Search

Calcium oscillations and waves induce depolarization in cardiac cells which are believed to cause life-threathening arrhythimas. In this work, we study the conditions for the appearance of calcium oscillations in both a detailed subcellular model of calcium dynamics and a minimal model that takes into account just the minimal ingredients of the calcium toolkit. To avoid the effects of homeostatic changes and the interaction with the action potential we consider the somewhat artificial condition of a cell without pacing and with no calcium exchange with the extracellular medium. Both the full subcellular model and the minimal model present the same scenarios depending on the calcium load: two stationary states, one with closed ryanodine receptors (RyR) and most calcium in the cell stored in the sarcoplasmic reticulum (SR), and another, with open RyRs and a depleted SR. In between, calcium oscillations may appear. The robustness of these oscillations is determined by the amount of calsequestrin (CSQ). The lack of this buffer in the SR enhances the appearance of oscillations. The minimal model allows us to relate the stability of the oscillating state to the nullcline structure of the system, and find that its range of existence is bounded by a homoclinic and a Hopf bifurcation, resulting in a sudden transition to the oscillatory regime as the cell calcium load is increased. Adding a small amount of noise to the RyR behavior increases the parameter region where oscillations appear and provides a gradual transition from the resting state to the oscillatory regime, as observed in the subcellular model and experimentally.

Ventricular contraction is roughly proportional to the amount of calcium released from the Sarcoplasmic Reticulum (SR) during systole. While it is rather straightforward to measure calcium levels and contractibility under different physiological conditions, the complexity of calcium handling during systole and diastole has made the prediction of its release at steady state impossible. Here we approach the problem analyzing the evolution of intracellular and extracellular calcium fluxes during a single beat which is away from homeostatic balance. Using an in-silico subcellular model of rabbit ventricular myocyte, we show that the high dimensional nonlinear problem of finding the steady state can be reduced to a two-variable general equilibrium condition where pre-systolic calcium level in the cytosol and in the SR must fulfill simultaneously two different equalities. This renders calcium homeostasis as a problem that can be studied in terms of its equilibrium structure, leading to precise predictions of steady state from single-beat measurements. We show how changes in ion channels modify the general equilibrium, as shocks would do in general equilibrium macroeconomic models. This allows us to predict when an enhanced entrance of calcium in the cell reduces its contractibility and explain why SERCA gene therapy, a change in calcium handling to treat heart failure, might fail to improve contraction even when it successfully increases SERCA expression.

Abstract: Ría de Vigo is a river valley flooded by the sea, with a bay (San Simón Bay) at its innermost part. The accumulation of Holocene sediment in San Simón Bay has been studied by the integration of 1) large scale high resolution seismic data, and 2) detailed geochemical analysis of a gravity core. In San Simón Bay the majority of the seismic records are obscured by acoustic turbidity which represents gassy sediments, but on records from Rande Strait it is possible to distinguish two Quaternary seismic sequences; an Upper Pleistocene sequence (SQ1) and a Holocene sequence (SQ2). Only SQ2 is recognized in San Simón Bay where it is comprised of two seismic units; the upper unit represents the HST sediment, i.e. the period of highest sea level. A gravity core taken within the gassy zone at 10 m water depth provided 3.55 m of fine-grained sediments (muds) from the youngest seismic unit (4 m thick). Geochemical analysis show high values (4 to 10%) of TOC. Sediment and porewater analyses indicate a distinct sulphate–methane transition zone (SMTZ) between 60 and 80 cm where sulphate is depleted (to <1.7 mM) and methane increases (to >0.4 mM). The top of the acoustic turbidity (the gas front) at 80 cm corresponds to the lower limit of the SMTZ. The methane cannot have been derived from the underlying metamorphic and granitic rocks, but was probably derived by microbial degradation of the organic matter in the Holocene sediments. We estimate that the sediments of the Bay contain approximately 1.8 × 106 m3 of organic carbon and 275 ton of methane. [ABSTRACT FROM AUTHOR]

