pressure (Pplat < 30 cm H2O), positive end expiratory pressure (PEEP > 5 cm H2O) and tidal volume (Vt of 6 ml/kg) of predicted body weight. In contrast, the ELSO guidelines suggest the evaluation of an indication of veno-venous extracorporeal membrane oxygenation (ECMO) due to hypoxemic or hypercapnic respiratory failure or as bridge to lung transplantation. Finally, these recommendations remain a wide range of scope of interpretation. However, particularly patients with moderate-severe to severe ARDS might benefit from strict adherence to lung protective ventilation strategies. Subsequently, we discuss whether extended physiological ventilation parameter analysis might be relevant for indication of ECMO support and can be implemented during the daily routine evaluation of ARDS patients. Particularly, this viewpoint focus on driving pressure and mechanical power.

L-2-oxothiazolidine-4-carboxylic acids slow down dialysate-induced senescence in human peritoneal mesothelial cells.

Peritoneal dialysis induces an intraperitoneal inflammatory reaction, which in the long term may cause deterioration of the peritoneal structure and function as the dialysis membrane. We studied the effect of the overnight effluent dialysate from patients on chronic peritoneal dialysis on aging of the human peritoneal mesothelial cells in an in vitro model of replicative cellular senescence. In the control group cells were cultured in the standard medium and in the studied groups in culture medium mixed 1:1 v/v with the dialysate ± L-2-oxothiazolodine-4-carboxylic acid 1 mmol/L (OTZ). OTZ was used as the precursor for the synthesis of glutathione in these cells. Dialysate accelerated senescence of the mesothelial cells as reflected by elongation of their population doubling time, reduced expression of KI-67 gene, and increased ß-galactosidase activity. Also, expression of the genes regulating the production of the inflammatory mediators (interleukin-6, monocyte chemoattractant protein-1, metalloproteinase-2, hyaluronan), proangiogenic (VEGF) and profibrotic (fibronectin) factors was increased in that group. At the same time, these cells secreted more inflammatory mediators. Simultaneous treatment of the cells with the dialysate and OTZ slowed down their senescence, whose intensity was similar to that in the control group. The results presented in this manuscript prove that the intraperitoneal inflammatory reaction induced by repeated infusions of the dialysis fluid accelerates the senescence of the mesothelial cells, which may result in fibrosis and neoangiogenesis within the peritoneum. Simultaneous supplementation of the cells with a glutathione precursor (OTZ) may prevent the development of these pathological changes.

Functional in vitro tension measurements of fascial tissue - a novel modified superfusion approach.

INTRODUCTION: While two laboratory techniques are commonly used to assess the tensile properties of muscle tissue, emerging evidence suggests that the fascial components of these tissues also serve an active role in force generation. Hence, we investigated whether these techniques are sensitive for assessment of fascial micromechanics. METHODS: Force measurements on dissected fascial tissue were performed either using the classical immersion organ bath or using an improved superfusion approach simulating pulsed pharmacological triggers. Rat deep dorsal fascial strips as well as rat testicular capsule were pharmacologically challenged either with mepyramine or oxytocin. RESULTS: The classical immersion technique yielded a lower force response to mepyramine than the superfusion method (median: 367.4 vs. 555.4µN/mm(2)). Pause in irrigation before application reduced irregularities during bolus application. The superfusion approach was improved further by the following points: The high sensitivity of the superfusion method to bolus addition was voided by deviation of fluid supply during bolus addition. CONCLUSION: Although both methods demonstrated pharmacologically induced contractile responses in lumbar fascia samples, the modified superfusion method may improve force registrations of slow contracting fascial tissue and minimize artefacts of fluid application.

Effective PEGylation of gold nanorods.

Standard procedures to coat gold nanorods (AuNR) with poly(ethylene glycol) (PEG)-based ligands are not reliable and high PEG-grafting densities are not achieved. In this work, the ligand exchange of AuNR with PEGMUA, a tailored PEG-ligand bearing a C10 alkylene spacer, is studied. PEGMUA provides AuNR with very high stability against oxidative etching with cyanide. This etching reaction is utilized to study the ligand exchange in detail. Ligand exchange is faster, less ligand consuming and more reproducible with assisting chloroform extraction. Compared to PEG ligands commonly used, PEGMUA provides much higher colloidal and chemical stability. Further analyses based on NMR-, IR- and UV/Vis-spectroscopy reveal that significantly higher PEG-grafting densities, up to ∼3 nm(-2), are obtained with PEGMUA. This demonstrates how the molecular structure of the PEG ligand can be used to dramatically improve the ligand exchange and to synthesize PEGylated AuNR with high chemical and colloidal stability and high PEG grafting densities. Such AuNR are especially interesting for applications in nanomedicine.

