Antenatal care (ANC) presents important opportunities to reach women with crucial interventions. Studies on determinants of ANC use often focus on household and individual factors; few investigate the role of health service factors, partly due to lack of appropriate data. We assessed how distance to facilities and level of service provision at ANC facilities in Zambia influenced the number and timing of ANC visits and the quality of care received.Using the 2005 Zambian national Health Facility Census, we classified ANC facilities according to the level of service provision. In a geographic information system, we linked the facility information to household data from the 2007 DHS to calculate straight-line distances. We performed multivariable multilevel logistic regression on 2405 rural births to investigate the influence of distance to care and of level of provision on three aspects of ANC use: attendance of at least four visits, visit in first trimester and receipt of quality ANC .We found no effect of distance on timing of ANC or number of visits, and better level of provision at the closest facility was not associated with either earlier ANC attendance or higher number of visits. However, there was a strong influence of both distance to a facility, and level of provision at the closest ANC facility on the quality of ANC received; for each 10 km increase in distance, the odds of women receiving good quality ANC decreased by a quarter, while each increase in the level of provision category of the closest facility was associated with a 54% increase in the odds of receiving good quality ANC.To improve ANC quality received by mothers, efforts should focus on improving the level of services provided at ANC facilities and their accessibility. Even though significant progress has been made in reducing maternal deaths globally since the 1990s Childbirth is the time when most deaths occur, and thus increased attention has been paid to intrapartum care in recent years. Antenatal care (ANC), while not sufficient to reduce maternal mortality on its own, still presents an important opportunity to reach women with a number of interventions crucial for their health and that of their babies Zambia has adopted the focused ANC strategy recommended by WHO. The proportion of pregnant women in Zambia who attend ANC at least once with a skilled provider stands impressively high at 94%, while 74% attend at least the recommended four antenatal visits Studies of the determinants of ANC use focus mostly on individual and household factors. According to a recent systematic review, only one  study One explanation for the scarcity of studies considering the role of the health service environment in determining service use is the lack of information on the level of service provision at health facilities in existing population survey datasets We used this approach of linking user and provider datasets to quantify the influence of distance and level of service provision at facilities on ANC use and on quality of ANC received in rural Zambia, taking other important individual-, household-, and community-level determinants into account. The specific objectives of this study were to assess (1) how distance to an ANC facility influences number and timing of women's ANC visits; (2) how level of service provision at the ANC facility influences number and timing of women's ANC visits; (3) how distance to care and level of service provision at the closest ANC facility influence the quality of care received by women.The 2007 Zambia Demographic and Health Survey (DHS) was a nationally representative household cluster survey that interviewed 7,146 women aged 15–49 years The 2005 Zambia Health Facility Census (HFC) The exposure variables of interest are distance to the closest facility providing ANC and level of service provision at the closest facility or within 10 km thereof. Straight-line distances in meters from each DHS cluster to the closest ANC facility of a given level of provision were calculated in the GIS platform ArcView 3.2 (ESRI) using the user-written extension “Nearest Neighbor 3.6”.For our classification of health facilities according to their level of service provision, we were guided by Donabedian's framework on quality of care assessment Based on the recommended interventions for pregnancy care We explored the effect of distance and level of provision on three binary outcome variables obtained from the DHS: (1) attendance of at least the four recommended ANC visits; (2) ANC visit in the first trimester and (3) receipt of “good quality ANC”. Having received good quality ANC was defined as attending at least four ANC visits with a skilled health worker and receiving more than eight of the eleven following antenatal interventions We performed frequency tabulations to describe outcome and exposure variables in the rural DHS subsample and compared the rural with the urban subsample. Crude measures of association of distance and level of provision with the three binary outcome variables were computed, using two-level random effects logistic regression models to account for clustering at the village level. Similarly, crude measures of association for all important potential confounding variables with the outcomes were computed. Variables that showed an association with the outcome  and were not considered to be on the causal pathway were added to the models containing both distance to the closest ANC facility and the highest ANC quality available at that distance or 10 km thereof, thus evaluating both distance and level of provision simultaneously and adjusting for each other. We used a forward-fitting approach, including mother's education and household wealth as a priori confounders and adding the other variables in the order of the strength of their separate confounding effects. Variables that caused at least a 10% change in the logOR of distance or quality were considered to be confounders and kept in the model. Three models were built, one for each of the three binary outcome variables. All statistical analysis was done using Stata version 11.All urban mothers had access to an ANC facility within 15 km and the majority (57%) had access to an ANC facility offering an optimum level of service within this distance. In contrast, 88% of rural mothers lived within 15 km of an ANC facility and only 9% had access to a facility with an optimum level of provision within this distance ; indicatThe cumulative distribution of distances to facilities offering various levels of ANC for rural mothers in Zambia is shown in While 1461 of 2405 rural mothers (61%) attended the recommended four or more visits, only 505 (21%) also received good quality ANC; i.e. attended four or more visits with a skilled health professional and received eight or more important antenatal interventions. Only 414 rural mothers (17%) attended ANC in the first trimester of pregnancy.Distance to care did not seem to significantly influence whether a mother had her first antenatal visit in the first trimester or later in either the crude or the adjusted models. By contrast, in the crude model of the effect of level of provision on ANC use in the first trimester, better level of provision at the nearest facility was associated with 26% decreased odds of attending ANC in the first trimester. This surprising association was diminished by adjusting for ethnic group and for women's media use in the cluster and there was only weak evidence for a 23% decrease in odds in the multivariable model. In the crude (bivariable) model, we found that the odds of attending the recommended four or more ANC visits reduced by about 20% for each 10 km increase in distance. Adjusting for the mother's individual fertility attitudes, her household wealth, and women's health-care seeking autonomy in the cluster and men's opinion on women's autonomy in the cluster weakened this effect, and there was no evidence that distance decreased the odds of having four or more ANC visits in the multivariable model. There was no evidence that the level of service provision at the closest ANC facility increased the odds of a mother attending the recommended minimum four antenatal visits. There was evidence for an effect of distance to the closest facility on the quality of ANC received by a mother: In the final model, adjusted for all confounders at individual, household and cluster level, the odds of a woman receiving good quality ANC (at least four visits with a skilled provider and at least eight interventions) decreased by a quarter (24%) for each 10 km increase in distance. Level of service provision at the closest ANC facility  also strongly influenced whether the mother received good quality ANC (i.e. had at least four visits with a skilled provider and received at least eight interventions). For each category improvement in the level of ANC provision at the closest facility, there was a 54% increase in the odds of receiving good quality ANC in the adjusted model. Linking data from a national health facility census with data from a national household survey in a geographic information system allowed us to analyze and quantify the relationship between the level of service provision at a facility and women's ANC use, while considering various quality dimensions. We furthermore quantified the influence of distance on ANC use, adjusting for a wide range of confounders, and we studied three different ANC use outcomes .Our study showed that most rural women in Zambia lived far away from facilities providing an optimum level of service, and that both farther distance to and level of provision at the closest ANC facility were associated with the quality of ANC received by expectant mothers in rural Zambia. Timing of first ANC visit, however, did not seem to be influenced by distance to the closest ANC facility, nor did better level of provision at the closest facility lead to earlier ANC attendance or a greater number of ANC visits.Our findings on distance to a health facility and ANC use agree with the results of several previous qualitative studies and some quantitative studies The effect of distance on delivery in a health facility in Zambia, using the same datasets, was stronger Studies investigating the influence of distance on the quality of ANC received are scarce, although the information to construct such an outcome variable is available in most DHS datasets. Since focused ANC was introduced, the aim is not only to achieve a sufficient number of visits, but also relevant content during visits The level of service provision, reflecting aspects of quality of care provided at the facility is considered an important determinant of service use Another quantitative study on quality of care and ANC use found that in Sudan, besides shorter walking time, better quality of care at the facility was associated with a higher proportion of women using ANC monthly from the second trimester onwards The overall poor first trimester attendance of ANC in Zambia raises questions about whether women are aware of the importance and expected content of an early first antenatal visit or whether ANC is rather still seen as a check-up before birth to ensure everything is normal. One could speculate that the technical quality of care at ANC facilities may not influence women's early care-seeking behaviour because they don't appreciate the meaning of the ANC interventions, but are rather influenced by interpersonal quality of care. That is to say that the personal experiences a woman had earlier with facility staff, or experiences her friends and family had, may greatly impact on her care-seeking behaviour. Our unexpected finding that a higher level of provision at the closest facility (adjusting for distance) was weakly associated with a later first antenatal visit is difficult to explain. If it is not a chance finding , it could be due to the fact that technically assessed quality of care captured as the level of service provision is not the same as quality of care as perceived by women, and higher-level facilities may offer less personal care – or charge higher costs. A study on ANC use among women in rural Kenya found that lower perceived quality of care was significantly associated with a later first ANC visit The interpretation of our findings needs to take into account certain study limitations. The 2005 Zambia Health Facility Census provides only a snap-shot picture of health facility quality at one point in time. The availability of services may have varied during the five-year period (2002–2007) for which the 2007 Zambia DHS recorded ANC use, and the situation today is also likely to be different. On the other hand, using secondary data allowed us to study all of Zambia with a large variety of facilities being considered. This made it possible to overcome previous limitations in investigating the influence of level of service provision, which requires a large range of facilities to be studied. While the DHS covered a large national sample of women, the restriction of ANC information in the DHS on last births and our exclusion of movers left a rural subsample of 2405 births. A larger sample size would have enabled us to draw firmer conclusions.Non-differential misclassification of distance, due to errors in the geographic coordinates (to which the geoscrambling practice of Measure DHS contributes This study provides evidence that quality of ANC received by expectant mothers in rural Zambia is strongly influenced by the level of services provided at the closest ANC facility and to a lesser degree by distance to care. This suggests that to improve ANC quality received by mothers, efforts and resources should focus on improving the level of service provision at ANC facilities. The need to focus more on quality of care received by expectant mothers has been echoed in a number of recent calls This implies scaling-up effective screening tests and interventions towards universal coverage, especially in rural health centers which make up the majority of ANC providers. As most rural mothers live within reasonable distance of an ANC facility providing an adequate level of service , it may Further research may be needed to better understand the factors influencing ANC care-seeking in the first trimester of pregnancy, as well as the difference between perceived quality of care and technically assessed quality of care at a facility, as this could help understand client behavior and form the basis for future behavior change campaigns. As antenatal care-seeking overall is rather good, the “quality gap” for ANC is much larger than the “coverage gap”