The aim of this work was to evaluate the ability of a line selected for reproductive longevity (LP) to confront productive challenges compared to a line selected during 31 generations for litter size at weaning (V). A total of 133 reproductive rabbit does were used (72 and 61 from LP and V lines, respectively). Within each line, three groups with different levels of productive effort were planned: PP9, inseminated at day 4 after the first partum and with nine kits during the second partum, and inseminated after first weaning (30 days) and with nine (PW9) or five kits (PW5) during the second partum. The reproductive performance, body condition (perirrenal fat thickness (PFT)) and lipolytic response were controlled. LP does showed greater mean live weight (LW; +128 g; P < 0.05), PFT (+0.47 mm; P < 0.05) and estimated body energy (EBE; +0.29 MJ/kg; P < 0.01) than V does at second partum. However, LP does that mated at first post partum did not significantly differ in EBE relative to V does at second partum. During the first week of lactation, dry matter (DM) intake was similar for both lines (94 and 95 g DM/kg LW0.75 day for V and LP does, respectively). There was a significant difference in milk yield between both lines during the first week when litter size was nine (60 v. 54 g of milk/kg LW0.75 day for LP and V does, respectively; P < 0.01), but no difference when litter size was five. Consequently, when litter size was nine, LP does showed a lower recovery of PFT (0.6 mm less; P < 0.05) than V does during the first 10 days of lactation. However, when litter size was five, LP does showed a higher LW (+210 g; P < 0.05) than V does at 10 days of lactation and a similar recovery of PFT. During the last 3 weeks of the lactation, LP does showed a higher feed intake (+6 g DM/kg LW0.75 day; P < 0.05) and milk yield (+27 g/day; P < 0.001) than V does when litter size was nine, resulting in no significant differences in LW at 30 days of lactation. However, when litter size was five, both lines showed similar feed intake and milk yield, maintaining their differences in LW at 30 days of lactation (+206 g for LP does; P < 0.05). These results show that the rabbit line selected for reproductive longevity is more robust with respect to coping with productive challenges, than a line selected for reproductive intensity. [ABSTRACT FROM AUTHOR]

Pulse-treatment of U-937 human promonocytic cells with cadmium chloride followed by recovery caused caspase-9/caspase-3-dependent, caspase-8-independent apoptosis. However, pre-incubation with the glutathione (GSH)-suppressing agent DL-buthionine-( S,R)-sulfoximine (cadmium/BSO), or co-treatment with H2O2 (cadmium/H2O2), switched the mode of death to caspase-independent necrosis. The switch from apoptosis to necrosis did not involve gross alterations in Apaf-1 and pro-caspase-9 expression, nor inhibition of cytochrome c release from mitochondria. However, cadmium/H2O2-induced necrosis involved ATP depletion and was prevented by 3-aminobenzamide, while cadmium/BSO-induced necrosis was ATP independent. Pre-incubation with BSO increased the intracellular cadmium accumulation, while co-treatment with H2O2 did not. Both treatments caused intracellular peroxide over-accumulation and disruption of mitochondrial transmembrane potential (ΔΨ m). However, while post-treatment with N-acetyl-L-cysteine or butylated hydroxyanisole reduced the cadmium/BSO-mediated necrosis and ΔΨ m disruption, it did not reduce the effects of cadmium/H2O2. Bcl-2 over-expression, which reduced peroxide accumulation without affecting the intracellular GSH content, attenuated necrosis generation by cadmium/H2O2 but not by cadmium/BSO. By contrast, AIF suppression, which reduced peroxide accumulation and increased the GSH content, attenuated the toxicity of both treatments. These results unravel the existence of two different oxidation-mediated necrotic pathways in cadmium-treated cells, one of them resulting from ATP-dependent apoptosis blockade, and the other involving the concurrence of multiple regulatory factors. [ABSTRACT FROM AUTHOR]

Along with the shift from a planned to market-oriented economy, as in many other developing countries, Lao PDR has promoted health care partnerships with the private sector, and cost recovery in public hospitals, to increase resources in the public sector, while at the same time attempting to ensure appropriate access to health care for those without means to pay. In a multi-case design, this study compares two neighbourhoods of different socioeconomic status comprising 10 households, representing urban districts in three provinces. In-depth interviews were conducted over a 1-year period with three visits to each household. Members of the households were interviewed on their perceptions and utilization of health care services. Focus group discussions of public providers and individual interviews of private providers, leaders of the villages and hospital administrators provided complementary perspectives. The study found that both socioeconomic groups utilized private health services as their first choice, including private clinics and treatment abroad for those with high socioeconomic status, while the low socioeconomic group preferred private pharmacies. The unwelcoming attitudes of health staff and procedural barriers have led both groups to meet their health care needs in the private sector. Here the health care they receive is strictly limited to what they can pay for. For the poor, in most cases, this means drugs alone, i.e. no examination, no diagnosis and only limited advice. Limited financial resources often means receiving inappropriate and insufficient medication. Equity in health care remains theoretical rather than practical and the social goals of the reform have not been achieved. [ABSTRACT FROM PUBLISHER]

