Role of coupled gating between cardiac ryanodine receptors in the genesis of triggered arrhythmias.

Mutations in the ryanodine receptor (RyR) have been linked to exercise-induced sudden cardiac death. However, the precise sequence of events linking RyR channel mutations to a whole heart arrhythmia is not completely understood. In this paper, we apply a detailed, mathematical model of subcellular calcium (Ca) release, coupled to membrane voltage, to study how defective RyR channels can induce arrhythmogenic-triggered activity. In particular, we show that subcellular Ca activity, such as spontaneous Ca sparks and Ca waves, is highly sensitive to coupled gating between RyR channels in clusters. We show that small changes in coupled gating can induce aberrant Ca release activity, which, under Ca overload conditions, can induce delayed afterdepolarization (DAD). We systematically investigate the properties of subcellular Ca during DAD induction and show that the voltage time course during a DAD is dependent on the timing and number of spontaneous Ca sparks that transition to Ca waves. These results provide a detailed mechanism for the role of coupled gating in the genesis of triggered arrhythmias.

Foot and mouth disease in the Borana pastoral system, southern Ethiopia and implications for livelihoods and international trade.

Participatory epidemiology (PE) was used on the Borana plateau of southern Ethiopia to understand pastoralist's perceptions of the clinical and epidemiological features of foot and mouth disease (FMD) in cattle. Matrix scoring showed good agreement between informant groups on the clinical signs of acute and chronic FMD, and findings were cross-checked by clinical examination of cattle and assessment of previous clinical FMD at herd level by detection of antibody to non structural proteins of FMD virus. The positive predictive value of pastoralist's diagnosis of FMD at herd level was 93.1%. The annual age-specific incidence and mortality of acute FMD in 50 herds was estimated using proportional piling. The estimated mean incidence of acute FMD varied from in 18.5% in cattle less than two years of age to 14.0% in cattle three to four years of age. The estimated mean mortality due to acute FMD varied from 2.8% in cattle less than two years of age to 0.3% in cattle three of age or older. Pearson correlation coefficients for acute FMD by age group were -0.12 (p>0.05) for incidence and -0.59 (p<0.001) for mortality. Estimates of the annual incidence of chronic FMD varied from 0.2% in cattle less than two years of age to 1.8% in cattle three to four years of age. The Pearson correlation coefficient for the incidence of chronic FMD by age group was 0.47 (p<0.001). Outbreaks of FMD peaked in Borana cattle during the two dry seasons and were attributed to increased cattle movement to dry season grazing areas. The mean seroprevalence of FMD was estimated at 21% (n=920) and 55.2% of herds (n=116) tested seropositive. Serotyping of 120 seropositive samples indicated serotypes O (99.2%), A (95.8%), SAT 2 (80%) and C (67.5%). The endemic nature of FMD in Borana pastoral herds is discussed in terms of the direct household-level impact of the disease, and the increasing export of cattle and chilled beef from Ethiopia.

Reproductive disorders of crossbred dairy cows in the central highlands of Ethiopia and their effect on reproductive performance.

The study was conducted to estimate the proportion of reproductive disorders and to determine factors affecting reproductive performance of crossbred dairy cows under four different production systems in the central highlands of Ethiopia. The principal postpartum reproductive disorders were retained fetal membranes (14.7%) and uterine infection (15.5%). Anoestrus was the major postpartum reproductive problem in the mixed crop-livestock production system (38.6%) and was significantly associated with this production system. Apart from anoestrus, the occurrence of reproductive disorders was not significantly associated with a production system. Most of the reproductive disorders occurred as a complex rather than as a single abnormality. Two or more abnormal conditions were seen in 11.4% of the cases. Each reproductive trait measured was affected adversely by reproductive disorders. Cows with reproductive disorders in each production system, lactation group and suckling and non-suckling group had longer intervals from calving to first service and to conception (p < 0.001) and required more services per conception (p < 0.001). Pregnancy rate and conception to first service were 84.7% and 51.7%, respectively, for cows without reproductive health problems; and 64.2%, and 15.1%, respectively, for cows with reproductive disorders (p < 0.001). Overall, intervals from calving to first service were shorter (p < 0.05) than in younger cows. Intervals from calving to first service and to conception were longer in suckling than in non-suckling cows (p > 0.05). Cows with a good body condition score (> 3.5) at calving had shorter calving to first service and conception intervals than cows in poor condition (p < 0.001). The results showed that reproductive abnormalities, coupled with poor body condition, are important factors that contributed to reproductive inefficiency. An appropriate reproductive health management, a reliable artificial insemination service and supplementary feeding could be the management options to reduce or alleviate some of the problems.

