Sensitivity analysis of a strongly-coupled human-based electromechanical cardiac model: Effect of mechanical parameters on physiologically relevant biomarkers.

The human heart beats as a result of multiscale nonlinear dynamics coupling subcellular to whole organ processes, achieving electrophysiologically-driven mechanical contraction. Computational cardiac modelling and simulation have achieved a great degree of maturity, both in terms of mathematical models of underlying biophysical processes and the development of simulation software. In this study, we present the detailed description of a human-based physiologically-based, and fully-coupled ventricular electromechanical modelling and simulation framework, and a sensitivity analysis focused on its mechanical properties. The biophysical detail of the model, from ionic to whole-organ, is crucial to enable future simulations of disease and drug action. Key novelties include the coupling of state-of-the-art human-based electrophysiology membrane kinetics, excitation-contraction and active contraction models, and the incorporation of a pre-stress model to allow for pre-stressing and pre-loading the ventricles in a dynamical regime. Through high performance computing simulations, we demonstrate that 50% to 200% - 1000% variations in key parameters result in changes in clinically-relevant mechanical biomarkers ranging from diseased to healthy values in clinical studies. Furthermore mechanical biomarkers are primarily affected by only one or two parameters. Specifically, ejection fraction is dominated by the scaling parameter of the active tension model and its scaling parameter in the normal direction ( k ort 2 ); the end systolic pressure is dominated by the pressure at which the ejection phase is triggered ( P ej ) and the compliance of the Windkessel fluid model ( C ); and the longitudinal fractional shortening is dominated by the fibre angle ( ϕ ) and k ort 2 . The wall thickening does not seem to be clearly dominated by any of the considered input parameters. In summary, this study presents in detail the description and implementation of a human-based coupled electromechanical modelling and simulation framework, and a high performance computing study on the sensitivity of mechanical biomarkers to key model parameters. The tools and knowledge generated enable future investigations into disease and drug action on human ventricles.

Central Diabetes Insipidus in a Preterm Neonate Unresponsive to Intranasal Desmopressin.

Central or neurogenic diabetes insipidus (DI) is uncommon in the pediatric age group and rarely occurs in neonates. It should be suspected in any neonate presenting with excessive urine output and hypernatremia that persists despite increased fluid administration. Diabetes insipidus may be secondary to asphyxia, intraventricular hemorrhage, infection, and structural abnormalities or may be idiopathic or genetic. Diagnosis includes a careful history, laboratory testing, and magnetic resonance imaging. Management of neonatal DI involves a careful balance between fluid intake and pharmacologic treatment. In this article we report a case of an extremely low birth weight infant presenting with central DI possibly caused by abnormality of the pituitary gland. Persistent hypernatremia was the initial presentation. Increased fluids were given initially but were only partially helpful. Eventually subcutaneous desmopressin (DDAVP) was required. The infant was unresponsive to intranasal DDAVP and required subcutaneous DDAVP upon discharge.

Nonlinear diffusion and thermo-electric coupling in a two-variable model of cardiac action potential.

This work reports the results of the theoretical investigation of nonlinear dynamics and spiral wave breakup in a generalized two-variable model of cardiac action potential accounting for thermo-electric coupling and diffusion nonlinearities. As customary in excitable media, the common Q10 and Moore factors are used to describe thermo-electric feedback in a 10° range. Motivated by the porous nature of the cardiac tissue, in this study we also propose a nonlinear Fickian flux formulated by Taylor expanding the voltage dependent diffusion coefficient up to quadratic terms. A fine tuning of the diffusive parameters is performed a priori to match the conduction velocity of the equivalent cable model. The resulting combined effects are then studied by numerically simulating different stimulation protocols on a one-dimensional cable. Model features are compared in terms of action potential morphology, restitution curves, frequency spectra, and spatio-temporal phase differences. Two-dimensional long-run simulations are finally performed to characterize spiral breakup during sustained fibrillation at different thermal states. Temperature and nonlinear diffusion effects are found to impact the repolarization phase of the action potential wave with non-monotone patterns and to increase the propensity of arrhythmogenesis.

Assessment of WINROP algorithm as screening tool for preterm infants in Manitoba to detect retinopathy of prematurity.

