We have used high-energy x-ray scattering to map the strain fields around crack tips in fracture specimens of a bulk metallic glass under load at room temperature and below. From the measured strain fields we can calculate the components of the stress tensor as a function of position and determine the size and shape of the plastic process zone around the crack tip. Specimens tested at room temperature develop substantial plastic zones and achieve high stress intensities ( Fracture behavior is important for many prospective engineering applications of metallic glasses. Unlike conventional crystalline alloys for which stable flow in tension is possible due to strain hardening resulting from dislocation activity, metallic glasses strain soften during plastic deformation leading to localization of flow into shear bands. The result is apparently brittle mechanical behavior with almost no ductility in tension in most cases. Microscopically, however, there is often clear evidence for extensive plastic deformation of the material near the crack path. This allows some metallic glasses to achieve high values of fracture toughness despite the lack of macroscopic ductility In any material there is a competition between flow (driven by shear stresses) and cleavage , the outcome of which influences the stress intensity at the crack tip and determines the fracture toughness Several groups have previously examined the plastic zone in metallic glasses using shear band patterns on the surface in situ high-energy synchrotron x-ray scattering to map out the strain field around the crack tip as a function of applied stress intensity at various temperatures well below the glass transition. This technique allows us to probe the entire volume of material, including the plane-strain region in the interior of the specimen around the crack tip. An analysis of the strain maps (and corresponding maps of stress) allows us to determine the size and shape of the plastic process zone around the crack tip. We observe that the extent of the plastic zone increases, as expected, with applied stress intensity. The plastic zone is reduced at cryogenic temperatures, an observation that is correlated with a reduction in fracture toughness.The present work is motivated by a desire for a deeper understanding of the fracture behavior of metallic glasses, and in particular the influence of stress and strain fields on competing mechanisms of deformation and fracture near the crack tip. To this end, we have conducted fracture toughness tests on specimens of a Zr-based metallic glass using Although plastic deformation of metallic glasses has been studied extensively, fracture has been less thoroughly investigated even though it is obviously of central importance for structural applications. Much of the early experimental work, limited as it was to studies of thin specimens not well suited to mechanical testing, focused on phenomenology and in particular on the development of the characteristic “river” patterns observed on fracture surfaces, and on the tendency for annealing to foster brittle behavior due to either structural relaxation or devitrification. A more fundamental understanding of fracture of metallic glasses developed from the work of Spaepen The development of bulk metallic glasses has enabled new studies with specimens appropriate for fracture mechanics experiments, and in particular proper plane-strain fracture toughness measurements. Gilbert and coworkers On the basis of this work it is clear that the strain state around the crack tip is of central importance for understanding fracture of metallic glasses. To probe the strain state in a spatially-resolved way we employ high-energy x-ray scattering. Although there is a long history of using scattering techniques to measure elastic strains in crystalline materials An important feature of the high-energy x-ray technique is that it allows us to make a direct assessment of the strain state in a thick specimen, including the interior region ahead of the crack tip that is in a state of plane strain. This is in contrast to earlier work that examined the plastic zone using shear band patterns on the surface The stress intensity at fracture from our tests on The degree of scatter in Fracture surfaces for specimens tested at room temperature and low temperature are shown in Using the analysis outlined in the As a check on our results, we compare the stresses determined from the x-ray data with a calculation based on a simple model for the stresses around a crack tip in mode I loading in an infinite, fully elastic body For all four quantities compared (It is particularly interesting to note that directly ahead of the crack tip  in  there isi.e. for a given stress intensity on a given specimen), and then compile these into plots showing the trends with stress intensity, as shown in With the ability to measure strains and stresses in a spatially-resolved way, we can examine trends that develop as a function of load, temperature, or both, using data collected from multiple specimens. We have found it convenient to look at the maximum value of the von Mises stress, hydrostatic stress, and stress triaxiality from each map  that is nominally elastic-perfectly plastic until fracture, with no strain hardening. We would expect a linear increase in the stress components with increasing stress intensity, except for the region immediately around the crack tip where plastic deformation can occur. Only when the size of the plastic zone exceeds the spatial resolution of the measurement would we expect to see the saturation in stress values apparent for The plateau in von Mises stress in The observation of a plateau in the stress components in A quantitative estimate of the plastic zone size can be made by calculating the radius of gyration . In particular, we observe