Rhamphorhynchus that lie adjacent to the rostrum of a large individual of the ganoid fish Aspidorhynchus. In one of these, a small leptolepidid fish is still sticking in the esophagus of the pterosaur and its stomach is full of fish debris. This suggests that the Rhamphorhynchus was seized during or immediately after a successful hunt. According to the fossil record, Rhamphorhynchus frequently were accidentally seized by large Aspidorhnychus. In some cases the fibrous tissue of the wing membrane got entangled with the rostral teeth such that the fish was unable to get rid of the pterosaur. Such encounters ended fatally for both. Intestinal contents of Aspidorhynchus-type fishes are known and mostly comprise fishes and in one single case a Homoeosaurus. Obviously Rhamphorhynchus did not belong to the prey spectrum of Aspidorhynchus.Associations of large vertebrates are exceedingly rare in the Late Jurassic Solnhofen Limestone of Bavaria, Southern Germany. However, there are five specimens of medium-sized pterosaur  Aspidorhynchus and the long-tailed pterosaur Rhamphorhychus from the Late Jurassic Solnhofen Limestone  that proves evidence that Rhamphorhynchus fell victim the fish of prey, likely as a result or possibly of a lethal accidental interaction of both animals. At last four additional Rhamphorhynchus specimens tightly entangled with the rostrum of a large Aspidorhynchus have been discovered but in contrast to the new specimen none of them proves that the Rhamphorhynchus was alive when it was seized. Today aerial vertebrate prey, such as birds and bats is recorded for sharks Pterosaurs, actively flying reptiles of the Mesozoic era, are well documented by an extraordinary fossil record, with the most informative specimens coming from the Middle Jurassic to Early Cretaceous lacustrine deposits of the Jinlingsi and Jehol Group of the western Liaoning Province, China Eudimorphodon ranzii  Parapholidophorus, which abundantly occurs in the Eudimorphodon bearing beds. Two specimens of Rhamphorhynchus muensteri  contain remnants of small leptolepidid fishes Pteranodon  and fish debris in the gular area of a Pterodactylus  respectively have been tentatively interpreted as the contents of a throat pouch Preondactylus specimen from the Middle Triassic of Northern Italy is preserved as a crushed agglomeration of bone that likely formed the regurgitation pellet produced by a large fish While much is known on the skeletal and soft tissue anatomy of pterosaurs evidence for their position in the Mesozoic food chains is exceedingly sparse in the fossil record. Remnants of fishes inside the ribcage of a pterosaur have been reported for a single specimen of Aspidorhynchus acutirostris closely associated with Rhamphorhynchus muensteri. In three of these slabs the virtually complete skeleton of a subadult or adult Rhamphorhynchus lies immediately adjacent to the jaws of the Aspidorhynchus , Thermopolis, U.S.A. under the collection number WDC CSG 255. The specimen was found in the year 2009 in a plattenkalk quarry NW of the town of Eichstätt  within the Solnhofen Lithographic Limestone , Rhamphorhynchus had just caught a small fish and was about to swallow it head first, when the Aspidorhynchus attacked. The fish tail yet sticking in the pharyngeal region of the throat and the excellent preservation of the tiny fish without any trace of digestion suggests that swallowing was not completed and that the Rhamphorhynchus was alive and airborne during the attack. A regurgitation of the leptolepidid fish tail first into the pharyngeal region as a result of agony of the pterosaur would not have been possible, because the fins and the opercula of the fish would have braced themselves against the wall of the narrow esophagus. Instead, the fins of the fish lay smoothly alongside the body ande the lepidotrichs of the caudal fin are folded together and lay perfectly straight because the caudal fin apparently had just passed the larynx of the Rhamphorhynchus. Furthermore, there is no evidence that the half digested fish debris in the abdominal area .For the ultraviolet-light investigation of the specimen we used a set of UVA lamps with a wavelength of 365 to 366 nanometers and an intensity between 4000 and more than 50000 microwatts per 10 mm


Even in small neuronal systems sensory stimuli evoke precise behavioral responses. The leech, possessing one of the smallest neuronal systems with ~10.000 neurons, shows as a response to a touch of the skin a locally limited bend away from this touch . BehavioThomson and Kristan investigated in their study  the encoBased on this study, we investigate how neurons of the medicinal leech encode information about the combination of stimulus location and intensity. We have recorded intracellularly from P cells and interneurons of the local bending network, while stimulating the skin mechanically with tactile stimuli of varied intensity and location. The neuronal responses of simultaneously recorded pairs of mechanosensory neurons were analyzed by calculating the difference of latencies and of spike counts of both cells. The discrimination performance was evaluated based on a pairwise classification of location distances and intensity differences.For the estimation of touch location, we found in agreement with Thomson and Kristan  that theFor the estimation of stimulus intensities spike counts provide significantly better classification results than response latencies. The classification of this stimulus property does not improve when using the difference between the responses of two cells compared to using the spike count of a single P cell.Preliminary results show that features of graded interneuron responses like the slope, the amplitude and the area under the EPSP depend clearly on the touch intensity and in a more complex way on the touch location.1. The touch location is accurately encoded by the latency difference of two P cells when higher stimulus intensities are used.2. Stimulus intensity can be classified best based on the spike count of single cells.3. The combined encoding of stimulus location and intensity is more complex for low intensity stimuli. This topic needs further investigation on the level of interneuron responses.


The vast amount of research over the past decades has significantly added to our knowledge of phantom limb pain. Multiple factors including site of amputation or presence of preamputation pain have been found to have a positive correlation with the development of phantom limb pain. The paradigms of proposed mechanisms have shifted over the past years from the psychogenic theory to peripheral and central neural changes involving cortical reorganization. More recently, the role of mirror neurons in the brain has been proposed in the generation of phantom pain. A wide variety of treatment approaches have been employed, but mechanism-based specific treatment guidelines are yet to evolve. Phantom limb pain is considered a neuropathic pain, and most treatment recommendations are based on recommendations for neuropathic pain syndromes. Mirror therapy, a relatively recently proposed therapy for phantom limb pain, has mixed results in randomized controlled trials. Most successful treatment outcomes include multidisciplinary measures. This paper attempts to review and summarize recent research relative to the proposed mechanisms of and treatments for phantom limb pain. The concept of phantom limb pain (PLP) as being the pain perceived by the region of the body no longer present was first described by Ambrose Pare, a sixteenth century French military surgeon . Silas WStump pain is described as the pain in the residual portion of the amputated limb whereas phantom sensations are the nonpainful sensations experienced in the body part that no longer exists , 7. SupePLP was once thought to be primarily a psychiatric illness. With the accumulation of evidence from research over the past decades, the paradigm has shifted more towards changes at several levels of the neural axis, especially the cortex . PeripheDuring amputation, peripheral nerves are severed. This results in massive tissue and neuronal injury causing disruption of the normal pattern of afferent nerve input to the spinal cord. This is followed by a process called deafferentation and the proximal portion of the severed nerve sprouts to form neuromas . There iThe axonal sprouts at the proximal section of the amputated peripheral nerve form connections with the neurons in the receptive field of the spinal cord. Some neurons in the areas of spinal cord that are not responsible for pain transmission also sprout into the Lamina II of the dorsal horn of the spinal cord which is the area involved in the transmission of nociceptive afferent inputs , 19. ThiCortical reorganization is perhaps the most cited reason for the cause of PLP in recent years. During reorganization, the cortical areas representing the amputated extremity are taken over by the neighboring representational zones in both the primary somatosensory and the motor cortex , 25, 26.Another proposed mechanism of PLP is based on the “body schema” concept that was originally proposed by Head and Holmes in 1912. The body schema can be thought of as a template of the entire body in the brain and any change to the body, such as an amputation, results in the perception of a phantom limb . A furthThe assumption that PLP is of psychogenic origin has not been supported in the recent literature even though stress, anxiety, exhaustion, and depression are believed to exacerbate PLP . A crossA number of different therapies relying on different principles have been proposed for the management of PLP as shown in Preemptive use of analgesics and anesthetics during the preoperative period is believed to prevent the noxious stimulus from the amputated site from triggering hyperplastic changes and central neural sensitization which may prevent the amplification of future impulses from the amputation site . HoweverA cross sectional study found that acetaminophen and NSAIDs were the most common medications used in the treatment of PLP . The anaOpioids bind to the peripheral and central opioid receptors and provide analgesia without the loss of touch, proprioception, or consciousness. They may also diminish cortical reorganization and disrupt one of the proposed mechanisms of PLP . RandomiTricyclic antidepressants are among the most commonly used medications for various neuropathic pains including PLP. The analgesic action of tricyclic antidepressant is attributed mainly to the inhibition of serotonin-norepinephrine uptake blockade, NMDA receptor antagonism, and sodium channel blockade . The rolGabapentin has shown mixed results in the control of PLP with some studies showing positive results while others not showing efficacy –59. CarbThe mechanism of action of calcitonin in treatment of PLP is not clear. Studies relative to its therapeutic role have been mixed , 62.The mechanism of action of NMDA receptor antagonism in PLP is not clear. Memantine has shown some benefits in some case studies but controlled trials have shown mixed results , 64. A rThe beta blocker propranolol and the calcium channel blocker nifedipine have been used for the treatment of PLP . HoweverTranscutaneous electrical nerve stimulation has been found to be helpful in PLP . HistoriMirror therapy was first reported by Ramachandran and Rogers-Ramachandran in 1996 and is suggested to help PLP by resolving the visual-proprioceptive dissociation in the brain , 70. TheAlthough there are earlier reports suggesting temperature biofeedback to be helpful for burning sensation of PLP, there is no specific evidence to match specific types of PLP with specific biofeedback techniques . There iSurgical interventions are usually employed when other treatment methods have failed. A case report relates the effectiveness of lesioning the dorsal root entry zone (DREZ) on upper limb phantom pain resulting from brachial plexus avulsions . AnotherA case report of positive outcome has been published even though the mechanism and role of ECT relative to PLP is not well understood .PLP is a relatively common and disabling entity. We have learned much about the pathophysiology and management of PLP since it was first described about five centuries ago. However, there is still no one unifying theory relative to the mechanism of PLP. Specific mechanism-based treatments are still evolving, and most treatments are based on recommendations for neuropathic pain. The evolution of the mechanistic hypothesis from body schema and neuropathic theories to the recently proposed role of mirror neurons in the mechanism of pain have added to our understanding of PLP. Further research is needed to elucidate the relationship between the different proposed mechanisms underlying PLP. A synthesized hypothesis explaining the phenomenon of PLP is necessary in the future for the evolution of more specific mechanism-based treatment recommendations.