Reduced milk production in udder quarters with subclinical mastitis and associated economic losses in crossbred dairy cows in Ethiopia.

The objective of the study was to estimate the losses associated with subclinical mastitis (SCM) in crossbred dairy cows in the Central Highlands of Ethiopia. A split udder investigation was performed with 30 cows to determine production losses associated with SCM. Each quarter of the study cows was examined using the California Mastitis Test (CMT) and quarter milk production was measured over a period of 8 days. Production losses were determined for different CMT scores by comparing production of quarters with CMT score 0 to quarters with CMT scores trace, 1, 2 and 3, respectively. Using data from a recently published study, economic losses were determined for different farm sizes and production subsystems by multiplying the prevalence of the respective CMT scores with the production losses associated with these CMT scores. Mean quarter milk production was 0.82 +/- 0.40 kg per milking in the split udder trial. Milk production was reduced by 1.2%, 6.3%, and 33% in quarters with CMT scores 1+, 2+, and 3+, respectively. Using data from the published study, a quarter with SCM lost an average of 17.2% of its milk production. Production losses associated with SCM were estimated at 5.6% for the Addis Ababa Milk Shed. Stratified losses were highest (9.3%) in urban dairy farms (UDF) and small-scale farms (6.3%). The estimates of the financial losses ranged from US dollars 29.1 in dairy herds in secondary towns (DHIST) to US dollars 66.6 in UDF. A total loss of US dollars 38 was estimated for each cow per lactation. Reducing mastitis in UDF (highest prevalence) to the level of DHIST (lowest prevalence) could reduce the loss by US dollars 35. As this does not include costs associated with treatment or culling of diseased cows, this figure probably underestimates the possible benefits of control measures.

Reproductive performance of crossbred dairy cows in different production systems in the Central Highlands of Ethiopia.

The study was conducted to examine the fertility status of crossbred dairy cows in mixed crop-livestock production (MCLP), market-oriented specialized dairy production (MSDP) and urban dairy production (UDP) systems, including the Holetta Agricultural Research Center (HARC). Data on general farm management variables and reproductive histories were collected from study farms by questionnaire and from individual cow records. Age at first service and age at first calving were 29.58 months (n = 424) and 40.6 months (n = 348), respectively. Cows managed under UDP were younger at first service and at first calving (p<0.05). The mean intervals from calving to first service and to conception were 141.98 days (n = 284) and 185.02 days (n = 219), respectively. The mean calving interval for cows was 551.82 days (n = 258). Cows in MCLP had longer intervals from calving to first service and to conception and longer calving intervals than those managed under MSDP, UDP and HARC. First service conception rate (43.42%), number of services per conception (1.75) and pregnancy rate (79.29%) did not differ significantly between production systems. Reproductive performance was best in UDP followed by HARC and MSDP. The difference between MCLP and the rest points to particular difficulties in that system. To improve reproductive performance and economic benefit, there should be conservative stocking rate, sensible year-round feeding, a herd health plan, and sustainable extension service.

Model of intracellular calcium cycling in ventricular myocytes.

We present a mathematical model of calcium cycling that takes into account the spatially localized nature of release events that correspond to experimentally observed calcium sparks. This model naturally incorporates graded release by making the rate at which calcium sparks are recruited proportional to the whole cell L-type calcium current, with the total release of calcium from the sarcoplasmic reticulum (SR) being just the sum of local releases. The dynamics of calcium cycling is studied by pacing the model with a clamped action potential waveform. Experimentally observed calcium alternans are obtained at high pacing rates. The results show that the underlying mechanism for this phenomenon is a steep nonlinear dependence of the calcium released from the SR on the diastolic SR calcium concentration (SR load) and/or the diastolic calcium level in the cytosol, where the dependence on diastolic calcium is due to calcium-induced inactivation of the L-type calcium current. In addition, the results reveal that the calcium dynamics can become chaotic even though the voltage pacing is periodic. We reduce the equations of the model to a two-dimensional discrete map that relates the SR and cytosolic concentrations at one beat and the previous beat. From this map, we obtain a condition for the onset of calcium alternans in terms of the slopes of the release-versus-SR load and release-versus-diastolic-calcium curves. From an analysis of this map, we also obtain an understanding of the origin of chaotic dynamics.