an Our results show that the fracture toughness of amorphous eratures . Based oOur observation that the crack-tip stresses do deviate from s stress  and thatOur data clearly show that a reduction in fracture toughness at low temperatures is associated with a reduction in the size of the plastic zone. Part of the explanation for this is that the flow stress of Zr-based metallic glasses increases with decreasing temperature, by amounts on the order of 15–20%  in size  and probTandaiya and coworkers recently proposed that fracture in ductile metallic glasses is not stress-controlled but rather is a strain-controlled process If attainment of a critical strain on an individual band is required for fracture, the number density of shear bands around the crack tip becomes an important consideration because a larger number of bands implies a smaller strain on each individual band, at least on average, for a given overall level of strain. Ravichandran and Molinari Although the bending geometry is not directly applicable to the mode I opening around the crack tip in our experiments, we assume that a similar scaling relationship holds. With increasing temperature the flow stress of metallic glasses decreases significantly slightly . Taken tSeveral groups have reported that tough metallic glasses tend to have high values of However, we also note that rack tip . The sigMore generally, we believe that the x-ray strain mapping technique demonstrated here can be broadly applied to amorphous materials in many contexts. A key concern for such studies will be the conditions under which shifts in the scattering peak position can be correctly interpreted in terms of elastic strain, and the precise nature of the relationship between the strains measured from such peak shifts and the stress state of the material. Although the elastic constants inferred from x-ray scattering strain measurements are in rough agreement with those measured via ultrasound, there may be systematic differences in some cases The specimens for this study were single edge-notch bend (SENB) samples of a Zr-based metallic glass. We prepared amorphous specimens of nominal composition specimen  is flattThe x-ray scattering experiments were performed at beamline 1-ID of the Advanced Photon Source (APS), with the SENB specimens loaded in three-point bending  requires that the specimen be sufficiently thick that plane-strain conditions predominate. The specified minimum thickness is The real-space structural information obtained in a scattering measurement is from a direction parallel to the scattering vector velength . BecauseElastic strain in amorphous alloys can be determined directly from shifts in the position of the first maximum in the scattering pattern We determined the positions of the first scattering maximum We can determine the normal component of elastic strain v.Although there is considerable uncertainty in the individual For more complex strain states we determine the principal strains as well as the rotation of the principal axes relative to the laboratory coordinate system  from theperiment . FurtherWith these expressions we can now write a new expression for the experimentally-observed component of normal strain along the his is where theTo find the principal strains and Due to limitations in the geometry of the experiment we cannot access any information about components of strain parallel to the x-ray beam  in . Calculasurfaces  and in pOnce we have the principal strains (High-energy x-ray scattering can be used to examine the strain state locally around crack tips in metallic glasses, and presumably in other amorphous materials as well. Care must be taken in interpreting the data due to the complicating effects of plastic deformation and a nonlinear relationship between peak shifts and stress. In amorphous


How sensory stimuli are encoded in neuronal activity is a major challenge for understanding perception. A prominent effect of sensory stimulation is to elicit oscillations in EEG and Local Field Potential (LFP) recordings over a broad range of frequencies. Belitski et al.  recordedTo understand better how different frequency bands of the LFP are controlled by sensory input, we computed analytically the power spectrum of the LFP of a theoretical model of V1 (a network composed of two populations of neurons - excitatory and inhibitory), subjected to time-dependent external inputs modelling inputs from the LGN, as a function of the parameters characterizing single neurons, synaptic connectivity, as well as parameters characterizing the statistics of external inputs.Our model consists in a two populations network of excitatory and inhibitory leaky integrate-and-fire neurons. Standard analytical methods using the Fokker-Planck formalism can be used to compute average firing rates of both populations in the asynchronous state of the network, as well as the region of parameters for which this state is stable ,3). The . The 3])We then used the analytical expression of the LFP power to fit the experimental data of . The datThe model provided excellent fits of the data. The fitting procedure permitted to extract the values of the firing rates of the excitatory and inhibitory populations and the parameters characterizing the external input for most of the scenes of the movie. These outcomes could be then correlated with experimental firing rates and the features of the movie itself, such as temporal and spatial contrast as well as orientation. We found a significant correlation both between firing rates extracted from fit and the multi-unit activity recorded during the movie and between the parameters characterizing the external input and the features of the movie.These results show how an analytical approach can be used to estimate the key parameters underlying changes in the LFP spectral dynamics.