OBJECTIVE: Developing less invasive methods for early detection of retinopathy of prematurity (ROP) is vital to minimizing blindness in premature infants. Lofqvist and colleagues developed a computer-based ROP risk algorithm (WINROP) (https://winrop.com), which detects downtrends in postnatal weight gain that correlate with the development of sight-threatening ROP. The aim of this study is to investigate the sensitivity and specificity of the WINROP algorithm to detect vision-threatening ROP. METHODS: This is a retrospective chart review study between January 2008 and December 2013. This study was conducted in the neonatal intensive care unit in Children's Hospital at Health Sciences Centre, Winnipeg, Manitoba, Canada. The study included preterm infants, less than 32 weeks' gestation, who were admitted to the hospital during the study period. The included 215 infants were eligible for ROP screening and had sufficient data to be entered into the WINROP algorithm. Infants were screened by a paediatric ophthalmologist for retinopathy of prematurity. The body weight of infants was measured weekly and entered into the WINROP algorithm; the sensitivity and the specificity of the WINROP algorithm were assessed. RESULTS: The mean gestational age was 28.6 ± 1.8 weeks. The mean body weight was 1244 ± 294 g. The sensitivity of the WINROP algorithm to detect vision-threatening retinopathy of prematurity in our cohort was 90% (P=0.021) with a specificity of 60% (P=0.002). CONCLUSION: The WINROP algorithm lacks sufficient sensitivity to be used clinically in our population. The algorithm needs to be reassessed in contemporary populations.

Radiographic confirmation of feeding tube placement: a diagnostic tool identifying gastrointestinal anomalies.

Feeding tubes are commonly used in neonatal intensive care units, and their abnormal position seen on radiographs may indicate underlying serious problems. We recently cared for two infants who presented with clinical deterioration. An abnormally placed feeding tube seen on the chest radiograph revealed underlying serious conditions. The first case was an infant 29 weeks of age who presented with right-sided pneumothorax after birth. By history and a right-side-displaced orogastric (OG) tube, iatrogenic esophageal perforation was diagnosed. The second case was a 16-day-old infant who presented with recurrent vomiting. An OG tube extending into a cystic mass at the right cardiophrenic angle resulted in diagnosis of a herniated stomach with organoaxial-type volvulus, which required surgical repair. Both cases recovered uneventfully. As illustrated in these two rare cases, feeding tube position is not only important for feeding practice, but it also has diagnostic implications in newborn infants.

Calcification inside artificial hearts: inhibition by warfarin-sodium.

Intracavitary calcium phosphate deposits were observed in smooth, elastomeric blood pump sacs implanted in male calves for periods of 115 to 166 days. These deposits occurred predominantly on the flexing surface of the sacs. In contrast, similar pump sacs remained generally free of mineral deposits for up to 150 days in calves treated with the anticoagulant warfarin-sodium. These results implicate a vitamin K-dependent process in calcium phosphate deposition on elastomeric sacs.

Error Bounds for Discontinuous Finite Volume Discretisations of Brinkman Optimal Control Problems.

We introduce a discontinuous finite volume method for the approximation of distributed optimal control problems governed by the Brinkman equations, where a force field is sought such that it produces a desired velocity profile. The discretisation of state and co-state variables follows a lowest-order scheme, whereas three different approaches are used for the control representation: a variational discretisation, and approximation through piecewise constant and piecewise linear elements. We employ the optimise-then-discretise approach, resulting in a non-symmetric discrete formulation. A priori error estimates for velocity, pressure, and control in natural norms are derived, and a set of numerical examples is presented to illustrate the performance of the method and to confirm the predicted accuracy of the generated approximations under various scenarios.

Emissions from corrosion protection systems of offshore wind farms: Evaluation of the potential impact on the marine environment.

Offshore wind energy is a fast growing sector of renewable energies worldwide. This will change the marine environment and thus, a wide range of environmental impacts of offshore wind farms are subject of current research. Here we present an overview about chemical emissions from corrosion protection systems, discuss their relevance and potential impact to the marine environment, and suggest strategies to reduce their emissions. Corrosion is a general problem for offshore infrastructures and corrosion protection systems are necessary to maintain the structural integrity. These systems are often in direct contact with seawater and have different potentials for emissions, e.g. galvanic anodes emitting substantial amounts of metals. Organic coatings may release organic substances due to weathering and/or leaching. Current assumptions suggesting a low environmental impact, but monitoring data is not sufficient to assess the environmental impact of this new source.