Heart failure is seen as a complex disease caused by a combination of a mechanical disorder, cardiac remodeling and neurohormonal activation. To define heart failure the systems biology approach integrates genes and molecules, interprets the relationship of the molecular networks with modular functional units, and explains the interaction between mechanical dysfunction and cardiac remodeling. The biomechanical model of heart failure explains satisfactorily the progression of myocardial dysfunction and the development of clinical phenotypes. The earliest mechanical changes and stresses applied in myocardial cells and/or myocardial loss or dysfunction activate left ventricular cavity remodeling and other neurohormonal regulatory mechanisms such as early release of natriuretic peptides followed by SAS and RAAS mobilization. Eventually the neurohormonal activation and the left ventricular remodeling process are leading to clinical deterioration of heart failure towards a multi-organic damage. It is hypothesized that approaching heart failure with the methodology of systems biology we promote the elucidation of its complex pathophysiology and most probably we can invent new therapeutic strategies. Systems biology is a term selected for the study of the vast amount of experimental data advanced from current technologies in genomics and proteomics . It is aThe explanation given to the clinical syndrome of heart failure is limited if only the pathophysiological mechanisms are described. Also the specific clinical models developed to interpret the variety of clinical phenotypes are not sufficiently coherent to explain the progressive deterioration of heart failure and some of the successful aspects of the new therapeutic agents. Targeting the involved molecular mechanisms, only the biomechanical model predicts that the novel therapeutic strategies interrupt the viscous cycle of myocardial dysfunction and cardiac remodeling .The present paper debates the biomechanical model of heart failure under the current concept of systems biology methodology exploring the connection of the complex metabolic and regulatory networks with the clinical phenotypes of heart failure. It is accepted that early  mechanical stresses applied in the myocytes and/or mechanical changes in the left ventricular cavity comprise the primary initiating causes for cardiac remodeling and neurohormonal activation.It is hypothesized that only through systems biology methodology can we explain the complex phenomenon of heart failure and defend the concept of the biomechanical model. This approach will increase the knowledge of the pathogenesis of heart failure and eventually will enable the development of effective drug therapy.The nature and the biological world constitute a complex system compiled of many interacting components that produce complex physical and biological phenomena. The research on complex phenomena extends from physics to biological and the medical world . The phyA network of interactions is considered modular if it is made of autonomous interconnected components that act together in performing some discrete physiological function  , 5. The Systems biology integrates diverse areas of science targeting the underlying principles of hierarchical metabolic and regulatory systems from the cell to an organismal level . It enta1). The heart should be considered as a multifunctional organ that participates in the homeostatic regulation of the body and is an essential element of a complex and integrated network of organs and systems. Human heart failure from the point of view of systems biology is considered as a syndrome with different causes that involves many clinical appearances or clinical phenotypes. Each clinical phenotype involves many biochemical pathways, pathophysiological changes and physiological regulatory systems. These regulatory systems are important in upgrading or inhibiting the cardiac cavity remodeling process that delineates the syndrome. Two of the most important regulatory systems in heart failure, the natriuretic peptide axis and the renin-angiotensin-aldosterone system (RAAS), are considered examples of critical functional modules . In the aAtrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and their prohormones (proANP and proBNP) are secreted by cardiomyocytes. Under normal circumstances the ANP and BNP are released after increase of the atrial and myocardial stretch or after excessive sodium intake. In patients with heart failure the natriuretic peptides release is considered the earliest regulatory mechanism that is motivated in contrast to later sympatho-adrenal system (SAS) and RAAS activation. It is accepted that the ANP is produced mainly from atria and BNP from ventricles, and they are differently regulated in the two cavities. Therefore two cardiac endocrine systems are working in parallel, one in the atria producing ANP and the other in the ventricles secreting BNP . In chroThe BNP is considered both as a biomarker of heart failure diagnosis and as a prognostic factor in various cardiovascular diseases. In clinical practice the BNP sensitivity and specificity for increased filling pressure detection are lower than the echocardiographic estimation criteria for filling pressure. In a recent article doppler echocardiography methodology increased the accuracy of heart failure diagnosis in the presence of intermediate BNP or amino-terminal proBNP (NT-proBNP) and improved the stratification of risk across all periods of heart failure . NeverthThe natriuretic peptides possess vasodilator, natriuretic and diuretic effects, and an inhibitory action on immunological and inflammatory systems, and on growth factors , 13. TheSystems biology approach to the natriuretic peptide axis is revealed from genomic and proteomic studies which identified many locations that were responsible for heart failure exacerbation. Genomic studies recognized multiple polymorphic structural variants of the BNP gene, which were responsible for the blood levels of BNP and NT-proBNP in normal subjects and in patients with heart failure , 16. Alsa diagnostic and prognostic point of view. Recent proteomic studies define some aspects of the functional importance of the natriuretic peptide axis in comprehending the heart failure syndrome. The BNP-32 is considered to represent the main biologically active form of BNP and predictably is increased in patients with heart failure. However, using a novel method of mass spectrometry, new high molecular weight forms of BNP have recently been discovered that are less biologically active than BNP-32, but with the current assays were erroneously identified as BNP-32 or NT-Pro BNP . The aboThe increased BNP in patients with heart failure is inadequate to delay the disease progression and its beneficial physiological effects are reduced partly because of the up-regulation of the phosphodiesterase type-5 enzyme (PDE5) . The PDEThe levels of natriuretic peptides in patients with chronic heart failure are increased compared with healthy individuals. Excessively high circulating levels of natriuretic peptides are confirmed in patients with chronic heart failure presented with fluid retention and vasoconstriction. The defective biological activity of the natriuretic peptides system suggests a kind of peripheral resistance to the biological effect of natriuretic peptides . This peThe above data support the hypothesis that the natriuretic peptides are elements of an integrated network that includes the cardiac muscular, endocrine, immune, and nervous system.bThe depressed left ventricular function generates a variety of physiological reactions in an endeavor to remedy the diseased myocardium. These counteracting responses that include the increased activity of both the SAS and the RAAS, are considered deleterious for the myocardium, and therefore correctly their association with the cardiovascular and cardiorenal disease became a therapeutic target. The SAS is activated early (but after the activation of BNP) in the course of heart failure due to autonomic imbalance or to loss of the inhibitory effect of the baroreceptor reflexes. The RAAS is activated later in the course of heart failure with the possible mechanisms of the renal hypoperfusion due to low cardiac output and the increased renin release due to sympathetic stimulation of the kidney.1 receptor blockers (ARBs) ( antagonize angiotensin II binding to AT1 receptors). The above therapeutic agents to a degree could prevent or reverse heart failure deterioration and progression. These treatments cope with the overexpression of the biologically active neurohormonal molecules that exert deleterious effects on the heart and circulation [The most significant classes of drugs targeting the RAAS are the β-adrenergic antagonists (β blockers) (reduce renin), the angiotensin-converting enzyme inhibitors (ACEI) (reduce levels of angiotensin II) and the ATculation . The metculation . The comSystems biology approach supports the hypothesis that there are two integrated and opposing systems acting not only at the cardiac level but in the whole body. The first system is the RAAS with vasoconstrictive, sodium retaining, thrombophylic, prohypertrophic, and proinflammatory properties, while the second is the natriuretic peptide system that manifests opposing qualities such as natriuretic, vasodilating, anti-inflammatory, anti-thrombotic and anti-hypertrophic. In