Can arterial elasticity be estimated from heart rate variability response to paced 0.066 Hz sighing?

Arterial elasticity is an important indicator of risk for cardiovascular disease (CVD). It is influenced by both gradual vessel wall damage due to aging and disease and vascular tone that responds, at the moment, to system loading. Measuring changes in arterial elasticity are critical to early detection of CVD but can be time and resource intensive. This study proposes and tests a new method to approximate arterial elasticity from heart rate variability (HRV). ECG and pulse were simultaneously recording in 71 young healthy adults during three rhythmical sighing tasks paced at 0.02, 0.033, and 0.066 Hz. We evaluated arterial elasticity by measuring the reaction of pulse transit time (PTT) and RRI to each task specifically at the pacing frequency. The goal of the study was to describe our method, ground the methodology in current theory and mechanisms, and scientifically justify and validate this method by assessing differences in arterial elasticity in groups of healthy adults who differed in drinking behaviors. The amplitude PTT and HR oscillation responses at the pacing frequency were significantly correlated only when sighing was paced at 0.066 Hz. Both amplitudes also significantly correlated with power in the very low-frequency range of the baseline HRV spectrum. Abnormalities in these measures were observed among binge drinking healthy adults compared to non-drinkers and social drinkers. These preliminary results support using the HRV response to paced 0.066 Hz sighing as a correlate of arterial elasticity and warrant further study.     

Can the prognosis of multiple sclerosis be predicted?

Though the global course of the disease is well known when considering large cohorts of patients, it is rather difficult to make a prognosis for a given patient. It is essential however to predict the course of the disease as early as possible in order to be able to give the patient the right treatment at the right time. Age at disease onset is one of the most important clinical predictive factors, as this has been proved by various analyses. The earlier the disease onset, the better the prognosis. The inaugural symptom of optic neuritis, the long interval between the first two relapses, a remitting form at onset are predictive factors of a good evolution. A normal brain magnetic resonance imaging performed on the occasion of a first isolated sign of the central nervous system is the marker of a good prognosis. Conversely, the presence of oligoclonal bands in the cerebrospinal fluid and the increase of IgG index increase the risk of occurrence of a second relapse. The new techniques of magnetic resonance imaging and the exhaustive initial clinical examination using several classifications of disability will allow a better prognosis for a given patient.     

Can echocardiographically estimated pulmonary arterial elastance be a non-invasive predictor of pulmonary vascular resistance?

Introduction

Measurement of pulmonary vascular resistance (PVR) is essential in evaluating a patient with pulmonary hypertension.

Material and methods

Data from right heart catheterization (RHC) and echocardiograms performed within 90 days of each other on 45 non-consecutive adult patients were reviewed in this retrospective study. Patients were recruited using an assortment of strategies to ensure the presence of patients with a wide range of PVR.

Results

The linear regression equation between RHC-derived PVR and echocardiographic pulmonary arterial elastance (PAE) was: PVR = (562.6 × PAE) – 38.9 (R = 0.56, p < 0.0001). An adjustment for echocardiographic PAE was made by multiplying it by hemoglobin (in g/dl) and (right atrial area)^1.5 (in cm³). As RHC-derived PVR varies with blood hemoglobin, an adjustment for PVR was made for hemoglobin of 12 g/dl. Visualization of the XY scatter plot of adjusted PVR and adjusted PAE isolated a subset of patients with PVR higher than 8.8 Wood units, where a strong linear relationship existed (adjusted PVR = (0.89 × adjusted PAE) + 137.4, R = 0.89, p = 0.008).

Conclusions

The correlation coefficient of the regression equation connecting echocardiographic PAE and RHC-derived PVR was moderate. In a subset of patients with very high PVR and after appropriate adjustment, a strong linear relationship existed with an excellent correlation coefficient.     

Can the sex of the second child be predicted by the birth-weight of the first child?