IL-10, IL-6 and CD14 polymorphisms and sepsis outcome in ventilated very low birth weight infants.

BACKGROUND: Genetic variation in the innate immune system of the host may play a role in determining the risk of developing infection, as well as outcome from infection. METHODS: Infectious complications were retrospectively determined in 293 (233 African-American (AA), 57 Caucasian and 3 Hispanic) mechanically ventilated very low birth weight (VLBW) infants (<1500 grams at birth) who were genotyped for the IL-6 -174 G/C, IL-10 -1082 G/A and CD14 -260 C/T single nucleotide polymorphisms (SNPs). RESULTS: The IL-6 -174C allele was associated with an increased incidence of late blood stream infection (BSI) in AA but not Caucasian infants. In AA infants with the C allele the incidence of late BSI was 20/29 (69%) compared to 94/204 (46%) in homozygous GG infants (RR 2.6, 95% CI: 1.1-6.0, p = 0.021). The IL-10 -1082A allele was associated with an increased incidence of late BSI. One or more episodes of late BSI developed in 14 (35%) of 40 infants with the GG genotype, 71 (49%) of 145 infants with the GA genotype and 63 (58%) of 108 infants with the AA genotype (p = 0.036). Infants with the A allele (AA or GA genotypes) had an incidence of late BSI that was 134/253 (53%) compared to 14/40 (35%) in homozygous GG infants (RR 2.1, 95% CI: 1.04-4.19, p = 0.035). The CD14 -260 C/T SNP did not alter the overall risk for BSI in ventilated VLBW infants. Multiple BSI episodes were more common in the TT genotype group (CC: 17%, CT: 11%, TT: 30%, p = 0.022). This effect was due to the strong effect of the TT genotype on the incidence of multiple BSI in AA infants (CC: 15%, CT: 11%, TT: 39%, p = 0.003). CONCLUSION: The IL-6 -174 G/C, IL-10 -1082 G/A and CD14 -260 C/T SNPs may alter risk for BSI in ventilated VLBW infants.

Binding of progesterone to the proteins of the uterine luminal fluid. Identification of uteroglobin as the binding protein.

1. The uterine luminal fluid of rabbits treated with estradiol and progesterone contains a protein factor with high affinity for [3-H] progesterone which is not present in the uterine secretion of control rabbits treated with estradiol. 2. This progesterone dependent factor is shown by gel filtration and polyacrylamide gel electrophoresis to be identical with the uterus specific protein uteroglobin, which seems to be required during the preimplantation phase. Uteroglobin specific antiserum, prepared in guinea pigs, completely inhibits the progesterone binding activity of the proteins of the uterine fluid. 3. Progesterone binding to uteroglobin is dependent upon millimolar concentrations of dithioerythritol. At saturation, one molecule of progesterone binds per uteroglobin molecule and the apparent association constant is 2 x 10-6 M-1 at 0 degrees C. 4. The progesterone binding species of uteroglobin exhibits a molecular weight of around 12 000 on polyacrylamide gels containing dodecylsulfate, and of 15 000 upon gel filtration, indicating a non-globular shape. This molecule is compased of two subunits of similar molecular size which are held together by a disulfide bridge among other forces.

Interleukin-10 -1082 G/A polymorphism and risk of death or bronchopulmonary dysplasia in ventilated very low birth weight infants.