patients with heart failure the first system controls the hemodynamic homeostasis, initially as a counterbalancing mechanism but later induces a progressive and deleterious worsening of the cardiac function. The second opposing mechanism, the natriuretic peptide system, seems to be inadequate in delaying the heart failure progression.1).The goal of modern clinical cardiology is to obtain a reliable description and understanding of the human physiology in various states and diseases, to incorporate the different physiological and interrelated derangements presented in databases, and finally to use the available clinical variables constructing specific clinical models  mechanical stimulus responsible for cardiac remodeling and neurohormonal activation, and also the progressive mechanical remodeling changes responsible for the persistence and progression of clinical heart failure syndrome . The oveLAX) and early diastole (ELAX) which were lower in the patients with diastolic heart failure [M) and early diastolic (EM) velocities in patients with HFrEF, HFpEF and isolated diastolic dysfunction [’) is useful to assess left ventricular filling pressure while a persistent elevation of this ratio may be a prognostic factor of diastolic heart failure in patients with HFpEF independent of left ventricular hypertrophy [’ ratio after optimized medical therapy is predictive of cardiac events [’ greater than 15, ejection fraction less than 50%, and severe functional mitral regurgitation were independent echocardiographic predictors of cardiac events [’<3 cm/s was associated with a significantly excess mortality, and this measurement added incremental prognostic value to E/E’ >15 [In a recent paper, a mathematical model is introduced that predicts the dominant role of remodeling as a compensatory physiological response in chronic heart failure resulting in a normalization of stroke volume . In the  failure . Left ve failure . Systolifunction . The Dopertrophy . In patic events . In patic events . In patiE/E’ >15 .In the end-stage of heart failure the persistent mechanical remodeling changes are self-determined probably without neurohormonal dependence operating until the end of the disease. In this stage it is improbable for the neurohormonal activation to have a sustained and effective inotropic performance and therefore the only compensatory mechanism that remains is the left ventricular remodeling. The compensatory mechanisms of left ventricular remodeling and neurohormonal activation are not sufficient to counterbalance effectively the initial mechanical left ventricular changes while the progressive mechanical remodeling changes that occur during the end-stage of the left ventricular dysfunction are deleterious and unopposed by any other compensatory mechanisms. In a sense significant left ventricular dysfunction begets progressive ventricular remodeling, that in turn begets progressive left ventricular dysfunction. The end-staged left ventricle represents a terminally remodeled and noncompliant cavity with low contractility and function.The mechanosensation is an old biological process to be found in all forms of life. In mechanotransduction the mechanical effect is closely related and affects the transduction systems of vasopeptides, hormones, sensing receptors, ionic fluxes and other autocrine/paracrine mechanisms.The endothelium of arteries and veins is constantly exposed to hemodynamic forces due to the pulsatile nature of blood pressure and flow. Therefore the endothelium is permanently detecting various biomechanical forces , which are translated into intra- and extracellular signals . The bioThe Kruppel-like factor (KLF2) is a transcriptional inhibitor of endothelial mediated inflammation . The KLFThe biomechanical stress is speculated as an early and most significant stimulus for cardiac hypertrophy and heart failure. The gp130 cytokine receptor plays a significant role in myocyte survival pathway in the transition to heart failure. During aortic pressure overload, in mice with ventricular restricted knockout of the gp139 cytokine receptor, was described a rapid onset of dilated cardiomyopathy and massive myocyte apoptosis in contrast to control mice that showed compensatory hypertrophy . The actin vivo analyses of intracardiac flow forces in zebrafish embryos [It is hypothesized that in the adult the early hemodynamic cavity stresses of left ventricular dysfunction induce ventricular endothelial dysfunction and remodeling. Probably that follows the embryonic model of flow-structure interactions that influence the process of cardiac development . The int embryos . The rec embryos . The ana embryos . The β aMyocardial biomarkers like natriuretic peptides are considered useful biochemical substances in the diagnosis of patients with heart failure. The natriuretic peptides ANP and BNP are secreted in response to increasing cardiac wall tension and/or circulating neurohormones. The blood levels of ANP and BNP are increased in patients with left ventricular dysfunction as well in patients with preserved ejection fraction. In patients with systolic heart failure the BNP blood levels are directly related to wall stress, ejection fraction and functional failure classification . In wome1R), as it is well known that angiotensin II is proinflammatory and proatherosclerotic. This was demonstrated in an immunohistochemical analysis in the aortic arch of transgenic mice where a pronounced expression of AT1R was found in the inner atheroprone regions of the aortic arch, characterized by disturbed or oscillatory shear stress, but not in the outer aortic arch exposed to high shear stress [1R protein expression.Shear stress demonstrates an atheroprotective role through downregulation of angiotensin type 1 receptors (ATr stress . In the 2).How can the early mechanical effects be translated into clinical phenotypes? The impact of the early mechanical changes on clinical outcome in heart failure patients remains to be established in a future study comparing initial mechanical changes with the earliest neurohormonal activation. It is significant from a clinical perspective the design of a trial with sufficient power to discern meaningful interactions between early mechanical effects and neurohormonal activation in order to improve our understanding of the later clinical outcome  give several reasons supporting the wall-stress hypothesis: 1) Pure mechanical overload that is not accompanied by a neurohormonal reaction is a rather rare phenomenon and therefore the coexistence of the two processes obscures the significance of the mechanical initial factor. 2) The transgenic hypothesis is impossible to reproduce the entire cascade that follows the mechanical stress. 3) During cardiogenesis the different transcription factors operate synergistically in a combinatorial way that is not documented in cardiac hypertrophy. They support the hypothesis that cardiac hypertrophy results from an initial mechanical effect and a re-expression of the fetal program, and during clinical conditions in humans the effects of mechanics are modified by senescence, obesity, diabetes and ischemia [The transgenic technology queries the validity of the wall-stress hypothesis that both cardiac hypertrophy and fetal reprogramming were a necessary adaptive response to mechanical load. It is suggested that the progression of heart failure depends on different mechanisms triggered by new molecular rearrangements. The above position is not absolutely valid and it is not necessary to reconsider the wall-stress hypothesis . Swyngheet al  give sev2). Phenotype in biology is considered any observable characteristic of an organism that includes morphology, biochemical properties, physiological functions, and behaviors. As phenotypic data from systems biology perspective are examined network functional states such as fluxomic data that give information about the actual flux distributions in a network . The comHuman heart failure is a syndrome exhibiting multiple clinical phenotypes implicating a number of common pathophysiological, biochemical and molecular mechanisms. The clinical phenotypes are marked by multiorgan dysfunction due to the upregulation or downregulation of the above mechanisms. It is important from experimental and clinical perspective to define these phenotypes and to schedule a therapeutic strategy of multifaceted heart failure targeting to a more personalized therapy. The described heart failure models represent clinical phenotypes that can be studied using the current available data from the advanced fields of genomics, proteomics and experimental model systems . RecentlTherefore the neurohormonal dysfunction initially compensates cardiac hemodynamic changes and in a later stage becomes toxic to the myocardium reducing myocardial contractility and increasing the deleterious processes of cardiac remodeling.In conclusion the systems biology analysis of heart failure will increase our understanding of the biological and mechanical basis of the disorder. The progressive nature of the mechanical model of the heart failure from early mechanical changes to left ventricular remodeling and the modular analysis of the neurohormonal homeostatic regulation will produce a comprehensive analysis of the disease process. The elucidation of the complex heart failure disease will also provide the material for further development of new therapeutic strategies.