The reproduction costs to a human mother are different if she has a son as opposed to a daughter. According to the Trivers-Willard hypothesis, evolution should promote those females who, having the ability to invest in the more expensive sex, are also able to adjust the sex of their offspring accordingly. It is therefore possible that a mother's biological condition (which is also connected with her reproductive potential), as measured by the neonatal weight of her first child, can be a good predictor of the second child's sex. From data for 227 healthy mothers from Wroclaw (Poland) we show that the probability of giving birth to a boy in the second pregnancy is higher after a relatively heavier first-born child (ANOVA, F(1,225)=3.79, P<0.053). This relationship, however, is only significant after a first-born daughter (F(1,117)=9.66, P<0.002) and not after a first-born boy. Some possible explanations of the fact that only the birth-weight of a first-born daughter--and not a son--can be a good predictor of the secondary sex ratio are also discussed.     

Can the whole be less than the sum of its parts? Pathway analysis in genome-scale metabolic networks using elementary flux patterns

Elementary modes represent a valuable concept in the analysis of metabolic reaction networks. However, they can only be computed in medium-size systems, preventing application to genome-scale metabolic models. In consequence, the analysis is usually constrained to a specific part of the known metabolism, and the remaining system is modeled using abstractions like exchange fluxes and external species. As we show by the analysis of a model of the central metabolism of Escherichia coli that has been previously analyzed using elementary modes, the choice of these abstractions heavily impacts the pathways that are detected, and the results are biased by the knowledge of the metabolic capabilities of the network by the user. In order to circumvent these problems, we introduce the concept of elementary flux patterns, which explicitly takes into account possible steady-state fluxes through a genome-scale metabolic network when analyzing pathways through a subsystem. By being similar to elementary mode analysis, our concept now allows for the application of many elementary-mode-based tools to genome-scale metabolic networks. We present an algorithm to compute elementary flux patterns and analyze a model of the tricarboxylic acid cycle and adjacent reactions in E. coli. Thus, we detect several pathways that can be used as alternative routes to some central metabolic pathways. Finally, we give an outlook on further applications like the computation of minimal media, the development of knockout strategies, and the analysis of combined genome-scale networks.In functional genomics and metabolic engineering, metabolic pathway analysis has proved to be a very useful methodology (Carlson et al. 2002; Schwender et al. 2004; Feist and Palsson 2008; Trinh et al. 2009). Elementary modes (Schuster et al. 2000) are a central concept in this field. An elementary mode represents a minimal set of reactions that can operate at steady state with all reactions proceeding in their appropriate direction (Schuster et al. 2000) and, hence, can be considered as a formal definition of a metabolic pathway. Elementary modes have been used in many areas of biotechnology, such as assessing network flexibility (Stelling et al. 2002), finding pathways with optimal yields for certain metabolic species (Schuster et al. 2002a; Krömer et al. 2006), finding possible targets for the engineering of metabolic networks (Klamt 2006), and analyzing the effect of such an engineering (Carlson et al. 2002; Schwender et al. 2004). Due to the growing availability of genome-scale metabolic networks (Duarte et al. 2004, 2007; Borodina and Nielsen 2005; Thiele et al. 2005; Feist et al. 2006, 2007; Jamshidi and Palsson 2007; Oh et al. 2007) and the comprehensive analysis conducted on them (for review, see Feist and Palsson 2008), it becomes desirable to apply elementary mode analysis in such networks.However, the principal problem encountered when trying to compute elementary modes in larger metabolic networks is that their number is growing exponentially with network size (Klamt and Stelling 2002; Schuster et al. 2002b; Acuña et al. 2009). Thus, they become difficult to analyze or even impossible to enumerate because of constraints in memory or computation time. Although there have been recent efforts to port the algorithms for the computation of elementary modes to larger networks by means of parallelization (Klamt et al. 2005) or improvements of the existing algorithms (von Kamp and Schuster 2006; Terzer and Stelling 2008), none of these algorithms permits the analysis of elementary modes in genome-scale metabolic networks.In consequence, elementary mode analysis is applied to smaller networks containing reactions of interest rather