Localization of a polymer in random media: relation to the localization of a quantum particle.

In this paper we consider in detail the connection between the problem of a polymer in a random medium and that of a quantum particle in a random potential. We are interested in a system of finite volume where the polymer is known to be localized inside a low minimum of the potential. We show how the end-to-end distance of a polymer that is free to move can be obtained from the density of states of the quantum particle using extreme value statistics. We give a physical interpretation to the recently discovered one-step replica-symmetry-breaking solution for the polymer [Phys. Rev. E 61, 1729 (2000)] in terms of the statistics of localized tail states. Numerical solutions of the variational equations for chains of different length are performed and compared with quenched averages computed directly by using the eigenfunctions and eigenenergies of the Schrödinger equation for a particle in a one-dimensional random potential. The quantities investigated are the radius of gyration of a free Gaussian chain, its mean square distance from the origin and the end-to-end distance of a tethered chain. The probability distribution for the position of the chain is also investigated. The glassiness of the system is explained and is estimated from the variance of the measured quantities.

Technical solution for an interactive functional MR imaging examination: application to a physiologic interview and the study of cerebral physiology.

Studies with functional magnetic resonance (MR) imaging produce large unprocessed raw data sets in minutes. The analysis usually requires transferring of the data to an off-line workstation, and this process frequently occurs after the subject has left the MR unit. The authors describe a hardware configuration and processing software that captures whole-brain raw data files as they are being produced from the MR unit. It then performs the reconstruction, registration, and statistical analysis, and displays the results in seconds after completion of the MR image acquisition.

Application of a 3D volume 19F MR imaging protocol for mapping oxygen tension (pO2) in perfluorocarbons at low field.

A limited flip angle gradient-echo 3D volume acquisition imaging protocol for mapping partial pressure of oxygen (pO2) in perfluorocarbon compounds (PFCs) at low field (0.14 T) is presented. The PO2 measurement method is based on the paramagnetic effect of dissolved molecular oxygen (O2) which reduces the PFC 19F T1. Specific objectives related to imaging of PFCs through use of the protocol include improved image signal-to-noise characteristics and elimination of 19F chemical shift artifacts. A parametric Wiener deconvolution filtering algorithm is used for suppression of 19F chemical shift artifacts. Application of the protocol is illustrated in a series of calculated PO2 maps of a gas equilibrated, multi-chamber phantom containing perfluorotributylamine (FC-43). The utility of the protocol is demonstrated in vivo through images of a commercially available perfluorocarbon based blood substitute emulsion containing FC-43 sequestered in the liver and spleen of a rat.

In vivo PO2 imaging in the porcine model with perfluorocarbon F-19 NMR at low field.

Quantitative pO2 imaging in vivo has been evaluated utilizing F-19 NMR in the porcine model at 0.14 T for the lungs, liver, and spleen following i.p. administration of the commercial perfluorotributylamine (FC-43)-based perfluorocarbon (PFC) emulsion, Oxypherol-ET. Calculated T1 maps obtained from a two spin-echo saturation recovery/inversion recovery (SR/IR) pulse protocol are converted into quantitative pO2 images through a temperature-dependent calibration curve relating longitudinal relaxation rate (1/T1) to pO2. The uncertainty in pO2 for a T1 measurement error of +/- 5% as encountered in establishing the calibration curves ranges from +/- 10 torr (+/- 40%) at 25 torr to +/- 16 torr (+/- 11%) at 150 torr for FC-43 (37 degrees C). However, additional uncertainties in T1 dependent upon the signal-to-noise ratio may be introduced through the SR/IR calculated T1 pulse protocol, which might severely degrade the pO2 accuracy. Correlation of the organ image calculated pO2 with directly measured pO2 in airway or blood pools in six pigs indicate that the PFC resident in lung is in near equilibrium with arterialized blood and not with airway pO2, suggesting a location distal to the alveolar epithelium. For the liver, the strongest correlation implying equilibrium was evident for venous blood (hepatic vein). For the spleen, arterial blood pO2 (aorta) was an unreliable predictor of pO2 for PFC resident in splenic tissue. The results have demonstrated the utility and defined the limiting aspects quantitative pO2 imaging in vivo using F-19 MRI of sequestered PFC materials.