Department for Congenital Heart Surgery at the Mother and Child Health Institute of Serbia dates from 1982.The team consists of 2 surgeons, one resident, three anaesthesiologists and 2 intensivists. The number of operated cases at the Mother and Child Health Institute of Serbia is between 130 and 160 per year.In 2003. four projects commenced: the arterial switch operation, Norwood I, redo surgery and valvular surgery. For arterial switch, after initial successes, came a series of deaths resulting in a high mortality of over 40% . The analysis of the risk factors showed that beside surgical misses, the reasons were various levels of motivation and dedication between different members of the surgical team. Only after reorganization the results changed dramatically: the mortality rate for ASO is now under 8%. The crucial identified risk factor was long anaesthesia induction and management of the immediate postoperative care. The results of treatment of HLHS with an overall mortality above 75% are still distant from the current standards. Inadequate preoperative management and late referrals are the main reasons for mortality. Children with valvular anomalies are dominantly treated with valve replacements. The univentricular heart patients have longer postoperative recovery, mortality varies between 12% and 16%. The results of the routine paediatric cardiac surgery are consistent with results of the major cited literature data.ECMO and heart transplant are not available in our country. The lack of financial and donor support and the potentially low number of patients gravitating towards our institution question the cost benefit ratio.Compared to the surrounding countries, the provided services offered at our hospital can be regarded as cheaper, available and up to the standards of contemporary mid developed European countries.


Contrast-enhanced ultrasonography (CEUS) is a dynamic digital ultrasound-based imaging technique, which allows quantification of the microvascularisation up to the capillary vessels. As a novel method for assessment of tissue perfusion it is ideally designed for use in the ICU. CEUS is cost-effective and safe and can be repeatedly performed at the bedside without radiation and nephrotoxicity.The frequency of CEUS use in the multidisciplinary surgical ICU was retrospectively evaluated for the period from 1 September 2011 to 1 September 2012. Furthermore, contributions of this novel method to the management of critically ill ICU patients as well as its accuracy were assessed.In total, 33 CEUS studies were performed in critically ill ICU patients. The most frequent indications included: assessment of the liver perfusion, assessment of the pancreas and kidney perfusion after pancreas and kidney transplantation, assessment of the renal perfusion in acute kidney injury (AKI), assessment of active bleeding and assessment of the bowel perfusion. In all studies, the correct diagnosis was achieved and the transport of critically ill patients to the radiology department for further diagnostic procedures as well as application of iodinated contrast agents was avoided. In 16 cases significant new findings were detected. Twelve of them were missed by conventional standard Doppler ultrasound prior to CEUS. In assessment of seven cases with AKI, impaired or delayed perfusion and microcirculation of the kidney was observed in six patients. In three patients urgent surgical intervention was performed because of CEUS results. In three cases active bleeding was excluded at the bedside due to absence of contrast agent extravasation into hematoma (thigh and perihepatic) or into abdominal cavity, without need for complementary CT imaging or angiography. In one case the regular perfusion of intestinal anastomosis was confirmed with no need for surgical exploration. None of patients undergoing CEUS manifested any adverse reactions or developed any complications associated with the imaging technique.Contrast-enhanced ultrasonography clearly improves visualization of the perfusion in various tissues. It is very likely to be superior to standard Doppler ultrasound, and is safe and well tolerated in critically ill patients. Promising indications for the use of CEUS in the ICU may be the assessment of kidney microcirculation and assessment of liver perfusion in liver transplant and liver trauma patients.