IL-10 is an anti-inflammatory cytokine that may have a protective role in acute lung injury. IL-10 expression is affected by a single-nucleotide polymorphism (SNP) located at position -1082 (G to A). The A allele is associated with lower IL-10 production. Low IL-10 production has been linked to the development of BPD. Thus, the IL-10 -1082 SNP may be a genetic risk factor for the development of BPD in the premature newborn. The IL-10 -1082 SNP was determined in 294 (235 African American, 56 Caucasian, and 3 Hispanic) mechanically ventilated very low birth weight (VLBW) infants and compared to outcome (death and/or development of BPD). Differences in groups were analyzed using ANOVA (continuous variables) or chi square (proportions). The frequency of the A allele in our population was 0.62. Thirty-nine (13.3%) infants were homozygous GG, 146 (49.7%) were heterozygous GA, and 109 (37.0%) were homozygous AA. There were no significant differences between genotype groups with respect to ethnic origin, gender, need for surfactant replacement therapy, and isolation of Ureaplasma urealyticum or Mycoplasma hominis from tracheal aspirates at birth. However, AA infants were slightly more mature and of greater birth weight than GA infants (26.9 +/- 0.2 weeks vs. 26.3 +/- 0.2 weeks, P < 0.05, and 940 +/- 22 g vs. 882 +/- 18 g, P < 0.05, respectively). There was no significant effect of the IL-10 -1082 SNP on mortality or the development of BPD (O2 on 28 days or 36 weeks postconceptional age). However, when considered together, the IL-10 -1082 AA/GA genotypes (lower IL-10 production) were associated with a trend toward reduction in risk for the combined outcome of BPD or death (18/39 vs. 80/255, respectively; P = 0.068). The incidence of other complications of prematurity (retinopathy of prematurity, intraventricular hemorrhage, or periventricular leukomalacia) was not different between groups. In conclusion, the IL-10 -1082 G/A SNP does not have a major influence on mortality or the development of BPD in ventilated VLBW infants.

Angiotensin converting enzyme insertion/deletion polymorphism does not alter sepsis outcome in ventilated very low birth weight infants.

OBJECTIVE: This study compared the effect of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphisms on the incidence and outcome of sepsis in ventilated very low birth weight infants. STUDY DESIGN: Infectious complications were retrospectively determined in 295 (234 African-American, 58 Caucasian and three Hispanic) mechanically ventilated very low birth weight (VLBW) infants (<1500 g at birth) and compared ACE I/D genotype. RESULTS: The incidence of the D allele in the study population was 0.60. A total of 113 (38.3%) infants were homozygous DD, 128 (43.4%) were heterozygous ID and 54 (18.3%) were homozygous II. One or more episodes of late BSI developed in 28 (52%) of 54 infants with the II genotype, 66 (52%) of 128 infants with the ID genotype and 52 (46%) of 113 infants with the DD genotype (p=0.618). Neither the rates of non-CONS BSI (II: 24%, ID: 23%, DD: 22%; p=0.937) nor multiple bacteremic/fungemic episodes (II: 13%, ID: 16%, DD: 12%; p=0.641) were different between genotype groups. The ACE I/D polymorphism had no effect on sepsis-related mortality (II: 7%, ID: 5%, DD: 4%; p=0.692). Sepsis mortality for infants with late BSI was 14% in infants with the II genotype, 9% with the ID genotype and 10% with the DD genotype (p=0.764). CONCLUSIONS: The ACE I/D polymorphism does not have a significant effect on the incidence or outcome of sepsis in ventilated VLBW infants.

Effects of passive immunization against parathyroid hormone-related protein: PTHrP is the responsible factor in mediating hypercalcemia in the Walker carcinosarcoma 256 rat model.

The Walker carcinosarcoma (WCS) 256 is a well-characterized rat model of humoral hypercalcemia of malignancy (HHM). We addressed the question of whether parathyroid hormone-related protein (PTHrP) is the factor responsible for mediating HHM in this model. WCS 256 cells were subcutaneously implanted in female rats. We examined the plasma at days 0, 2, 4, 6, and 8. The midregional PTHrP measured by radioimmunoassay (RIA) and the plasma calcium increased significantly. Measuring PTHrP by a two-site immunoradiometric assay (IRMA) showed comparable results. There was a strong positive correlation between plasma calcium and midregional PTHrP (r = 0.85, p < 0.0001). A strong positive correlation between tumor weight and both midregional PTHrP (r = 0.83, p < 0.0001) and plasma calcium (r = 0.87, p < 0.0001) was also found. After surgical removal of the tumor at day 5, both plasma calcium and plasma PTHrP levels fell to within the normal range. Ip administration of native polyclonal antiserum against PTHrP(53-84) led to a significant decrease of plasma calcium. Extracted WCS 256 tumor showed 5-fold increased levels of midregional PTHrP compared with liver. Immunohistochemistry and Western blot were positive for PTHrP. RNA from the WCS 256 tumor was positive for PTHrP whereas liver tissue RNA was negative. WCS 256 cells grown in vitro also secreted PTHrP into the medium. We conclude that PTHrP is synthesized and secreted by WCS 256 and that PTHrP is the factor responsible for mediating hypercalcemia in the WCS 256 rat model.