Understanding tumor induced angiogenesis is a challenging problem with important consequences for diagnosis and treatment of cancer. Recently, strong evidences suggest the dual role of endothelial cells on the migrating tips and on the proliferating body of blood vessels, in consonance with further events behind lumen formation and vascular patterning. In this paper we present a multi-scale phase-field model that combines the benefits of continuum physics description and the capability of tracking individual cells. The model allows us to discuss the role of the endothelial cells' chemotactic response and proliferation rate as key factors that tailor the neovascular network. Importantly, we also test the predictions of our theoretical model against relevant experimental approaches in mice that displayed distinctive vascular patterns. The model reproduces the in vivo patterns of newly formed vascular networks, providing quantitative and qualitative results for branch density and vessel diameter on the order of the ones measured experimentally in mouse retinas. Our results highlight the ability of mathematical models to suggest relevant hypotheses with respect to the role of different parameters in this process, hence underlining the necessary collaboration between mathematical modeling, in vivo imaging and molecular biology techniques to improve current diagnostic and therapeutic tools. Sprouting angiogenesis - the process by which new blood vessels grow from existing ones - is a ubiquitous phenomenon in health and disease of higher organisms Recent progresses on high resolution microscopy e.g. the activation and subsequent sprouting of new branches) and on the large scale collective movements of the cells due to endothelial cell proliferation and the tissue properties Mathematical models of tumor induced angiogenesis have been fundamentally of two types: either microscopic descriptions accounting for cell dynamics The process of tumor angiogenesis starts when endothelial cells of existing capillaries acquire the tip cell phenotype by the action of a protein cocktail produced by tumor and related-tissue cells, generally induced by a hypoxic microenvironment. Tip cells lead the growth of new capillaries in conjunction with further endothelial cells which acquire the stalk cell phenotype. The migration of endothelial tip cells is directed towards increasing concentrations of relevant growth factors. These, such as VEGF , have a three-fold role at the cell scale: (i) to trigger the permeability of the capillaries and the subsequent activation of the tip cell phenotype, (ii) to promote migration of tip cells in the direction of its gradient, and (iii) to promote the proliferation and survival of the stalk endothelial cells. The angiogenic role of VEGF is opposed by different anti-angiogenic factors in the tissue.Tip migration is associated with the production of extracellular MMPs  that are responsible for the remodeling of nearby ECM (ExtraCellular Matrix), and that affects the affinity of VEGF species towards different extracellular locations. This has relevant consequences in the bio-availability of VEGF The different isoforms of VEGF are distinguishable by the degree in which they anchor to negativelly-charged molecules in the ECM or the cell surface After an opened path in the ECM is generated by the tip cells, a reorganization of the stalk proliferating cells is required in order to form a new lumen for blood circulation, in precise coordination with pericytes and other stromal components. Further processes such as anastomosis (connection between different branches on the network), the action of pressure forces and the intrinsic mechanical properties of the tissue, contribute to the formation of the new vessel network and are finely tuned to determine vascular patterning In this work the dynamics of the interface between the newly formed capillaries and the stroma is treated with a phase-field model formalism In the model we introduce an angiogenic factor that represents the balance between pro and anti angiogenic signaling proteins We analyze the capillary network morphology for different values of the stalk endothelial cells proliferation rate and of the velocity of the tip endothelial cells in the tissue.We describe the dynamics of an effective factor tion see .Proliferative and non-activated cells are described by an order parameter v  see .In order for the endothelial tip cell activation to occur, points with large values for both per se, but the density of stalk cells on the vicinity of the tip cell.To merge tip cell and capillary dynamics, we relate the value of the order parameter inside the tip cell Starting from a single vessel  We test our mathematical model against two experimental situations.First, we compare with results obtained by Haigh et al Although the final goal of these authors was to determine the role of VEGF-A during the development of the nervous system, their neat approach allowed the visualization of the vascular network in the developing cortex and retina of embryos and newborn mice. The authors reported that the decrease of VEGF-A is accompanied by a sparser vessel network when compared to the wild type used as a control condition Click here for additional data file.Figure S2Capillary network morphology obtained for different number of angiogenic factor sources. Figures A, B, C, and D have respectively 120. 240, 480 and 960 initial hypoxic cells approximately. At low density of sources  the network forms a tree-like structure, with a low number of branches, similar to the network at low values of  of  see . As the (EPS)Click here for additional data file.Figure S3Capillary network morphology obtained for a large initial circular source of angiogenic factor. Figures A, B, C, and D are snapshots of the vasculature growth. The resulting network is tree-like and very dense when reaches the source. This is a brush-like network as observed in various solid tumor situations (both in silico and in vivo) (EPS)Click here for additional data file.Figure S4Capillary network for deficient Notch signaling . The figures represent the observed capillary network morphology for low and high proliferation rates; respectively t al see .(EPS)Click here for additional data file.Text S1Supporting information with details on the model equations.(PDF)Click here for additional data file.Video S1Formation of the capillary network shown in . The tip cell velocity and stalk cells proliferation rate in this simulation are (MOV)Click here for additional data file.


Previous studies have reported an association of altered fibrin clot network architecture with several diseases including sepsis, bleeding or acute thromboembolic disease . We inveRheometry and confocal laser scanning microscopy (CLSM) were used to monitor and image the formation of fibrin clots. Clotting was initiated by the addition of different levels of thrombin to solutions of a fixed concentration of fibrinogen. Each sample was divided into two aliquots; one added to the measuring geometry of an AR-G2 rheometer and one to the microscope slide for the spinning disk CLSM (Olympus IX71).The micrographs of formed clots Figure  show marWe demonstrate, for the first time, that the fractal dimen-sion obtained by rheometry is a sensitive measure of visually observed structural differences within the fibrin network. Rheometrical detection of incipient clots formed in whole blood provides the clinician with a powerful tool for the diagnosis of thromboembolic disease.


Insects have evolved obligate, mutualistic interactions with bacteria without further transmission to other eukaryotic organisms. Such long-term obligate partnerships between insects and bacteria have a profound effect on various physiological functions of the host. Here we provide an overview of the effects of endosymbiotic bacteria on the insect immune system as well as on the immune response of insects to pathogenic infections. Potential mechanisms through which endosymbionts can affect the ability of their host to resist an infection are discussed in the light of recent findings. We finally point out unresolved questions for future research and speculate how the current knowledge can be employed to design and implement measures for the effective control of agricultural insect pests and vectors of diseases. Insects comprise about 95% of all known animal species and are considered one of the most successful groups of living organisms on earth. They possess an extremely efficient immune system that allows them to deal with pathogenic infections. The insect immune system consists of a wide variety of defense mechanisms that act individually or in combination to prevent foreign organisms from entering the insect body or to suppress the growth and replication of pathogens once they gain access to host tissues.The first line of defense is represented by the insect's epithelia, which serves as a barrier against biotic and abiotic factors, and produce local antimicrobial peptides (AMP) upon infection or wounding  produce essential vitamins that are not present in the vertebrate blood meal  and in uninfected control flies  on the Drosophila immune response   (ortholog of the DrosophilaPGRP-LB) was increased in the bacteriome and this increase coincides with the release of the endosymbiotic bacteria from the bacteriocytes. In turn, high PGRP gene transcription at the nymphal stage of Sitophilus is accompanied by significant up-regulation of the endosymbiont virulence genes   and a positive regulator in the immune deficiency (Imd) signaling pathway (Kenny). Similarly, transcription profiles of Wolbachia infected and uninfected Drosophila S2 cells revealed the up-regulation of several genes involved in the Imd, Toll, and c-Jun N-terminal kinase (JNK) pathways  in the interaction between the endosymbiont and immune genes in mosquitoes. The authors used cell lines from A. gambiae, which is not a natural host for Wolbachia, and A. albopictus, which is naturally infected with the strain wAlbB, and compared the transcriptional induction of immune genes between the two cell lines  genes, prophenoloxidase, and NO cascade genes  or E. carotovora (Gram-negative), respectively. Surprisingly, infection of wild type flies with the plant pathogenic bacterium Spiroplasma citri failed to activate the immune system, leading to bacterial proliferation in the hemolymph and death of the flies. In addition, wild type and immune mutants infected by S. citri showed no differences in their survival rates following infection with this bacterium. The ability of S. citri to kill flies is probably due to the fact that these bacteria are not detected by the Drosophila immune system.The impact of Wolbachia-infected D. melanogaster and D. simulans flies , with three gram-negative bacterial pathogens  did not affect their survival ability compared to Wolbachia-free control flies  with two intracellular bacterial pathogens, Salmonella typhimurium and Listeria monocytogenes, and an extracellular pathogen, Providencia rettgeri, showed no differences in pathogen load between the two types of flies  and showed that they were sensitive to systemic infection with E. coli bacteria , Flock House Virus (FHV) and Cricket Paralysis Virus (CrPV) , but not to Insect Virus 6 (DNA virus), and reduced viral burden in flies carrying the endosymbionts  and the avian malaria parasite  to establish infection in the mosquito  reactions  in D. melanogaster have been introduced into A. aegypti mosquitoes where they have been found to increase the transcriptional levels of melanization genes as well as AMP and Toll related genes   compared to control treatments  and wPip(Mc), naturally found in Culex pipiens were also shown to confer protection to mosquitoes following infection with Plasmodium relictum parasites  compared to uninfected mosquitoes, which may be responsible for the inhibitory effect on the development of B. pahangi parasites  and D. simulans (wRi) larvae have no influence on the encapsulation of parasitoid eggs, although there is a minor decrease in parasitoid development in flies infected by the endosymbiont  in the parasitoid wasp Leptopilina victoria do not affect encapsulation of its eggs by various Drosophila host species (Gueguen et al., The effect of Wolbachia on fungal infections (Fytrou et al., Wolbachia and Spiroplasma, co-existing in an insect host and efficiency of the immune function. It will also be important to elucidate the precise mechanisms employed by endosymbiotic bacteria to modulate immune signaling in insects. Similar research will undoutedly reveal the relative contribution of endosymbiotic bacteria to the overall host immune response against various classes of pathogenic organisms.Despite impressive advances in the broad field of insect innate immunity, our understanding of the role of endosymbiotic bacteria in the host immune response to pathogenic infections remains incomplete. Previous and recent studies have started to determine the phenotypic response of various insects carrying endosymbionts to infection by bacterial and viral pathogens as well as parasites. These studies have substantially improved our understanding of the complex interactions between insects, their endosymbiotic bacteria and pathogenic organisms in the infection and host immunity processes. It will further be of particular interest to test the immune response of insects with or without endosymbionts to infection by entomopathogenic fungi, as there is currently clear conflict within the literature on the effect of Wolbachia endosymbionts in mosquitoes has a direct effect on insect sensitivity to pathogenic infections has attracted the attention of scientists for the development of novel approaches for the control of human diseases (Hancock et al., Wolbachia introduced into A. aegypti resulted in successful invasion of natural populations of mosquitoes (Hoffmann et al., From the practical point of view, the recent discovery that the presence of The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Current Neuropharmacology experts discuss pathophysiology, clinical features and treatment of various neurologic autoimmune disorders. In the last decade we have witnessed remarkable scientific advances which have greatly improved our understanding of pathophysiology of the autoimmune disorders leading to an increasing number of treatment options with many of new therapies already being used in the treatment of neurologic disorders as their role continues to evolve [Autoimmune disorders affect 5-10% of the general population, [o evolve . The firCurrent Neuropharmacology issue for all their time and effort in preparing their articles to create a comprehensive and up-to-date collection of articles on the wide spectrum of autoimmune neurologic disorders.I would like to thank the authors of this