We investigated the association of the intensity of newspaper reporting of charcoal burning suicide with the incidence of such deaths in Taiwan during 1998–2002. A counting process approach was used to estimate the incidence of suicides and intensity of news reporting. Conditional Poisson generalized linear autoregressive models were performed to assess the association of the intensity of newspaper reporting of charcoal burning and non-charcoal burning suicides with the actual number of charcoal burning and non-charcoal burning suicides the following day. We found that increases in the reporting of charcoal burning suicide were associated with increases in the incidence of charcoal burning suicide on the following day, with each reported charcoal burning news item being associated with a 16% increase in next day charcoal burning suicide (p<.0001). However, the reporting of other methods of suicide was not related to their incidence. We conclude that extensive media reporting of charcoal burning suicides appears to have contributed to the rapid rise in the incidence of the novel method in Taiwan during the initial stage of the suicide epidemic. Regulating media reporting of novel suicide methods may prevent an epidemic spread of such new methods. We assessed whether the intensity of newspaper reporting was associated with subsequent increases in charcoal burning suicides.Because no personal data were involved, this study was exempted from ethical review by the Human Research Ethics Committee, Taipei City Hospital, Taiwan.During 1998–2002, three major newspapers, China Times (CT), United Daily (UD) and Liberty Times (LT) accounted for more than 90% of newspaper sales in Taiwan with approximately equal market shares for these three newspapers The electronic archives for LT did not cover the study period. To assess possible bias from the exclusion of this paper, we randomly selected two months in 2001/2002 and hand searched the newspaper archives to investigate the concordance of suicide reporting in LT with UD and CT. The reporting of charcoal burning suicides in the LT was lower than the other two daily newspapers. In the two months selected in 2001, we identified a total of ten news items on charcoal burning suicide in UD, seven in CT and only one news item in LT. In 2002, 23 news items on charcoal burning suicide were identified for UD and 19 for CT, but only 3 news items on charcoal burning suicide were reported in LT, indicating the reporting of charcoal burning suicide in LT was probably lower than in the other two newspapers. Throughout the study period, suicide news stories  were never reported on the front pages of the papers reviewed.Data on suicide deaths, classified according to the International Classification of Disease (ICD-9) were obtained from official death records in Taiwan. The ICD-9 codes used were deaths registered in E950–959  and E980–989 (intent undetermined). Deaths certified as undetermined intent were also included because previous research indicated that many suicide deaths were included in this category t, and the intensity function The cumulative number of charcoal burning  news items about suicide from time 0 (beginning of 1998) up to time t. The same approach was used for suicides by methods other than charcoal burning. The adjusted models are obtained by including q lagged terms (up to one week) of the corresponding covariates. Our primary hypothesis concerned the impact of news reporting on the incidence of charcoal burning suicides, but of course if there were no suicides there would be no reporting, so we also investigated the strength of association between the incidence of suicides and subsequent reporting of these deaths. To do this we used a Poisson generalized linear autoregressive model similar to (1) except that the number of reported news items acted as the dependent variable. For interpretability, the lag parameter q was set to 7 in all the aforementioned models as prior studies tended to assume that the effect of news reporting of non-celebrity suicides lasted for about 1 week To formally assess the potential impact of news reporting of charcoal burning suicides on suicide incidence, analyses using conditional Poisson generalized linear autoregressive models were performed. We first fitted an unadjusted Poisson generalized linear autoregressive model to examine the effect of newspaper reporting of charcoal burning suicide on the incidence of charcoal burning deaths. In this model only lag terms of the predictor  and outcome  were included. We then fitted an adjusted model by adding potential confounders to the model. The potential confounders were the daily count of non-charcoal burning suicide (which served as an indicator of background suicide rate) and day of the week (as the number of newspaper pages and suicide count could vary according to different days of the week). Equivalent models for the impact of news reporting of non-charcoal burning suicide on non-charcoal burning suicide deaths were fitted as well. Specifically, the Poisson generalized linear autoregressive model we used for the count of charcoal burning suicides The incidence of charcoal burning suicide began to increase in 2000, with a more rapid and prominent rise in 2001, whereas the incidence of suicide using all other methods was relatively stable during the study period with a slight fall towards the end of 2002 , the peak of charcoal burning suicide (June 2002) occurred after the peak of reporting of charcoal burning suicide (Feb. 2002), suggesting that news reporting could have contributed to the momentum for the spread of charcoal burning suicide in the community. Furthermore, when the rate of change of charcoal burning suicide increased, the rate of change of other methods declined (panel 3) indicating some possible substitution of methods; similarly, when charcoal burning suicide was excessively reported, the reporting intensity (number of