Evaluation of the influence of the aqueous phase bioconstituent environment on the F-19 T1 of perfluorocarbon blood substitute emulsions.

Oxygen-sensitive F-19 magnetic resonance imaging of perfluorocarbon compounds requires that fluorocarbon T1 changes correlate with the local PO2 and not with the composition of the surrounding aqueous phase. The influence of various bioconstituents and paramagnetic ions within the aqueous phase on the F-19 fluorocarbon phase T1 for PFC emulsions was evaluated at 0.14 and 0.66 T. T1 was measured for FC-43, perflubron, and a fluorinated surfactant. Controlled variables introduced in the aqueous phase included annex solution constituents, blood, pH changes, and Gd-DTPA. For a constant PO2, the F-19 T1s were independent of the emulsion constituents, blood concentration, and pH. For FC-43 and perflubron, F-19 T1 was independent of the Gd-DTPA concentration, while the aqueous phase T1 decreased by more than an order of magnitude. XMO-10 (smallest emulsion particle size) showed a slight decrease in F-19 T1 with increasing Gd-DTPA concentration at 0.66 T.

Quantitative pO2 imaging in vivo with perfluorocarbon F-19 NMR: tracking oxygen from the airway through the blood to organ tissues.

The physiological redistribution of perfluorocarbon (PFC) compounds to liver, spleen, bone marrow, and lung after intravenous (i.v.) or intraperitoneal (IP) administration of PFC emulsions affords the unique opportunity for non-invasive monitoring of oxygenation status of these organs and tissues utilizing fluorine (F-19) nuclear magnetic resonance (NMR) imaging techniques. PFCs also may be introduced directly into the pulmonary airways by procedures such as liquid ventilation, intratracheal instillation, or aerosol inhalation. Considerations of importance when establishing methodology for accurate quantitation of oxygen partial pressure (pO2) in vivo using F-19 NMR include: 1.) error analysis of the calibration curves which relate pO2 to the measured PFC F-19 relaxation rate, 2.) optimization of the NMR pulse sequence for efficient oxygen sensitive data acquisition and, 3.) fluorine signal independence from emulsion aqueous phase bioconstituents. The porcine model was investigated at 0.14T following i.v. or IP administration of the PFC emulsion containing perfluorotributylamine (FC-43) to demonstrate the capability for tracking oxygen with F-19 NMR from the lung through the blood to selected organ tissues. Quantitative pO2 projection images and isobaric contour graphs were derived for the liver, spleen, and lungs as a function of inspired oxygen. Blood pO2 levels in aorta, pulmonary artery, and hepatic vein were monitored simultaneously with NMR imaging for correlative analysis.

Perfluorocarbon distribution to liver, lung and spleen of emulsions of perfluorotributylamine (FTBA) in pigs and rats and perfluorooctyl bromide (PFOB) in rats and dogs by 19F NMR spectroscopy.

Perfluorocarbon emulsion (FCE) particles are reported to be taken up by the reticuloendothelial system (RES) and ultimately eliminated by the lung. This distribution provides an opportunity to measure oxygen partial pressure in vivo with fluorine-19 magnetic resonance imaging (19F MRI). Since the MR image signal-to-noise ratio is directly proportional to the fluorine concentration in the tissue, a greater concentration of perfluorocarbon (PFC) in the tissue will result in a greater confidence in the oxygen image and reduce measurement time. It was postulated that the biodistribution of PFC administered in emulsion form may depend on species RES or FCE composition. The distribution of an emulsion (Oxypherol-E.T.) containing perfluorotributylamine (FTBA) 5 days after administration to pigs (11 g FTBA/kg body weight i.p.) and rats (19 g FTBA/kg i.p.) and an emulsion (Oxygent) containing perfluorooctyl bromide (PFOB) 7 days after administration to dogs (11 g PFOB/kg i.v.) and 5 days after administrations to rats (19 g PFOB/kg i.p.) was analyzed by F-19 NMR spectroscopy of tissue samples. PFC concentrations in spleen are 2 to 3 times those in liver. This pattern appears to be independent of PFC emulsion or species. In contrast, lung PFC content was less than that in the liver and showed a dependence upon both species and PFC emulsion.