Transverse and axial tubules (TATS) are an essential ingredient of the excitation-contraction machinery that allow the effective coupling of L-type Calcium Channels (LCC) and ryanodine receptors (RyR2). They form a regular network in ventricular cells, while their presence in atrial myocytes is variable regionally and among animal species We have studied the effect of variations in the TAT network using a bidomain computational model of an atrial myocyte with variable density of tubules. At each z-line the t-tubule length is obtained from an exponential distribution, with a given mean penetration length. This gives rise to a distribution of t-tubules in the cell that is characterized by the fractional area (F.A.) occupied by the t-tubules. To obtain consistent results, we average over different realizations of the same mean penetration length. To this, in some simulations we add the effect of a network of axial tubules. Then we study global properties of calcium signaling, as well as regional heterogeneities and local properties of sparks and RyR2 openings. In agreement with recent experiments in detubulated ventricular and atrial cells, we find that detubulation reduces the calcium transient and synchronization in release. However, it does not affect sarcoplasmic reticulum (SR) load, so the decrease in SR calcium release is due to regional differences in Ca2+ release, that is restricted to the cell periphery in detubulated cells. Despite the decrease in release, the release gain is larger in detubulated cells, due to recruitment of orphaned RyR2s, i.e, those that are not confronting a cluster of LCCs. This probably provides a safeguard mechanism, allowing physiological values to be maintained upon small changes in the t-tubule density. Finally, we do not find any relevant change in spark properties between tubulated and detubulated cells, suggesting that the differences found in experiments could be due to differential properties of the RyR2s in the membrane and in the t-tubules, not incorporated in the present model. This work will help understand the effect of detubulation, that has been shown to occur in disease conditions such as heart failure (HF) in ventricular cells, or atrial fibrillation (AF) in atrial cells.

The study was undertaken to assess the impact of health sector reform from 1993 to 1997 in Zambia in respect of health care service utilization and the shift of caseload from hospitals to health centres. Four key indicators were chosen: general attendance, measles vaccinations, general admissions, and deliveries. Complete sets of district data were analyzed, covering 4.5 million people out of the total population in 1997 of 9.7 million. The results show, on the one hand, a dramatic decrease of about one-third in general attendance for both hospitals and health centres over a 2-year period, followed by a period with a continued but slower decrease. On the other hand, the results also show increases at health centres in measles vaccinations (up 40%), in admissions (up 25%) and in deliveries (up 60%). The study further documents a shift of caseload from hospitals to health centres for some key services. The health centre share increased from 72.2% to 79.8% for measles vaccinations, from 23.9% to 31.0% for general admissions, and from 22.9% to 32.4% for deliveries. However, the intended overall shift in outpatient caseload from hospitals to health centres did not materialize. The main lessons are: utilization patterns can be influenced by policies such as user-payment and decentralization; user payment in poor populations leads to dramatic declines in utilization of services; and decentralization with local control of resources could be an alternative to the traditional vertical disease programme approach for priority interventions. [ABSTRACT FROM AUTHOR]

A policy of allowing public hospitals to provide some better quality, higher priced hospital beds for those able to pay was introduced as government policy in Indonesia after 1993. A study was conducted in 1998 in three public hospitals in East Java to investigate if the policy objective of cost-recovery was being achieved. Hospital revenue from these commercial beds was less than both the recurrent and total costs of providing them in all three hospitals, but exceeded recurrent costs minus staff salaries in two hospitals. One reason for the low cost-recovery ratios was that between 55% and 66% of the revenue was used as staff incentives, mostly to doctors. This was more than the maximum of 40% stipulated in the policy. The high proportions of total revenue going to staff were a result of hospital management having set bed fees too low. The policy may be contributing to the retention of doctors within public sector employment; however, it is not achieving its stated objective, especially over the longer term where full recovery of salaries and investment costs needs to be considered. Public hospitals that wish to invest in commercial beds need effective management and accounting systems so as to be able to monitor and control costs and set fees at levels that recoup the costs incurred. Further research is required to determine if this form of public-private mix has negative effects on equity and access for poorer patients. [ABSTRACT FROM AUTHOR]