reports per case) of other methods of suicide decreased and vice versa (panel 4). It is important to note that the incidence of charcoal burning remained at a high level even after the reporting intensity has reduced. This suggests that by this stage the method of charcoal burning suicide had penetrated into the community and become self-perpetuating, regardless of further reporting.To assess potential mutual causation (i.e. increased suicide led to increased reporting), Newspaper reporting of charcoal burning suicide was associated with an increase in the number of charcoal burning suicides in Taiwan during the early period of the epidemic. Based on our estimation, each reported charcoal burning news item was associated with a 16% increase in next day charcoal burning suicide; whereas the reporting of all other methods of suicide was unrelated to their incidence on the following day. The period when the rate of increase in the newspaper reporting of charcoal burning suicides was at its highest preceded the peak rate for charcoal burning suicide, providing some evidence for a causal effect of news reporting, although other explanations are possible. The reporting intensity of charcoal burning suicide decreased after early 2002 but the incidence of charcoal burning suicide remained high, although the rate of increase of charcoal burning suicides decreased slightly during this period. This finding indicates that when a novel method is made well known, it may become self-sustaining and further reporting may not influence its relative incidence.Our study provides the first empirical evidence of the possible role of newspaper reporting on the charcoal burning suicide epidemic in Taiwan. This is also the first report that illustrates the dynamic and competitive relationships of news coverage for different types of suicide news. However, our study results should be interpreted in light of the following limitations. First, a challenge in the assessment of the association between media reporting and suicide incidence is the problem of reverse causation, i.e. media reporting of suicide events is in part a reflection of its increasing incidence, rather than media ‘causing’ the increase in suicide rates. We assessed the causal direction by exploring the temporal association between media reporting and suicide incidence, i.e. whether rises in reporting preceded rises in suicide and found some evidence that this was the case. Second, suicide rates in Taiwan have been rising since 1993, it is possible that the increasing use of charcoal burning suicide is a reflection of underlying trends in suicide rather than an effect of media reporting, although the rise in charcoal burning deaths occurred 5 years after the more general increase in Taiwan’s suicide rates. Third, ICD codes did not allow us to distinguish charcoal burning suicides from other suicide by gassing, but as the great majority of such suicides were by charcoal burning th”; on UD the news read “Two students from Taipei First Girls High School left death notes and said goodbye to the world together”. Our finding suggests that cumulative media reporting of a new method adopted by the general population may have the potential to induce a suicide epidemic through a gradual diffusion process.Although charcoal burning suicide has become one of the most common methods of suicide in some Asian countries The finding that after Feb. 2002, the reporting intensity of charcoal burning suicide decreased (second panel, Our analysis demonstrates the mutual causation between news reporting of charcoal burning suicide and its actual incidence; i.e. the incidence of charcoal burning suicide was associated with its reporting and the reporting of the novel method was related to its future incidence. The process of self-perpetuation through mutual causation may have been a crucial factor for the emergence and the diffusion of the novel method in Taiwan.Our analysis reveals that reporting of different types of suicide news are competitive. When one type of suicide news gets media attention, other types of suicide news items get less reported.This analysis indicates that newspaper reporting may have fuelled Taiwan’s charcoal burning suicide epidemic. Repetitive reporting appears to be harmful, despite the fact that the news items were not placed in the front page, and no celebrity suicides were linked to the use of the method at the early stage of the epidemic. However, once the method had become rooted in the community, the impact of media reporting becomes less prominent; the method takes its own path and becomes self-sustaining. Hence, working proactively with the media to improve the quality of reporting of these tragic deaths and regulate potential harmful reporting are particularly important in the early stage of a suicide epidemic. When a new method becomes widely used, prevention focusing only on regulating media reporting is not adequate. Other intervention measures such as method restriction, gatekeeper training and improve mental health of high risk groups should all be considered.


Matched-Molecular Pair (MMP) analysis has recently emerged as a data analysis technique in medicinal chemistry. It quickly gained scientific momentum because it tackles key questions in lead optimization. In contrast to classical global QSAR models that attempt to predict the absolute numbers of ADME  and toxicological properties, MMP analyses predict the difference in (bio-) chemical properties that can be expected due to small chemical modifications to lead structures, with a much smaller and well-controlled error than global QSAR models.The power of MMP analysis depends on the number of previously documented similar molecular transformations, whereas the definition of chemical similarity plays a key role: the more generous the definition of similarity of the anchoring region, the more examples are available. The more strict the definition of similarity, the lower the variability and thus the clearer the effect on ADME-Tox parameters, but also the less data pairs will be available .The (bio-) chemical effect and the significance of the results depends on the experimental uncertainty (=noise) in the data. There is a clear mathematical association between the noise level and the minimum activity difference necessary for statistical significance. Here we demonstrate how the experimental uncertainty and variability,3 affect