The understanding of the effective functionality that governs the enzymatic self-organized processes in cellular conditions is a crucial topic in the post-genomic era. In recent studies, Transfer Entropy has been proposed as a rigorous, robust and self-consistent method for the causal quantification of the functional information flow among nonlinear processes. Here, in order to quantify the functional connectivity for the glycolytic enzymes in dissipative conditions we have analyzed different catalytic patterns using the technique of Transfer Entropy. The data were obtained by means of a yeast glycolytic model formed by three delay differential equations where the enzymatic rate equations of the irreversible stages have been explicitly considered. These enzymatic activity functions were previously modeled and tested experimentally by other different groups. The results show the emergence of a new kind of dynamical functional structure, characterized by changing connectivity flows and a metabolic invariant that constrains the activity of the irreversible enzymes. In addition to the classical topological structure characterized by the specific location of enzymes, substrates, products and feedback-regulatory metabolites, an effective functional structure emerges in the modeled glycolytic system, which is dynamical and characterized by notable variations of the functional interactions. The dynamical structure also exhibits a metabolic invariant which constrains the functional attributes of the enzymes. Finally, in accordance with the classical biochemical studies, our numerical analysis reveals in a quantitative manner that the enzyme phosphofructokinase is the key-core of the metabolic system, behaving for all conditions as the main source of the effective causal flows in yeast glycolysis. Yeast glycolysis is one of the most studied dissipative pathways of the cell; it was the first metabolic system in which spontaneous oscillations were observed Glycolysis is the central pathway of glucose degradation and it is implied in relevant metabolic processes, such as the maintenance of cellular redox states, the provision of ATP for membrane pumps and protein phosphorylation, biosynthesis, etc; and its activity is linked to a high variety of important cellular processes, e.g., glycolysis has a long history in cancer cell biology Over the last 30 years a large number of different studies focused on different molecular mechanisms allowing for the emergency of self-organized glycolytic patterns The theoretical basis of dissipative self-organization processes was formulated by Ilya Prigogine From a dissipative point of view, the essential enzymatic states are those corresponding to the biochemical irreversible processes, and they are the only metabolic processes which might allow that the enzymatic system to work far from the thermodynamic equilibrium. Once the irreversible enzymatic system operates sufficiently far-from-equilibrium as the nonlinear nature of its kinetics, the steady state may become unstable leading to dynamical behaviours and new instabilities originating the emergence of different biochemical temporal patterns In the yeast glycolysis, the main instability-generating mechanism is based on the self-catalytic regulation of the irreversible enzyme phosphofructokinase, specifically, the positive feed-back exerted by the reaction products, the ADP and fructose-1,6-bisphosphate In this paper, to go a next step further in the understanding of the relationship between the classical topological structure and functionality we have analyzed the effective connectivity of yeast glycolysis, which in inter-enzyme interactions accounts for the influence that the activity of one enzyme has on the future of another For this purpose, we considered a yeast glycolytic model described by a system of three delay-differential equations in which there is an explicit consideration of the rate equations of the three irreversible enzymes hexokinase, phosphofructokinase and pyruvatekinase. These enzymatic activity functions were previously modeled and tested experimentally by other different groups We have obtained time series of enzymatic activity under different sources of the glucose input flux. The data corresponded to a typical quasi-periodic route to chaos which is in agreement with experimental conditions Using the non-linear analysis technique of Transfer Entropy TE has been proposed as a rigorous, robust and self-consistent method for the effective connectivity i.e., causal quantification of the functional information flow among nonlinear processes In The monitoring of the fluorescence of NADH in glycolyzing bakerIn order to simulate these metabolic processes, the glycolytic system is considered under periodic input flux with a sinusoidal source of glucose Under these conditions, a wide range of different types of dynamic patterns can emerge as a function of the control parameter, hereafter the amplitude A of the sinusoidal glucose input flux  pattern . An incrs emerge . Above As appear . After aappear , , as predTo go a next step further in the understanding of the relationship between the classical topological structure and effective functionality we have analyzed by means of non-linear statistical tools the catalytic patterns belonging to this scenario to chaos, and for each transition represented in the Transfer Entropy (TE) quantifies the reduction in uncertainty that one variable has on its own future when adding another. This measure allows for a calculation of the functional influence in terms of effective connectivity between two variables The values of functional influence are ranging in The glycolytic effective connectivity is illustrated in In all cases analyzed, the values of TE present a maximum statistical significance .Next, we have measured the total information flow, defined as the total outward of Transfer Entropy arriving to one enzyme minus the total inward. Positive values mean that that enzyme is a source of causality flow and negative flows are interpreted as sinks or targets. The results of the total information flows are represented For all conditions the enzyme EThe attributed role to each enzyme, namely ETime correlations allows for quantification about how much two time series are statistically independent. According to that, we have measured the time pairwise correlations in the enzymatic system, and the corresponding results are shown in These values of time correlations were almost constant through the quasi-periodic route to chaos and established that the activities of EThe Mutual Information (MI) quantifies how much the knowledge of one variable reduces the entropy or uncertainty of the another The high values of MI (close to 0.50) proved a high redundancy in information between the pairs of enzymes. In other words, the number of bits of information transferred from one enzyme to another is much larger than the actually needed.The values in the principal diagonal of The values of MI have a maximum statistical significance .Finally, we have computed the Mutual Information between the glucose input fluxes and the activity patterns of the different enzymes. In all cases, the MI was equal to zero, proving that the oscillations of the glucose were statistical independent of the glucose- 6-phosphate, fructose 1-6-biphosphate and pyruvate, products of the main irreversible enzymes of glycolysis.In this paper we have quantified essential aspects of the effective functional connectivity among the main glycolytic enzymes in dissipative conditions.First, we have computed under different source of glucose the causality flows in the metabolic system. This level of the functional influence accounts for the contribution of each enzyme to the generation of the different catalytic behavior and adds a directionality in the influence interactions between enzymes.The results show that the flows of functional connectivity can change significantly during the different metabolic transitions analyzed, exhibiting high values of transfer entropy, and in all considered cases, the enzyme phosphofructokinase  corresponds to the Eerge cf. . This fiThe level of influence in terms of causal interactions between the enzymes is not always the same but varies depending on the substrate fluxes and the dynamic characteristics emerging in the system. In addition to the glycolytic topological structure characterized by the specific location of enzymes, substrates, products and regulatory metabolites there is an functional structure of information flows which is dynamic and exhibit notable variations of the causal interactions.Another aspect of the glycolitic functionality was observed during the quantification of the Mutual Information, which measures how much the uncertainty about the one enzyme is reduced by knowing the other; we found that the uncertainty for ESecond, the numerical results show that for all analyzed cases the maximum effective connectivity corresponds to the Transfer Entropy from EThird, our analysis allows for a hierarchical classification in terms of what glycolytic enzyme is improving the future prediction of what others, and the results reveals in a quantitative manner that the enzyme EFrom the biochemical point of view the EForth, the dynamics of the glycolytic system changes substantially through the quasi-periodic route to chaos when the amplitude of the input-flux varies. However, the hierarchy obtained by transfer entropy, EWe want to emphasize that Transfer Entropy as a quantitative measure of effective causal connectivity can be a very useful tool in studies of enzymatic processes that operate far from equilibrium conditions. Moreover, many experimental observations have shown that the oscillations in the enzymatic activity seem to represent one of the most striking manifestations of the metabolic dynamic behaviors, of not only qualitative but also quantitative importance in cells  is an open system formed by a given set of dissipative enzymatic sets interconnected by substrate fluxes and three classes of regulatory signals: activatory , inhibitory  and all-or-nothing type . Certain enzymatic sets may receive an external substrate flux. In the DMN, the emergent output activity for each dissipative enzymatic set can be either oscillatory or steady state with an infinite number of distinct activity regimes. The first model of a Dissipative Metabolic Network was developed in 1999 Transfer Entropy is able to detect the directed exchange of causality flows among the irreversible enzymes which might allow for a rigorous quantification of the effective functional connectivity of many dissipative metabolic processes in both normal and pathological cellular conditions.The TE method applied to our numerical studies of yeast glycolisis shows the emergence of a new kind of dynamical functional structure which is characterized by changing connectivity flows and a metabolic invariant that constrains the activity of the irreversible enzymes.When the metabolite S (glucose) feeds the glycolytic system , it is tThe main instability-generating mechanism in yeast glycolysis is the self-catalytic regulation of the enzyme EIn the determination of the enzymatic kinetics of the enzyme ETo study the kinetics of the dissipative glycolytic system we have considered normalized concentrations; From the dissipative point of view the essential enzymatic stages are those that correspond to the biochemical irreversible processes The initial functions present a simple harmonic oscillation in the following form:The dependent variables http://www.webassign.net/pas/ode/odewb.html.The numerical integration of the system was performed with the package ODE Workbench, which created by Dr. Aguirregabiria is part of the Physics Academic Software. Internally this package uses a Dormand-Prince method of order 5 to integrate differential equations. Further information at This model has been exhaustively analyzed before, revealing a notable richness of emergent temporal structures which included the three main routes to chaos, as well as a multiplicity of stable coexisting states, see for more details TE allows for a quantification of how much the temporal evolution of the activity of one enzyme helps to improve the future prediction of another. The oscillatory patterns of the biochemical metabolites might have information which can be read-out by the TE. Further evidence about oscillatory behaviour in cellular conditions is given in For a convenient derivation, let generally assume that each of the pairs of enzymatic activity is represented by the two time series Rewriting the conditional probabilities as the joint probability divided by its marginal, one obtains an explicit form for the Transfer Entropy:http://www.mathworks.com/matlabcentral/fileexchange/14888.The problem of binning probabilities was solved by rounding at each time the values of the variables to the nearest integer, thus coarse-graining the continuous signal and counting the number of times (frequency) in which a variable is in a certain state. Similar choice were taking by Peng in his Matlab toolbox to compute the Mutual Information, further details in Another important parameter in the calculation of TE is the order We also addressed the statistical significance for TE. This was achieved by comparing the obtained values of TE between two series of enzymatic activity, say X and Y, with the values obtained when considering a random permutation of the future of Y, what we called, the shuffled-future of Y. The values of TE in The formula (6) is fully equivalent to the Mutual Information between directed graphs, the graph of information flows between pairs of enzymes.It is important to remark that the TE from Recently it was proved that the measures of effective connectivity based on Granger Causality MI quantifies how much the knowledge of one variable reduces the entropy or uncertainty of another. Therefore, MI says about how much information the two variables are sharing. Against other measures to compute correlations or statistical dependency, the strongest point of the MI is that it extends functionality to high order statistics For statistical independent Table S1Model parameter values.(PDF)Click here for additional data file.Appendix S1Initial functions domains and phase shift.(PDF)Click here for additional data file.Appendix S2Metabolic oscillatory behavior in cellular conditions.(PDF)Click here for additional data file.