Zambia underwent a period of health sector reform from 1993 to 1998. The reform attracted substantial support from the World Bank and bilateral donors. While significant achievements were made with respect to decentralization, increased accountability and donor collaboration, the reform stalled in 1998 without having achieved its objectives, largely because of the handling of hospital reform and the civil servants in the health sector. This study was an attempt to analyze this experience with the hospital issue. Service and infrastructure information was collected from all 88 hospitals in the country. Further, information was collected about the social, economic, and political context of the reform. The results show that an historical legacy from the colonial and post-colonial eras has left the country with an expensive and skewed hospital structure that is rapidly deteriorating and very difficult to reform. The referral system is not functioning: higher-level hospitals provide a higher level of care to their immediate catchment populations than is available to the population in general. The reality is thus far from the vision of equity of access to cost-effective quality care. Zambian doctors have either left the country or are concentrated at the highest referral levels in two provinces, leaving the lower levels and most of the country in the hands of expatriate doctors. There are no resources in the government or the private systems to maintain the current hospital infrastructure and things will likely deteriorate unless radical decisions are taken and implemented. The study further shows that the question of hospital reform is a political high-risk zone. If the problems are to be dealt with, the Zambian planners must, together with the politicians, work to create a broad national consensus for understanding the situation, its urgency, and the limited options for forward action. [ABSTRACT FROM AUTHOR]

The globalization of the economy is the pillar that triggered the implementation of accounting standards and assurance of financial information worldwide acceptance in Colombia, who in order to begin the process of convergence, had to amend its legislation, issuing mandatory standards, which means a challenge for accountants, especially those working as revisor fiscal.This article is descriptive, its analysis was based on data collection through surveys and the methodology used is the literatu-re review. The population on which it has made the study make all public accountants in Colombia and the sample consists of five professionals of this union who serve as Revisores fiscales.To develop the work one resorted to secondary, such sources as: books , theses and related normativities focused on the exercise of statutory audit and ISAs (International Standards on Auditing) and also went to primary sources, such as surveys, documents: to develop the work to secondary sources such as was used which they underwent an exploratory data analysis that allowed achieve the objective, which was to describe the impact of the mandatory implementation of the new regulatory framework in the performance audit of the Revisores fiscales in Colombia.With the results obtained in this research, we can conclude that the Revisoría Fiscal as generating public confidence figure, should be prepared and trained to meet the requirements, as there will be major changes that will impact the exercise of their profession.

The presence of antibodies in rheumatoid arthritis (RA) patients lo antigens on the synoviocyte surface has recently been reported (Scand. J. Immunol. 27, 295, 1988). Here we have further characterized these antigens and found that they are exogenous proteins acquired from the bovine serum used in the culture medium. By immunoprecipitation and ELISA studies, we have identified bovine albumin and transferrin as the antigens recognized by the RA antibodies, These specificities were found not only in the sera but also in the synovial fluid from RA patients. A comparative study with a large panel of RA sera did not show a correlation in the antibody specificities for bovine albumin, bovine transferrin, or the 65-kDa heat shock protein from Mycobacterium bovis. Similar experiments using rabbit and monkey sera as well as human synovial fluid and serum as a source of antigen did not reveal any reactivity with a highly positive RA scrum. By sequence alignment, a high degree of homology between residues 142-156 from bovine albumin and residues 65-78 from human pro-collagen α 1 (I) was found. The capacity of the synoviocytes to bind exogenous antigens and the presence of antibodies lo bovine proteins, normally present in the diet, suggest a role for these type A synoviocytes as well as a possible involvement of food antigens in the pathogenesis of RA. [ABSTRACT FROM AUTHOR]

In cardiac cells, calcium is the mediator of excitation-contraction coupling. Dysfunctions in calcium handling have been identified as the origin of some cardiac arrhythmias. In the particular case of atrial myocytes, recent available experimental data has found links between these dysfunctions and structural changes in the calcium handling machinery (ryanodine cluster size and distribution, t-tubular network, etc). To address this issue, we have developed a computational model of an atrial myocyte that takes into account the detailed intracellular structure. The homogenized macroscopic behavior is described with a two-concentration field model, using effective diffusion coefficients of calcium in the sarcoplasmic reticulum (SR) and in the cytoplasm. The model reproduces the right calcium transients and dependence with pacing frequency. Under basal conditions, the calcium rise is mostly restricted to the periphery of the cell, with a large concentration ratio between the periphery and the interior. We have then studied the dependence of the speed of the calcium wave on cytosolic and SR diffusion coefficients, finding an almost linear relation with the former, in agreement with a diffusive and fire mechanism of propagation, and little dependence on the latter. Finally, we have studied the effect of a change in RyR cluster microstructure. We find that, under resting conditions, the spark frequency decreases slightly with RyR cluster spatial dispersion, but markedly increases when the RyRs are distributed in clusters of larger size, stressing the importance of RyR cluster organization to understand atrial arrhythmias, as recent experimental results suggest (Macquaide et al., 2015).