Recent findings of aldosterone-independent stimulation of ENaC by vasopressin challenge the completeness of dogmatic understanding where ENaC serves solely as an end-effector of the RAAS important for control of sodium balance. Rather the consequences of activating ENaC in the distal nephron appear to depend on whether the channel is activated in the absence  or presence [by vasopressin (AVP)] of simultaneous activation of aquaporin 2 water channels. Thus, a unifying paradigm has ENaC at the junction of two signaling systems that sometimes must compete: one controlling and responding to changes in sodium balance, perceived as mean arterial pressure, and the other water balance, perceived as plasma osmolality.Due to the abundance of seminal discoveries establishing a strong causal relation between changes in aldosterone signaling, the activity of the epithelial Na The epithelial NaNormal ENaC function is required for proper sodium balance and thus, normal blood pressure. Gain-of-function mutations in ENaC cause inappropriate renal sodium retention and consequent increases in mean arterial pressure  Figure Because of the abundance of seminal discoveries establishing this strong causal relation between changes in aldosterone, ENaC activity and blood pressure, the role of ENaC in health and disease is understood almost exclusively through the concept of feedback regulation by the RAAS  being shifted by AVP from protecting plasma sodium to facilitating water reabsorption. This exciting idea raises several questions centered on the hypothesis that the function of ENaC in the ASDN  dependents on whether the channel is activated in the absence or presence of simultaneous activation of AQP2 water channels where AVP activates both ENaC and AQP2.+]: a question that largely remains to be answered. Insight, though, can be gleamed from several recent findings as discussed below.Upon initial consideration, the idea that AVP-activated ENaC facilitates free water reabsorption seems counter-intuitive to the established role for this channel in protecting plasma sodium. However, the essential question here is whether ENaC activated in the ASDN in the presence of AQP2 contributes more to the draw for free water reabsorption or plasma [Na+] is significant for it will define the paradigm  renal sodium excretion, transport and the activity of ENaC in the ASDN are in agreement that increases in aldosterone are sufficient to increase ENaC activity  results form two events. There is loss of negative-feedback regulation by glucocorticoids of the hypothalamic-pituitary axis controlling AVP release and there is strong non-osmotic stimulation of AVP release resulting from volume depletion due to sodium and water wasting by the kidney  secretion (SIADH) is not associated with hypovolemia. No results are available currently regarding ENaC activity in this condition and thus, it is unclear if increases in AVP in this setting also stimulate ENaC. Prolonged agonism of the VWhile several key questions remain about the physiological and pathological consequences of AVP-stimulation of ENaC, it is clear that AVP can increase the activity of this channel. This positions ENaC to be an end-effector of both aldosterone, as the final signal in the RAAS and AVP. Signaling through RAAS, in part because it activates ENaC, influences plasma sodium and thus, blood pressure; and signaling by AVP influences free water reabsorption, in part, because it activates AQP2. As argued above, AVP-stimulated ENaC likely facilitates water reabsorption. This contributes to protection of vascular volume as likely is the case in adrenal insufficiency, but does it do so at the expense of facilitating hyponatremia? Such a question highlights the potential limitations imposed by the mechanics of water movement only through osmosis in biological systems and by the evolution of the mammalian renal tubule where ENaC sits at the intersection of two homeostatic control systems one responding to and influencing plasma sodium, and the other plasma osmolality that must by their nature sometimes be in competition.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The transport and accumulation of anticancer nanodrugs in tumor tissues are affected by many factors including particle properties, vascular density and leakiness, and interstitial diffusivity. It is important to understand the effects of these factors on the detailed drug distribution in the entire tumor for an effective treatment. In this study, we developed a small-scale mathematical model to systematically study the spatiotemporal responses and accumulative exposures of macromolecular carriers in localized tumor tissues. We chose various dextrans as model carriers and studied the effects of vascular density, permeability, diffusivity, and half-life of dextrans on their spatiotemporal concentration responses and accumulative exposure distribution to tumor cells. The relevant biological parameters were obtained from experimental results previously reported by the Dreher group. The area under concentration-time response curve (AUC) quantified the extent of tissue exposure to a drug and therefore was considered more reliable in assessing the extent of the overall drug exposure than individual concentrations. The results showed that 1) a small macromolecule can penetrate deep into the tumor interstitium and produce a uniform but low spatial distribution of AUC; 2) large macromolecules produce high AUC in the