Percolation on fitness-dependent networks with heterogeneous resilience.

The ability to understand the impact of adversarial processes on networks is crucial to various disciplines. The objects of study in this article are fitness-driven networks. Fitness-dependent networks are fully described by a probability distribution of fitness and an attachment kernel. Every node in the network is endowed with a fitness value and the attachment kernel translates the fitness of two nodes into the probability that these two nodes share an edge. This concept is also known as mutual attractiveness. In the present article, fitness does not only serve as a measure of attractiveness, but also as a measure of a node's robustness against failure. The probability that a node fails increases with the number of failures in its direct neighborhood and decreases with higher fitness. Both static and dynamic network models are considered. Analytical results for the percolation threshold and the occupied fraction are derived. One of the results is that the distinction between the dynamic and the static model has a profound impact on the way failures spread over the network. Additionally, we find that the introduction of mutual attractiveness stabilizes the network compared to a pure random attachment.

Contractile elements in muscular fascial tissue - implications for in-vitro contracture testing for malignant hyperthermia.

Malignant hyperthermia is a dreaded complication of general anaesthesia. Predisposed individuals can be identified using the standardised caffeine/halothane in-vitro contracture test on a surgically dissected skeletal muscle specimen. Skeletal muscle is composed of muscle fibres and interwoven fascial components. Several malignant hyperthermia-associated neuromuscular diseases are associated with an altered connective tissue composition. We analysed adjacent fascial components of skeletal muscle histologically and physiologically. We investigated whether the fascial tissue is sensitive to electrical or pharmacological stimulation in a way similar to the in-vitro contracture test for diagnosing malignant hyperthermia. Using immunohistochemical staining, α-smooth muscle actin-positive cells (myofibroblasts) were detected in the epi-, endo- and perimysium of human fascial tissue. Force measurements on isolated fascial strips after pharmacological challenge with mepyramin revealed that myofascial tissue is actively regulated by myofibroblasts, thereby influencing the biomechanical properties of skeletal muscle. Absence of electrical reactivity and insensitivity to caffeine and halothane suggests that, reassuringly, the malignant hyperthermia diagnostic in-vitro contracture test is not influenced by the muscular fascial tissue.

Clinical relevance of fascial tissue and dysfunctions.

Fascia is composed of collagenous connective tissue surrounding and interpenetrating skeletal muscle, joints, organs, nerves, and vascular beds. Fascial tissue forms a whole-body, continuous three-dimensional viscoelastic matrix of structural support. The classical concept of its mere passive role in force transmission has recently been disproven. Fascial tissue contains contractile elements enabling a modulating role in force generation and also mechanosensory fine-tuning. This hypothesis is supported by in vitro studies demonstrating an autonomous contraction of human lumbar fascia and a pharmacological induction of temporary contraction in rat fascial tissue. The ability of spontaneous regulation of fascial stiffness over a time period ranging from minutes to hours contributes more actively to musculoskeletal dynamics. Imbalance of this regulatory mechanism results in increased or decreased myofascial tonus, or diminished neuromuscular coordination, which are key contributors to the pathomechanisms of several musculoskeletal pathologies and pain syndromes. Here, we summarize anatomical and biomechanical properties of fascial tissue with a special focus on fascial dysfunctions and resulting clinical manifestations. Finally, we discuss current and future potential treatment options that can influence clinical manifestations of pain syndromes associated with fascial tissues.

Mutual selection in time-varying networks.

Time-varying networks play an important role in the investigation of the stochastic processes that occur on complex networks. The ability to formulate the development of the network topology on the same time scale as the evolution of the random process is important for a variety of applications, including the spreading of diseases. Past contributions have investigated random processes on time-varying networks with a purely random attachment mechanism. The possibility of extending these findings towards a time-varying network that is driven by mutual attractiveness is explored in this paper. Mutual attractiveness models are characterized by a linking function that describes the probability of the existence of an edge, which depends mutually on the attractiveness of the nodes on both ends of that edge. This class of attachment mechanisms has been considered before in the fitness-based complex networks literature but not on time-varying networks. Also, the impact of mutual selection is investigated alongside opinion formation and epidemic outbreaks. We find closed-form solutions for the quantities of interest using a factorizable linking function. The voter model exhibits an unanticipated behavior as the network never reaches consensus in the case of mutual selection but stays forever in its initial macroscopic configuration, which is a further piece of evidence that time-varying networks differ markedly from their static counterpart with respect to random processes that take place on them. We also find that epidemic outbreaks are accelerated by uncorrelated mutual selection compared to previously considered random attachment.