than the entire known system. The remainder of the system is modeled using abstractions like exchange fluxes and external metabolites. Exchange fluxes correspond to the production or consumption of a species by a large set of reactions of the remaining model. External species, in contrast, are considered to be buffered by reactions of the complete system. Hence, they are excluded from the steady-state condition. However, as we show in this study, there are three important drawbacks involved in the introduction of such abstractions (cf. Liebermeister et al. 2005).First, the approach is usually biased by the modeler''s knowledge of the network. For instance, glycolysis and pentose phosphate pathways are usually considered the principal routes for the supply of metabolites from glucose in the growth media to the tricarboxylic acid (TCA) cycle. Thus, the Entner–Doudoroff pathway—which represents an alternative route for the production of pyruvate in several bacteria—is often ignored even though it is of importance in some conditions (Fischer and Sauer 2003; Li et al. 2006). In consequence, some of the possible pathways of a large network through a subnetwork are not found by elementary mode analysis (Fig. 1A). Second, the aforementioned abstractions might not be able to take into account the dependencies between the production and consumption of metabolites that constitute the interface of the subnetwork to the remaining system. This can give rise to elementary modes that obey the steady-state condition within the subnetwork but are not part of any steady-state flux through the entire network (Fig. 1B,C). Third, by only focusing on a small part of the known network, the integration of a pathway through this subnetwork into a pathway on the scale of the entire system is not straightforward, and the interdependencies between the pathways of several subsystems cannot be analyzed (Fig. 1D).Open in a separate windowFigure 1.Examples for problems in elementary mode analysis. (A) Condensed network of glycolysis (dark reactions) and Entner–Doudoroff pathway (gray reactions). The pentose phosphate pathway has been omitted for clarity. In most analyses of glycolysis, the Entner–Doudoroff pathway is not considered. Hence, not all pathways from glucose into the TCA cycle are found, and the wrong conclusion might be drawn that only the pentose–phosphate pathway (not shown) can be used to bypass the knockout of one of the enzymes converting G6P to FDP. In vivo the knockout of the corresponding reactions is partially bypassed by a flux through the Entner–Doudoroff pathway (Fischer and Sauer 2003). (B) Modeling the Entner–Doudoroff pathway by adding an outflow of G6P and an inflow of G3P and Pyr only partially resolves the problem (thick arrows). Such an approach is often used in elementary mode analysis to avoid the consideration of some pathways in detail (e.g., the outflow of succinyl-CoA from the TCA cycle in Schuster et al. 1999, analyzed in Results). However, this can lead to fluxes like in C, which are not part of any feasible pathway when the entire network in A is considered. This is because the coupling of the influx of Pyr with the outflow reactions of G6P and the inflow reaction of G3P are neglected in B. (D) Elementary mode analysis does not allow one to analyze the dependencies between the subsystems S₁ and S₂ unless the reactions connecting them are taken into account. Thus, it is not possible to deduce that a zero flux from G6P to FDP in S₁ would imply that there cannot be a positive flux from DHAP to G3P in S₂. A list of abbreviations can be found in Supplemental material S2.The concept of “elementary flux patterns” that we introduce in this study circumvents these problems by taking into account the possible fluxes through the entire network, when analyzing the steady-state fluxes through a subnetwork. An elementary flux pattern is defined as a set of reactions within a subsystem of a larger network that represents the basic routes of each steady-state flux of the larger network through the subnetwork. Thus, flux modes in a subsystem can be determined that are feasible in the context of the entire genome-scale system. Through their definition, elementary flux patterns allow a consistent application of concepts from elementary mode analysis to genome-scale metabolic networks without the drawbacks that arise by the definition of external species or exchange fluxes. Furthermore, each elementary flux pattern can be mapped to at least one elementary mode in the complete system, even allowing the user to analyze pathways on the genome scale.This article is sectioned into three main parts. First, we will introduce elementary flux patterns and an algorithm to compute them. Subsequently, we apply this concept to a genome-scale metabolic network of Escherichia coli. Then we discuss our results and give an outlook on further applications of elementary flux patterns.     