perivascular region, but low AUC in the distal region away from vessels; 3) medium-sized macromolecules produce a relatively uniform and high AUC in the tumor interstitium between two vessels; 4) enhancement of permeability can elevate the level of AUC, but have little effect on its uniformity while enhancement of diffusivity is able to raise the level of AUC and improve its uniformity; 5) a longer half-life can produce a deeper penetration and a higher level of AUC distribution. The numerical results indicate that a long half-life carrier in plasma and a high interstitial diffusivity are the key factors to produce a high and relatively uniform spatial AUC distribution in the interstitium. Delivery of chemotherapeutic nanodrugs to the targeted tumor cells from intravenous injection includes transport and distribution of nanodrug to tumors and other organs via system circulation, extravasation from tumor vasculature, and interstitial transport to reach individual tumor cells. The chemotherapeutic efficacy depends on the spatial and temporal concentration distribution of nanodrugs in the entire tumor, which is related to tumor micro-environments and physicochemical properties of nanodrug carriers. In addition, the toxicity of nanodrugs to normal tissues should also be taken into consideration.The characteristics of tumor vasculature and interstitial space significantly influence drug delivery in solid tumors. In contrast to normal tissues, tumor vessels are leaky, chaotic, and non-homogeneously distributed et al.Modeling the effects of critical factors on the spatial and temporal responses of nanodrug carriers in tumor tissues can offer an insight into the efficiency of tumor chemotherapy. A mathematical model describing the delivery of monoclonal antibodies (mAb) in prevascular tumor nodule was constructed by Banerjee et al.et al.In 2008, Goodman et al. were used to obtain the transport parameters of macromolecular carriers for the proposed mathematical model and we then extended these transport parameters to study their effects on the spatiotemporal distribution of macromolecular concentration in tumor tissues In this study, the vascular density of tumors and transport parameters, such as vascular permeability, interstitial diffusivity, and half-life time of macromolecular nanodrug carriers, were investigated by a mathematical model. Our model displays the spatial and temporal responses of macromolecular carriers with different transport parameters and vascular density in tumor tissues. The experimental results published by Dreher The primary goal of drug delivery is to increase the concentration and accumulative exposure of therapeutic agents in the tumor tissue. In other words, the larger the AUC in the tumor, the better. The delivery efficiency of a therapeutic agent is highly dependent on the internal structure of tumors. Different from normal tissue, the tumor structures are much more complicated and vary largely with respect to the size and type of tumors et al. showed that the pressure rises rapidly in the periphery and soon reaches a maximum plateau value throughout the rest of a tumor. They also indicated that the maximum values were reached at a distance of 0.15 to 1.2 mm from the surface of most of the isolated tumors studied. Zero pressure gradient was maintained throughout the plateau within the tumor The heterogeneity of blood perfusion in tumors is caused by the uneven distribution of vasculature in neoplastic tissues vice versa. Applying symmetry, a square element of this periodic structure with a pair of arterial and venous microvessels located at two opposite corners of the square would be the geometric configuration for the current problem naturally, as shown in In this work, we do not investigate the drug transport across the entire tumor, which is a very difficult problem both in modeling and simulation, but rather study the drug delivery behavior locally. Under the assumption that the microvessel network can be considered tightly arranged and periodically distributed like crystals, a small zoom-in region is considered here with negligible pressure gradient imposed from the surrounding tissue. In such a small region, the pressure gradient occurs only due to the source and sink of local, leaky microvessels. The two-dimensional cross-sectional view of the distribution of these microvessels is illustrated in Here, as shown in We assume that the injected drug is well circulated, and thus the concentrations along microvessels are set equal. The change of concentration is caused by tissue absorption, elimination through the lymphatic system and other physiological uptakes. The joint effects of these drug uptakes result in a temporal change of the drug concentration inside blood vessels, which can be approximated by fitting the experimental data. Consequently, the concentration decay, combining all the elimination effects in the body, can be described in terms of half-life in plasma of each drug carrier as,In our work, the nanodrug delivery in tumor tissues was investigated. For convection, the drug is transported across the wall of arterial microvessel (high pressure area), travels through the tumor interstitium and is finally drained by venous microvessel (low pressure area). For diffusion, drug is diffused from high-concentration area (blood microvessels) to low-concentration one (interstitium). The whole mechanism of drug transport is the interplay between convection and diffusion with the wish that the AUC of drug is as large as possible in tumor interstitium. Convection would be the dominant transport mechanism for large molecules since they move slowly by diffusion. In contrast, small molecules diffuse faster and therefore their dominant transport mechanism is diffusion The leaky microvessels can be modeled as hollow cylinders with semi-permeable walls embedded in a porous medium (tumor interstitium). According to Starling's hypothesis, the net