A multicenter cohort study of pregnancy outcomes among women with laboratory-confirmed H1N1 influenza.

OBJECTIVE: To evaluate associations between laboratory-confirmed 2009 H1N1 influenza infection and obstetric and neonatal outcomes. STUDY DESIGN: A multicenter cohort study was performed comparing laboratory-confirmed cases of 2009 H1N1 infection during pregnancy (N=142) with matched controls (N=710). Subanalysis was also performed comparing severely infected (hospitalized) women with controls. RESULT: No outcome differences were noted in comparing all women with H1N1 with controls. Women with severe infection had a higher incidence of delivering a small for gestational age (SGA) infant: 18.8% (6/32) versus 7.4% (52/707), adjusted odds ratio 2.35 (95% confidence interval 1.03, 5.36, P=0.02). Mean birth weight was 3013.0 g among severely infected women and 3223.3 g in controls (P=0.08), and incidence of preterm delivery was 25.0% (8/32) and 11.6% (82/710) (P=0.08), respectively. CONCLUSION: Pregnant women with mild clinical illness secondary to 2009 H1N1 were not at a greater risk of adverse pregnancy outcomes. However, severely infected women were more likely to deliver SGA infants.

Network growth model with intrinsic vertex fitness.

We study a class of network growth models with attachment rules governed by intrinsic node fitness. Both the individual node degree distribution and the degree correlation properties of the network are obtained as functions of the network growth rules. We also find analytical solutions to the inverse, design, problems of matching the growth rules to the required (e.g., power-law) node degree distribution and more generally to the required degree correlation function. We find that the design problems do not always have solutions. Among the specific conditions on the existence of solutions to the design problems is the requirement that the node degree distribution has to be broader than a certain threshold and the fact that factorizability of the correlation functions requires singular distributions of the node fitnesses. More generally, the restrictions on the input distributions and correlations that ensure solvability of the design problems are expressed in terms of the analytical properties of their generating functions.

Pathways to certifications in physical medicine and rehabilitation in the United States: past, present, and future.

This article describes the certification pathways for Physiatrists in the United States, reviews the licensure, certification and accreditation pathways for rehabilitation facilities in the United States, examines the evolving models of health care in the United States, evaluates the impact of health care reform within the United States with particular emphasis on the intrinsic value of Physiatric services, and discusses how the intersection of certification, accreditation and emerging models of care in the United States present opportunities for Physiatrists instead of threats. These principles and practices should be relevant to Physiatrists and physiatric programs globally.

In vitro muscle contracture investigations on the malignant hyperthermia like episodes in myotonia congenita.

BACKGROUND: A common form of congenital myotonia, myotonia congenita (MC), is caused by mutations in the skeletal muscle Cl(-) channel gene type 1 (CLCN1). Due to the reduced Cl(-) conductance of the mutated channels, the patients may develop generalized muscle rigidity and hypermetabolism during general anaesthesia. The clinical symptoms resemble malignant hyperthermia (MH), which may lead to mistreatment of the patient. METHODS: Muscle specimens of ADR mice (an animal model of MC) as well as of human individuals were used and exposed to potent ryanodine receptor type 1 (RyR1) activators and increasing K(+) concentration. Muscle force was monitored by a standardized diagnostic method for MH, the so-called in vitro contracture test. RESULTS: Neither muscle of ADR mice nor MC muscle (murine and human myotonic muscle) showed pathological contractures after exposure to the potent RyR1 agonists caffeine and halothane. Increasing concentrations of K(+) had a dose-dependent preventive effect on myotonic stiffness. CONCLUSION: We conclude that the adverse anaesthetic MH-like episodes observed in MC patients do not primarily originate from an altered Ca(2+) release in skeletal muscle. In MC muscle, this hypermetabolism is facilitated by a (pharmacologically induced) sustained depolarization due to an instable membrane potential. The in vitro results suggest that these patients benefit from tight K(+) monitoring because of the membrane potential stabilizing effect of K(+) .

Assessment of airborne exposures and health in flooded homes undergoing renovation.