Can Lupus Flares be Associated with Tuberculosis Infection?

Systemic lupus erythematosus (SLE) is an autoimmune disease that frequently requires treatment with high doses of corticosteroids and immunosuppressive drugs. Primary defects in the innate immunity also contribute to an increased susceptibility to infections. Patients with SLE are at an increased risk for infections with several pathogens, among them Mycobacterium tuberculosis, which is a significant cause of morbidity and mortality, especially in endemic regions. TB infection requires awareness for several reasons: first, TB infection thrives under conditions of immunosuppression, may it be secondary to the disease itself or its treatment. Second, shared antigens by mycobacteria and autoantigens have been described, which may be targets for autoantibodies. We present four Brazilian patients, in whom a diagnosis of tuberculosis was determined during or following persistent flares of their disease. The association of SLE and TB is discussed, as well as different aspects of the tuberculosis infection in this selected population, and its possible role in the course of SLE.     

Can interventional ablation be applied to the treatment of arterial aneurysm?

Interventional therapy is commonly applied to the treatment of arterial aneurysm. Thermal ablation features rapid and minimal invasive treatment. A hypothesis of combining these two techniques was proposed to treat arterial aneurysm. An antenna is delivered with a catheter into the aneurysm sac and heated with microwave or RF, and hence induces instant coagulation and thrombosis of blood flow in the aneurysm sac so that the treatment motivation is achieved. The initiation of this hypothesis is to overcome the disadvantages of biological/mechanical mismatch between the interventional devices and the arteries in the interventional therapy, also utilize the advantages of rapid treatment and minimal invasion in the thermal ablation procedure.     

Can a good short form of the MMPI ever be developed?

At least seven short forms of the MMPI have been proposed in the last 15 years. In each case, the initial enthusiasm has been replaced by questions about the clinical utility of the abbreviated version. It is argued that the statistical properties of the test (high intercorrelations among scales) and reduced reliability due to shortening the scales always will produce these poor results. Our efforts would be better spent in developing new tests rather than attempting to validate new versions of a dated instrument.     

Can the contra-lateral limb be used as a control with respect to analyses of bone remodelling?

Bone loss may result from remodelling initiated by implant stress protection. Quantifying remodelling requires bone density distributions which can be obtained from computed tomography scans. Pre-operative scans of large animals however are rarely possible. This study aimed to determine if the contra-lateral bone is a suitable control for the purpose of quantifying bone remodelling. CT scans of 8 pairs of ovine tibia were used to determine the likeness of left and right bones. The deviation between the outer surfaces of the bone pairs was used to quantify geometric similarity. The density differences were determined by dividing the bones into discrete volumes along the shaft of the tibia. Density differences were also determined for fractured and contra-lateral bone pairs to determine the magnitude of implant related remodelling. Left and right ovine tibiae were found to have a high degree of similarity with differences of less than 1.0 mm in the outer surface deviation and density difference of less than 5% in over 90% of the shaft region. The density differences (10–40%) as a result of implant related bone remodelling were greater than left-right differences. Therefore, for the purpose of quantifying bone remodelling in sheep, the contra-lateral tibia may be considered an alternative to a pre-operative control.     

Can synchronous cultures of bacteria be manufactured?