Improvement of utilization of malaria treatment services will depend on provision of treatment services that different population groups of consumers prefer and would want to use. Treatment of malaria in Nigeria is still problematic and this contributes to worsening burden of the disease in the country. Therefore this study explores the socio-economic and geographic differences in consumers' preferences for improved treatment of malaria in Southeast Nigeria and how the results can be used to improve the deployment of malaria treatment services.This study was undertaken in Anambra state, Southeast Nigeria in three rural and three urban areas. A total of 2,250 randomly selected householders were interviewed using a pre tested interviewer administered questionnaire. Preferences were elicited using both a rating scale and ranking of different treatment provision sources by the respondents. A socio-economic status (SES) index was used to examine for SES differences, whilst urban-rural comparison was used to examine for geographic differences, in preferences.The most preferred source of provision of malaria treatment services was public hospitals (30.5%), training of mothers (19%) and treatment in Primary healthcare centres (18.1%). Traditional healers (4.8%) and patent medicine dealers (4.2%) were the least preferred strategies for improving malaria treatment. Some of the preferences differed by SES and by a lesser extent, the geographic location of the respondents.Preferences for provision of improved malaria treatment services were influenced by SES and by geographic location. There should be re-invigoration of public facilities for appropriate diagnosis and treatment of malaria, in addition to improving the financial and geographic accessibility of such facilities. Training of mothers should be encouraged but home management will not work if the quality of services of patent medicine dealers and pharmacy shops where drugs for home management are purchased are not improved. Therefore, there is the need for a holistic improvement of malaria treatment services. Malaria is a major cause of mortality and morbidity in Nigeria, and is responsible for 30% of childhood mortality, 11% of maternal mortality and more than 60% of out-patient visits . One of The limited healthcare facilities that exist in rural Nigeria make it difficult to provide the required good quality malaria management services ,5. Poor The preferences of consumers for sources for improving treatment of malaria should be understood and used to improve provision and utilization of appropriate malaria treatment services. Peoples' perception of the ease of accessing the various providers of malaria treatment can potentially determine their health-seeking behavior  and by eThere is need to increase the body of knowledge about the link of socio-economic status to consumers' preferences for improved malaria treatment, for proving appropriate and timely treatment of malaria. However, some strategies have been suggested which will be useful for providing timely, appropriate, and potentially equitable management of malaria within communities these include health education to mothers ,14,15; aMany of the recommended interventions for improving appropriate treatment of malaria could be at variance with what the communities really prefer. This will lead to poor utilization of such services thereby negating the original ideas behind their deployment. The ability for successful and sustainable disease control programs depends very much on "listening to the people" . TherefoThis study examined the preferences for improved malaria treatment by consumers and disaggregates these preferences by socio-economic status and geographic location of the respondents. The study also compared whether the rating and ranking scales will produce similar results, so as to assure the internal validity of the preferences. The findings are useful for evidence-based policy-making and development of strategies for equitably improving the deployment of demand-responsive malaria treatment services in different geographic areas for different population groups.This study was undertaken in Anambra state; Southeast Nigeria. The state has a high malaria transmission rate all year round and the annual incidence rate is between 10 to 35%. On the basis of discussions with Anambra State Ministry of Health (MOH) officials, 6 sites were chosen for the study. These were the three largest urban centres , Nnewi and Onitsha) from each of the three senatorial zones and one rural LGA randomly selected from each senatorial zone .Then, one community from each of the three rural LGAs: Enugwu-Ukwu (Njikoka LGA), Ekwulobia (Aguata LGA) and Okpoko (Ogbaru LGA) was selected using two-stage sampling, by first stratifying the communities according to whether they have a general hospital and then randomly selecting the sites from those that have general hospitalsThe software for population survey in EPI Info 6 was used for sample size calculation. The parameters that were used for sample size calculation were a power of 80%, 95% confidence level and considering 2% as the proportion of people with malaria that used services from the least commonly visited providers  and 5 hamlets  were randomly selected and the number of households in the selected areas enumerated to produce the household list. In the second stage, households were systematically included at regular intervals down the list, the starting point being chosen at random . InformaA pre-tested interviewer-administered questionnaire was used to obtain information from respondents in the randomly selected households. Local educated residents of each community were recruited and trained as field workers to administer the questionnaire. The respondents were asked to rank and also rate their preferences for improved malaria treatment services. Respondents were given a list of different sources of treatment  centers, pharmacy shops, patent medicine dealers, trained mothers, herbalists and community health workers (CHWs). Colorful option cards that depicted the different providers were also shown to the respondents to help them in visualizing them and aid their ranking and rating.The contingent ranking and rating of preferences of consumers for different providers was elicited after the different sources of treatment provision were explained to them. The ranking was done before the rating scale. They were first asked to rank the 3 they most preferred then rate each treatment source from 1 to 10. The ranking allowed respondents to state relative preferences amongst the top 3 and in each rating multiple options could be scored at the same level of preference. The questionnaire was also used to collect data on the general socio-economic and demographic characteristics of the respondents and their households, expenditures on food as well as value of home produced and consumed food, and their asset holdings  was used to generate the SES index ,23 that Ethical Clearance: The authors received the approval of the ethics committee of the College of Medicine, University of Nigeria, Enugu Campus before carrying out this study.Table Table Table Table Public hospitals were ranked and rated the most preferred choice for the improvement of malaria treatment services in both the higher socio-economic status (SES) group and rural areas. The fact that majority of the respondents stated that the best way to improve malaria treatment services in their community was to improve the quality in services being rendered by public hospitals, might be because public hospitals are known to have a large array of specialist services. Training of mothers that was also highly preferred will help to improve the treatment of malaria. This is line with the Roll Back Malaria (RBM) target for provision of timely and appropriate treatment of malaria . The useThe SES of the individual influenced their preferences. The finding that the preference for public hospital was highest for the least poor SES (Q4) compared to others may be because the better-off quartiles are usually more educated, and thus have more information about the advantages of having treatment in a public hospital where there is usually a presence of qualified personnel. Herbalists must have been viewed as inferior goods, where preferences fall as SES increases as was alluded to by their low preference as SES increased. The finding that the use of PMDs was ranked higher by poorer quartiles compared to the least poor quartile for improving malaria treatment is most likely due to the fact that it might be cheaper and easier for the poorer SES to visit PMDs. This corroborates the findings of some studies which showed that the poorer households were more likely to seek treatment from low level and informal providers rather than use the hospitals ,24.The geographic differences in consumer preferences for providers which showed that herbalist were ranked higher in rural areas than in urban may be because of more familiarity and higher levels of availability of herbalists in the rural areas when compared to the urban areas. The higher preference of public hospitals in the rural area compared to the urban area suggest that those in the rural areas actually need increased availability of public hospitals which would invariably have more qualified health workers and would most likely provide good quality malaria treatment services.It was seen that the rating scale and ranking of preferences produced similar findings, which is a sign of convergent validity of the findings . Apart fA limitation of the study was the fact that only two risk factors, namely socio-economic status and geographic locations were explored in this study because the study was primarily concerned with issues of socio-economic and geographic equity. However, other factors such as parity, occupation and age may also affect the preferences of consumers for different providers. The exploration of the role of these other factors should be the focus of future studies. Also, the study did not have a qualitative component, which would have helped to generate qualitative data that will either strengthen or disprove the quantitative findings. Another possible limitation is that use of local residents to act as fieldworkers might bias the results, but regular quality assurance by the investigators ensured that data collected was of very good quality.All in all, the paper has shown that preferences for provision of improved malaria treatment services were influenced mostly by SES and also by geographic location of the respondents to a lesser extent. The reasons for the differences in preferences were not explored in the study, but could be as a result of prior knowledge, experiences, costs and availability of the providers. However, it was obvious that people mostly preferred that improved malaria treatment services should be delivered through public health facilities such as hospitals and PHC centers. Hence, there should also be re-invigoration of public facilities for appropriate diagnosis and treatment of malaria, in addition to improving the financial and geographic accessibility of such facilities. However, there is a role of home management of malaria through training of mothers. However, home management will not work if the quality of services rendered by providers where drugs for home management are purchased are not improved. Therefore, there is the need for the government and development partners to also improve the quality of services of PMDs and pharmacy shops so that there is a holistic improvement of malaria treatment services.The authors declare that they have no competing interests.OO conceived the study. All the authors participated in data collection and analysis. NU wrote the manuscript with input from all the authorsThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/10/7/prepubContains a household questionnaire on the preferences of different household for where they sought treatment for malaria treatment. It also contains the socio-demographic detail of each respondent and their socio-economic status based on household owned assets and food expenditure pattern.Click here for file