UNLABELLED: In June 2008, the Cedar River crested flooding more than 5000 Cedar Rapids homes. Residents whose homes were flooded were invited to participate in this study. Household assessments and resident interviews were conducted between November 2008 and April 2009. We characterized exposures and symptoms experienced by individuals inhabiting 73 flood-damaged homes. Active air sampling and passive electrostatic dust collectors were used to assess exposures to culturable mold, culturable bacteria, fungal spores, inhalable particulate matter (iPM), endotoxin, glucans, allergens, lead, asbestos, radon, carbon dioxide, and carbon monoxide. Wall moisture levels and relative humidity were also measured. Exposures and questionnaire-based health assessments were compared at two levels of remediation, in-progress and completed. Homes with remediation in-progress (N = 24), as compared to the completed homes (N = 49), had significantly higher airborne concentrations of mold, bacteria, iPM, endotoxin, and glucan. Residents of in-progress homes had a significantly higher prevalence of doctor-diagnosed allergies (adjusted OR = 3.08; 95% CI: 1.05, 9.02) and all residents had elevated prevalence of self-reported wheeze (adjusted OR = 3.77; 95% CI: 2.06, 6.92) and prescription medication use for breathing problems (adjusted OR = 1.38; 95% CI: 1.01, 1.88) after the flood as compared to before. Proper post-flood remediation led to improved air quality and lower exposures among residents living in flooded homes. PRACTICAL IMPLICATIONS: The number and severity of floods is on the rise, and health departments need evidence-based information to advise homeowners on recovery after such disasters. Our study suggests that proper remediation of flood-damaged homes can reduce bioaerosols to acceptable levels but exposures are significantly increased while remediation is in-progress leading to an increased burden of allergy and allergic rhinitis.

Monolithic integration of microfluidic channels and optical waveguides in silica on silicon.

Sealing of the flow channel is an important aspect during integration of microfluidic channels and optical waveguides. The uneven topography of many waveguide-fabrication techniques will lead to leakage of the fluid channels. Planarization methods such as chemical mechanical polishing or the etch-back technique are possible, but troublesome. We present a simple but efficient alternative: By means of changing the waveguide layout, bonding pads are formed along the microfluidic channels. With the same height as the waveguide, they effectively prevent leakage and hermetically seal the channels during bonding. Negligible influence on light propagation is found when 10-mum-wide bonding pads are used. Fabricated microsystems with application in absorbance measurements and flow cytometry are presented.

The correlation of ATP-binding cassette 1 mRNA levels with cholesterol efflux from various cell lines.

Studies show that lipid-free apoA-I stimulates release of cholesterol and phospholipid from fibroblasts and macrophages. ATP-binding cassette 1 (ABC1) is implicated in this release and has been identified as the genetic defect in Tangier disease, evidence that ABC1 is critical to the biogenesis of high density lipoprotein. We quantified levels of ABC1 mRNA, protein, and cholesterol efflux from J774 mouse macrophages +/- exposure to a cAMP analog. Up-regulating ABC1 mRNA correlated to increased cholesterol efflux in a dose- and time-dependent manner. mRNA levels rose after 15 min of exposure while protein levels rose after 1 h, with increased efflux 2-4 h post-treatment. In contrast to cells from wild-type mice, peritoneal macrophages from the Abc1 -/- mouse showed a lower level of basal efflux and no increase with cAMP treatment. The stimulation of efflux exhibits specificity for apoA-I, high density lipoprotein, and other apolipoproteins as cholesterol acceptors, but not for small unilamellar vesicles, bile acid micelles, or cyclodextrin. We have studied a number of cell types and found that while other cell lines express ABC1 constitutively, only J774 and elicited mouse macrophages show a substantial increase of mRNA and efflux with cAMP treatment. ApoA-I-stimulated efflux was detected from the majority of cell lines examined, independent of treatment.

High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1.

Recently, the human ATP-binding cassette transporter-1 (ABC1) gene has been demonstrated to be mutated in patients with Tangier disease. To investigate the role of the ABC1 protein in an experimental in vivo model, we used gene targeting in DBA-1J embryonic stem cells to produce an ABC1-deficient mouse. Expression of the murine Abc1 gene was ablated by using a nonisogenic targeting construct that deletes six exons coding for the first nucleotide-binding fold. Lipid profiles from Abc1 knockout (-/-) mice revealed an approximately 70% reduction in cholesterol, markedly reduced plasma phospholipids, and an almost complete lack of high density lipoproteins (HDL) when compared with wild-type littermates (+/+). Fractionation of lipoproteins by FPLC demonstrated dramatic alterations in HDL cholesterol (HDL-C), including the near absence of apolipoprotein AI. Low density lipoprotein (LDL) cholesterol (LDL-C) and apolipoprotein B were also significantly reduced in +/- and -/- compared with their littermate controls. The inactivation of the Abc1 gene led to an increase in the absorption of cholesterol in mice fed a chow or a high-fat and -cholesterol diet. Histopathologic examination of Abc1-/- mice at ages 7, 12, and 18 mo demonstrated a striking accumulation of lipid-laden macrophages and type II pneumocytes in the lungs. Taken together, these findings demonstrate that Abc1-/- mice display pathophysiologic hallmarks similar to human Tangier disease and highlight the capacity of ABC1 transporters to participate in the regulation of dietary cholesterol absorption.