Differential effects of 1,25-dihydroxyvitamin D3 on cell proliferation and calcitonin gene expression.

1,25-Dihydroxyvitamin D3 (1,25D3) inhibits cell growth and induces differentiation in many cell systems by inhibition of c-myc gene expression. In the human medullary thyroid carcinoma cell line (TT), c-myc gene expression appears to be closely related to cell proliferation and differentiation. TT cells are also a well known target system for 1,25D3, which inhibits calcitonin (CT) gene expression in these cells. So far, no direct cis-acting vitamin D-responsive element could be identified in the promoter region of the CT gene. We, therefore, investigated potential indirect mechanisms of 1,25D3-mediated CT gene expression by examining the hormone's effects on proliferation. In contrast to its well established antiproliferative action in other cell systems, addition of 1,25D3 to TT cells led to a 2.3-fold stimulation of DNA synthesis, which was maximal after 48 h and was preceded by a 4.8-fold increase in c-myc gene expression. c-Myc antisense DNA oligomers abolished the proliferative effect of 1,25D3, but not the latter's inhibition of CT gene expression. Here we present evidence that activation of c-myc gene expression mediates 1,25D3-stimulated TT cell proliferation, but not the 1,25D3-induced inhibition of CT gene expression.

Alfalfa and tobacco cells react differently to chitin oligosaccharides and sinorhizobium meliloti nodulation factors

Alfalfa (Medicago sativa L.) suspension cultures respond to yeast elicitors with a strong alkalinization of the culture medium, a transient synthesis of activated oxygen species, and typical late defence reactions such as phytoalexin accumulation and increased peroxidase activity. The alkalinization reaction as well as the oxidative burst were also observed when tobacco (Nicotiana tabacum L. ) cell-suspension cultures were treated with yeast elicitors. Depending on the degree of polymerization, N-acetyl chitin oligomers induced the alkalinization response in both plant cell-suspension cultures, while only tobacco cell cultures developed an oxidative burst. Suspension-cultured tobacco cells responded to Sinorhizobium meliloti nodulation factors with a maximal alkalinization of 0.25 pH units and a remarkable oxidative burst. In contrast, addition of Sinorhizobium meliloti nodulation factors to suspension-cultured alfalfa cells induced a slight acidification of the culture medium, instead of an alkalinization, but no oxidative burst.

Selective use of vancomycin to prevent coagulase-negative staphylococcal nosocomial bacteremia in high risk very low birth weight infants.

OBJECTIVE: To determine whether vancomycin added to parental nutrition (PN) fluids could prevent nosocomial infections in very low birth weight newborns and which infants would benefit most from prophylaxis. DESIGN: Double blind, randomized controlled study. SETTING AND STUDY POPULATION: Very low birth weight infants receiving PN in a tertiary neonatal intensive care unit. METHODS: Thirty-eight infants with and without central vascular catheters were randomized to receive no medication or 25 microg/ml vancomycin added to PN for the duration of the infant's PN requirements. RESULTS: The addition of 25 microg/ml vancomycin to PN prevented bacteremia in very low birth weight infants receiving PN. There was a significant reduction in the number of coagulase-negative staphylococcal (CONS) bacteremias (defined as isolation of the same organism from two positive blood cultures) during PN (5 vs. 0; P = 0.037) as well as the total number of bacteremias and fungemias (9 vs. 1; P = 0.036). The total number of hospital days (108 +/- 13 vs. 76 +/- 6; P = 0.039) were reduced in infants receiving vancomycin. Infants with birth weights of < 1000 g who received corticosteroids for treatment of chronic lung disease benefitted most from treatment. No vancomycin-resistant strains of CONS or enterococci were detected during the study period. CONCLUSIONS: Prophylactic treatment with vancomycin effectively prevented CONS bacteremia under the conditions of the study. Its use was most effective in infants with birth weights of <1000 g.