The bacterial cell cycle is simpler and different than that of the typical eukaryotic cell cycle. The selective pressure during evolution has been directed to achieve optimal growth of the individual free-living microbial cell instead of a variety of replication rates of the differentiated cell within an entire multicellular organism. This means that for most bacterial cells division depends more critically on their success in acquiring and using resources than is the case for most eukaryotic cells. The further implication is that bacterial cells somehow measure their own success in growth and from this 'decide' when they should attempt cell cycle events such as cell division and chromosome replication. On the assumption that bacterial division is responsive, directly or indirectly, to cell size, the cell cycle is analyzed here through Monte Carlo simulations. The results are used to consider the possibility of generating bacterial cultures growing synchronous. Because the precision of the size-at-division is surprisingly good, it appears that some organisms, at least, have a sensory mechanism that responds to their success in cell growth. It is known that the division size of some strains, however, is more precisely regulated than in others. Also, some strains are more precise in dividing the mother's cell cytoplasm to give the same sized daughters. Because some strains are much more precise than others, the possibility is raised that useful synchrony could be obtained with selected strains that are precise in these two aspects. These cultures would useful in studying other aspect of the physiology of cell growth.     

Can morphotaxa be assessed with photographs? Estimating the accuracy of two-dimensional cranial geometric morphometrics for the study of threatened populations of African monkeys

The classification of most mammalian orders and families is under debate and the number of species is likely greater than currently recognized. Improving taxonomic knowledge is crucial, as biodiversity is in rapid decline. Morphology is a source of taxonomic knowledge, and geometric morphometrics applied to two dimensional (2D) photographs of anatomical structures is commonly employed for quantifying differences within and among lineages. Photographs are informative, easy to obtain, and low cost. 2D analyses, however, introduce a large source of measurement error when applied to crania and other highly three dimensional (3D) structures. To explore the potential of 2D analyses for assessing taxonomic diversity, we use patas monkeys (Erythrocebus), a genus of large, semi-terrestrial, African guenons, as a case study. By applying a range of tests to compare ventral views of adult crania measured both in 2D and 3D, we show that, despite inaccuracies accounting for up to one-fourth of individual shape differences, results in 2D almost perfectly mirror those in 3D. This apparent paradox might be explained by the small strength of covariation in the component of shape variance related to measurement error. A rigorous standardization of photographic settings and the choice of almost coplanar landmarks are likely to further improve the correspondence of 2D to 3D shapes. 2D geometric morphometrics is, thus, appropriate for taxonomic comparisons of patas ventral crania. Although it is too early to generalize, our results corroborate similar findings from previous research in mammals, and suggest that 2D shape analyses are an effective heuristic tool for morphological investigation of small differences.     

Can cognitive deterioration associated with Down syndrome be reduced?

Individuals with Down syndrome have signs of possible brain damage prior to birth. In addition to slowed and reduced mental development, they are much more likely to have cognitive deterioration and develop dementia at an earlier age than individuals without Down syndrome. Some of the cognitive impairments are likely due to post-natal hydrogen peroxide-mediated oxidative stress caused by overexpression of the superoxide dismutase (SOD-1) gene, which is located on the triplicated 21st chromosome and known to be 50% overexpressed. However, some of this disability may also be due to early accumulation of advanced protein glycation end-products, which may play an adverse role in prenatal and postnatal brain development. This paper suggests that essential nutrients such as folate, vitamin B6, vitamin C, vitamin E, selenium, and zinc, as well as alpha-lipoic acid and carnosine may possibly be partially preventive. Acetyl-L-carnitine, aminoguanidine, cysteine, and N-acetylcysteine are also discussed, but have possible safety concerns for this population. This paper hypothesizes that nutritional factors begun prenatally, in early infancy, or later may prevent or delay the onset of dementia in the Down syndrome population. Further examination of these data may provide insights into nutritional, metabolic and pharmacological treatments for dementias of many kinds. As the Down syndrome population may be the largest identifiable group at increased risk for developing dementia, clinical research to verify the possible validity of the prophylactic use of anti-glycation nutrients should be performed. Such research might also help those with glycation complications associated with diabetes or Alzheimer's.