Discharge destination and motor function outcome in severe stroke as measured by the functional independence measure/function-related group classification system.

OBJECTIVES: Function-related groups based on the Functional Independence Measure have been proposed as a model for a prospective payment system for medical rehabilitation. This study describes discharge destination and motor function outcomes in a sample of patients with stroke from the FIM-FRG STR1 classification. STUDY DESIGN: A retrospective review of 293 cases of stroke from the years 1993 to 1995. The demographic and outcome characteristics of this sample were described. RESULTS/CONCLUSIONS: Forty-five percent of the patients were discharged to home after a mean length of stay of 23.8 days in acute medical rehabilitation. Patients who were discharged home had higher admission and discharge motor FIM scores than those discharged to a subacute facility or long-term care facility, although the correlation between motor FIM score and discharge destination was low to moderate. Median discharge motor FIM scores indicate considerable residual disability in this classification after rehabilitation. Research problems that address methods to improve the usefulness of the FIM-FRG system in a prospective payment system are discussed.

Binding and functional effects of transcription factors Sp1 and Sp3 on the proximal human lecithin:cholesterol acyltransferase promoter.

Human lecithin:cholesterol acyltransferase (LCAT) circulates in plasma bound to high density lipoproteins (HDL) and modulates the rate by which cholesteryl ester is transported to the liver. So far, little is known about the regulation of the expression of the LCAT gene. In this study we have defined the cis-elements, identified the trans-acting factors and demonstrated their functional effects and significance in determining transcriptional activity of the proximal LCAT promoter. Using deletion mutants having 5' variable ends (from nucleotides -72 to -27), we have identified the presence of two non-consensus GC-rich regions that stimulate transcription in HepG2 and HeLa cells. These regions designated sites A (-29 to -47) and B (-49 to -65) contain the CCTCC core sequence which in electromobility shift analysis is critical for the formation of two DNA-protein complexes designated I and II. Site-directed mutagenesis suggests that both sites are equally important in promoter activity, and that cooperative interactions between both sites are not required for activity. Electromobility shift and supershift experiments using oligonucleotides spanning sites A and B identified Sp1 and Sp3 as the transcription factors interacting at these sites. To determine the significance and functional effects that Sp1 and Sp3 have in regulating LCAT promoter activity, we performed transfection experiments in Drosophila SL-2 cells as they lack endogenous Sp1 and Sp3. Sp1 but not Sp3 activates the human LCAT promoter and when Sp1 is co-transfected along with Sp3, Sp3 functions as a dose-dependent repressor of Sp1-mediated activation. These findings indicate that Sp1 is capable of transactivating a reporter gene linked to the LCAT promoter containing Sp binding sites and suggests that the levels of Sp3 or the nuclear Sp1/Sp3 ratio may play an important role in determining the transcriptional activity of the LCAT promoter in vivo.

[The psychophysics of sweet taste. 8. Interindividual variability of differential findings]. / Beiträge zur Psychophysik des Süssgeschmacks, 8. Mitt. Zur interindividuellen Variabilität der Unterschiedsempfindlichkeit.

Contribution to the psychophysics of sweet taste. Part 8. On the inter-individual variability of the difference sensitivity. The variability of sensitivity of volunteers is a considerable imponderability for the comparison of sensoric results. The paper deals with the quantitative determination of the different sensitivity of sweet taste of 132 persons, 38 men and 94 women at the age of 19 to 64 years, using a statistically defined method. The numbers of errors are estimated for each person by means of one test difference of two saccharose concentrations using 10 pairs of comparisons and 4 runs. The average number of error of 10 comparisons corresponds to the individual measure of sensitivity. The medium value of the total distribution is 1.54 and the standard deviation is 1.19 errors. The value is only less above the binomial calculated number. In random test women show in comparison to men a significant higher variance at the statistical identical mean. A variance analysis based on the cutting of the distribution edges in the range of 0.5 to 4.0 errors can detect high significantly the steady learning effect of the volunteers during the runs. The method is applicable to determine classified subjective characteristics. The calculations of necessary group numbers for such experiments on the base of binomial distribution are discussed.