Tumor necrosis factor alpha -- 308 polymorphism associated with increased sepsis mortality in ventilated very low birth weight infants.

BACKGROUND: Sepsis commonly complicates the clinical course of critically ill very low birth weight infants, with as many as 30% developing hospital-acquired bacteremia. The tumor necrosis factor alpha (TNF-alpha) -- 308 G/A single nucleotide polymorphism (SNP) is associated with adverse outcome in septic adult patients. METHODS: One hundred seventy-three mechanically ventilated very low birth weight infants were genotyped for the TNF-alpha -- 308 G/A SNP. RESULTS: One hundred twenty (69%) infants were homozygous GG, 45 (26%) were heterozygous AG and 8 (5%) were homozygous AA; 2 of 120 (2%) infants developed early bacteremia in the GG group, and 1 of 53 (2%) developed early bacteremia in the AA/AG group (P = 0.919). One or more episodes of late bacteremia/fungemia developed in 59 of 120 (49%) infants with the GG genotype and 23 of 53 (43%) infants with the AG/AA genotype (P = 0.484). Endotracheal tube colonization rates were 65 of 120 (54%) for infants with the GG genotypes and 28 of 53 (53%) for infants with the AG/AA genotypes (P = 0.871). Nosocomial pneumonia developed in a similar number of infants in both genotype groups (9 of 120 infants vs. 3 of 53 infants; P = 0.461). Mortality from sepsis was 3 times greater in infants with the AA/AG genotypes than in those with the GG genotype (10%vs. 3%; P = 0.038). This difference in sepsis mortality was even greater when only bacteremic/fungemic infants are considered (4 of 59 infants vs. 6 of 23 infants; P = 0.026). CONCLUSIONS: These data suggest that the TNF-alpha -- 308 A allele does not affect the development of sepsis in ventilated premature infants but may increase mortality once sepsis develops.

Surface properties of mussel adhesive protein component films.

Mussel adhesive protein (MAP) is the adhesive agent used by the blue sea mussel (Mytilus edulis) to attach the animal to various underwater surfaces. It is composed of 75-->85 repeating decameric units with the reported primary sequence NH2-A(1)-K(2)-P(3)-S(4)-Y(5)-Hyp(6)-Hyp(7)-T(8)-DOPA(9)-K(10)-COOH. This study identifies and compares the surface properties of the decameric unit, selected fragments and individual amino acid constituents with the complete MAP preparation. These molecular systems were examined: (a) in the solid state as thin films formed on germanium substrata using multiple-attenuated-internal-reflectance infrared (MAIR-IR) spectroscopy, ellipsometry and contact angle analysis; and (b) in the solution state using circular dichroism (CD) spectroscopy. Extensive molecular modelling of the decamer was performed making integral use of the experimentally derived data. These cumulative semi-empirical and empirical results suggest a conformation for the decamer that closely associates the L-DOPA and tyrosine residues with the solid substratum. This model provides the first representation of MAP derived from a rational integration of theoretical and experimental data. On the basis of this model, a possible explanation for the bioadhesive properties of MAP is suggested.

Degradative effects of conventional steam sterilization on biomaterial surfaces.

Prior to implantation trials in animals, the effect of steam sterilization on the surface properties of metallic and coated biomaterials was studied. Pure germanium plates and cast surgical Vitallium discs and subperiosteal implants were treated to present three standard types of biomaterials surfaces prior to steam sterilization, ranging from scrupulously clean, high-energy metals to uniformly low-energy organic layers. Both before and after sterilization, the sample surfaces were characterized by a variety of nondestructive physiochemical techniques. The results indicate that steam sterilization is likely to compromise the properties of otherwise carefully prepared biomedical implants by depositing hydrophobic organic and hygroscopic salt contaminants over the implant surfaces.

Hard-thermal-loop resummed pressure of a degenerate quark-gluon plasma

We compute the pressure of a finite-density quark-gluon plasma at zero temperature to leading order in hard-thermal-loop perturbation theory, which includes the fermionic excitations and Landau damping. The result is compared with the weak-coupling expansion for finite positive chemical potential &mgr; through order alpha(2)(s) and with a quasiparticle model with a mass depending on &mgr;.