The obtained closed form solutions are presented in the form of simple or multiple integrals in terms of Bessel functions and terms with only Bessel functions. The numerical integration is performed and the graphical results are displayed for the involved flow parameters. It is found that the velocity decreases whereas the shear stress increases when the Hartmann number is increased. The solutions corresponding to the Stokes' first problem for hydrodynamic Burgers' fluids are obtained as limiting cases of the present solutions. Similar solutions for Stokes' second problem of hydrodynamic Burgers' fluids and those for Newtonian and Oldroyd-B fluids can also be obtained as limiting cases of these solutions.The present work is concerned with exact solutions of Stokes second problem for magnetohydrodynamics (MHD) flow of a Burgers' fluid. The fluid over a flat plate is assumed to be electrically conducting in the presence of a uniform magnetic field applied in outward transverse direction to the flow. The equations governing the flow are modeled and then solved using the Laplace transform technique. The expressions of velocity field and tangential stress are developed when the relaxation time satisfies the condition γ = λ Magnetohydrodynamics is the study of flow of electrically conducting fluids in electric and magnetic fields. This phenomenon is essentially one of the mutual interaction between the fluid velocity and electromagnetic field i.e. the motion of the fluid affects the magnetic field and the magnetic field affects the fluid motion. Basically, magnetohydrodynamics is a research area that involves the study of motion of electrically conducting fluids such as plasma and salt water. MHD flows are found to have influential applications in many natural and man made flows. They are frequently used in industry to heat, pump, stir and levitate liquid metals. Another application for MHD is the magnetohydrodynamic generator in which electrically conducting fluid is used to generate electric power. The flows of an electrically conducting fluid in the presence of a magnetic field have important applications in various areas of technology such as, accelerators centrifugal separation of solid from fluid, purification of crude oils, astrophysical flows, petroleum industry, polymer technology, solar power technology, nuclear engineering applications and other industrial areas The literature on the study of MHD viscous fluid is abundant , the continuity Eq. We consider the unsteady incompressible flow of an electrically conducting Burgers' fluid occupying the upper half space of For such type of motions the governing equations are (8) and (9) with the following initial and boundary conditionsMoreover, the natural conditions Introducing the following non-dimensional variablesThe corresponding initial and boundary conditions In order to solve the initial and boundary-value problem Case-I: Solution of the problem forIn order to determine exact solutions for our problem, we substitute In order to find Of course, in view of Eq. Applying the inverse Laplace transform to Eqs. Now using Eqs. Similarly for the sine part of velocity, we get the following expressionIn order to find the dimensionless shear stress, we write For withThe Laplace inverse transforms of Eqs. The convolution product of Eqs. Similarly for sine oscillation we obtainFurthermore, it is noted that the expressions The inverse Laplace transforms of Eqs. Now taking the convolution product of Eqs. In the same way we find thatNow, in order to find the associated expressions for velocity, we directly put andEquivalent expressions for the velocities we can writewhereApplying the inverse Laplace transforms to Eqs.Consequently, introducing Eqs. (63) and (64) into Eq. (62), we obtainFollowing a similar way, we also obtainCase-II: Solution of the problem forLet us now consider the expressions of velocity fields and tangential stresses when Here the second grade equation In order to find the Laplace inverse transform of The Laplace inverse transform of Eq. Moreover, the Laplace inverse transform of Eq. In view of the relations Adopting a similar procedure for the sine oscillation of the boundary, we get an expression similar to Eq.whereThe corresponding expressions for the shear stresses are given byIn this section, for the accuracy of results, we consider a limiting case of our solutions. More exactly, we substitute The objective of the present paper is to study the unsteady MHD flow of a Burgers' fluid over an oscillating plate when the relaxation time satisfies the conditions In this paper, we have studied the MHD flow of Burgers' fluid when the relaxation time satisfies the conditions


Unfortunately the submitting author omitted the pathologists involved in the case by accident. The following authors have contributed to the scientific content of the published article as follows: Adnan Aali, Faris Kubba, and William Lynn, all processed the original tissue samples, and after much research and collaboration provided us with the overall results. They produced the slides and educated the orthopaedic authors on the subject matter. Andrew Borman provided detailed analysis of the rare eumycetoma and spent copious time examining the tissue material to give us a definite diagnosis. He also oversaw the whole manuscript.


Imaging technology with its advancement in the field of urology is the boon for the patients who require minimally invasive approaches for various kidney disorders. These approaches require a precise knowledge of the normal and variant anatomy of vascular structures at the hilum of the kidney in terms of their pattern of arrangement and division. The present paper describes a bilateral anomalous arrangement of the structures at the renal hilum as well as their peculiar branching pattern which is of clinical and surgical relevance. Multiple branching of the renal vessels was observed in both kidneys due to which the hila were congested. The right renal artery immediately after its origin divided into 2 branches. The upper branch represented an aberrant artery whereas the lower branch gave 5 divisions. The left renal artery also divided into 2 branches much before the hilum as anterior and posterior divisions. The anterior branch took an arched course and gave 6 branches. The posterior branch gave 3 terminal branches before entering the renal substance. In addition to anomalous hilar structures, normal architecture of both kidneys was altered and the hilum of the left kidney was found on its anterior surface. Kidneys are a pair of excretory organs situated one on each side of the vertebral column retroperitoneally. Being with a bean shape, it presents thick and rounded superior pole and thin and pointed inferior pole. Renal hilum is deep vertical slit situated in its medial border which lies about 5 cm from the midline opposite the lower border of L1 vertebra. It communicates with the renal sinus within the kidney  Various Knowing the anatomy of the ureteropelvic junction of the kidney is essential for understanding urinary tract disorders and various nephron sparing surgical procedures. The present study describes the bilateral anomalous arrangement of the structures at the hilum of kidney which is of clinical and surgical relevance.During dissection of about 60-year-old male cadaver, we observed anomalous positions and branching pattern of the renal vessels causing a congested renal hilum. The variation was bilateral . The hilRenal artery (RA) with its normal origin and course from abdominal aorta divided immediately into 2 branches . The supThe hilum was wide and situated on the anterior surface instead of its normal anatomical situation in the medial border .Left renal artery arose from abdominal aorta, before entering the hilum branched into 2 divisions. Anterior division presented an arched course superficial to the tributaries of renal veins and gave 6 branches. The upper 2 branches of it represented the aberrant arteries and entered the upper pole of the kidney. One of the aberrant arteries before piercing the substance of the kidney gave the right inferior suprarenal artery. The posterior division ran behind the renal pelvis and posterior division of renal vein and gave 3 branches. So altogether, 8 branches pierced the renal hilum and 2 branches pierced the upper pole of the kidney.Anterior and posterior tributaries of renal vein after emerging separately from hilum of the left kidney united to form a single trunk that drained into inferior vena cava. Before the union, the posterior division joined the anterior division in a twisted manner. Anterior division received left testicular vein (LTV). The left suprarenal vein (LSRV) drained into the trunk of the left renal vein. So the arrangement of the structures in the hilum of left kidney from anterior to posterior aspect was anterior division of the renal vein-anterior division of renal artery-renal pelvis-posterior division of renal vein-posterior division of renal artery (A-V-P-V-A).The schematic representation of bilateral renal hilar pattern with distorted shapes of kidneys is shown in Although abnormal shapes, positions, and vascular variations of the kidney have been reported earlier, to our knowledge, there are no reports on bilateral anomalous variations of the renal vessels as presented in this paper. The variations reported here are peculiar and unique. Variations in the branching pattern of the renal vessels probably might be the cause for the change in the shape of the kidney from the normal bean shape to the retort flask shape which is seen here. Morishima et al. reported a diamond shaped left kidney situated lower than usual, the hilum of which was widely opened and was facing anteriorly . A discoThe abnormalities in the renal arteries are mainly due to the various developmental positions of the kidney . InsuffiStudy conducted by Kaneko et al. presented 25% of multiple renal arteries which included the polar renal arteries . In the Rouvière et al. observed 29%–65% incidences with anomalous course of renal vessels crossing the renal pelvis cause of ureteropelvic obstruction . Obstruc