fluid flow across a vessel wall is given byThe flow in the interstitial area satisfies Darcy's law as Provided the velocity distribution in the interstitium, determined from To compute It is important to have an anticancer nanodrug access all tumor cells in lethal quantities to avoid tumor recurrence caused by certain cells that remain alive after treatments. Therefore, the penetration depth and accumulative exposure of an anticancer nanodrug in the interstitial region of tumors are crucial to the tumor's overall drug exposure, in particular for distant cancer cells residing away from the vasculature. This means we wish the spatial distribution of AUC to be of a high level and as uniform as possible at the same time. In general, the nanodrug distribution within a tumor is determined by its supply, the vascular permeability, interstitial transport of the nanodrug, and nanodrug-cell interactions. Below, we investigate and discuss how AUC distribution depends on vascular density, vascular permeability, interstitial diffusivity, and half-life in plasma. Though the computational domain shown in To determine the physiological parameters of macromolecular dextrans in tumor tissues, we used the current model to fit the experimental results of spatial-temporal distributions for different molecular weights of dextrans The physiological parameters of macromolecular dextrans shown in Furthermore, To study the influence of vascular permeability of dextran on their AUC distributions, we simulated the conditions with the vascular permeability both increased and decreased by different multiples of their respective values in The vascular permeability depends on the properties of particles  and the vessel wall . As the particle size increases, the permeability decreases and becomes zero when the particle size is larger than the pore cut-off size. Nanoparticles that are larger than albumin are most likely to transport through intercellular junctions since inter-endothelial junctions in tumors can be as large as hundreds of nanometers to a few micrometers To investigate the influence of interstitial diffusivity of dextran macromolecules on their AUC distributions, we simulated the conditions with various interstitial diffusivities while the other parameters remain the same. The spatial distributions of AUC  A higher vascular density means a shorter transport distance between vessels for sources of dextran macromolecules, and hence a higher and relatively more uniform spatial AUC distribution can be produced. Also the effect of vascular density on the spatial AUC distribution is more pronounced for large dextran macromolecules than small ones. 2) A medium-sized dextran macromolecule has the best performance among all three kinds of dextrans with various molecular weights considering both the level and uniformity of spatial AUC distribution in tumor interstitium. 3) A large dextran macromolecule possesses a long half-life while it results in a shallow penetration with a very high AUC in the perivascular region due to its low diffusivity, and the condition gets much worse for a tumor region with lower vascular density. 4) A small dextran macromolecule has the most uniform distribution of AUC among all due to its high interstitial diffusivity, but has the lowest level of AUC distribution due to short half-life in plasma. 5) Enhancement of vascular permeability implying more leaky vessels helps elevate the level of AUC for all three kinds of dextrans, but has little effect on the uniformity of distribution of AUC. 6) Enhancement of interstitial diffusivity would elevate the level of AUC and at the same time make AUC more uniform for all three kinds of dextrans. 7) A longer half-life of dextran macromolecules in plasma can produce a deeper penetration and a much higher AUC distribution.et al. developed a nanoparticle-based drug modified by multicomponent nano chains, which help anticancer drug delivery into deep interstitial and avascular regions A small dextran macromolecule generally has much better uniformity of spatial distribution of AUC due to large interstitial diffusivity compared to larger macromolecules. However, the level of its AUC is rather low because of its short half-life in plasma. Appropriate surface modification of dextran macromolecules may be able to extend the dextran macromolecule half-life in blood. Alternatively, we may physically or chemically transform large nanoparticles, when they enter tumor interstitium, to small ones that have greater vascular permeability and interstitial diffusivity to enable transport deeper into tumor tissues We present a small-scale mathematical model to study the concentration and AUC distributions for localized tumor regions under various conditions. The results clearly depict 1) the limitation of nanoparticle delivery in the local tumor tissues, 2) the treatable domain for a nanoparticle when the tumor and particle properties are given, and 3) the potential improvement when vascular permeability, interstitial diffusivity and half-life in plasma are enhanced. The current model is a two-dimensional model and can only be used to analyze the delivery and transport of nanoparticle-based drugs in a local tumor region with uniformly distributed blood vessels, which is well justified by its small scale. With the assorted results from various vascular densities in The effectiveness of cancer tumor treatment depends on the delivery of therapeutic agents to all tumor cells in different regions of a tumor in order to help avoid tumor regrowth and development of resistant cells. This study numerically elucidates the barriers to drug transport in the tumor tissues to assess methods that aim to achieve a higher and more uniform AUC distribution in the tumor tissues within regions of different vasculature. Thus we provide a better understanding of significant factors that contribute to therapeutic strategies aiming to improve passive and/or active tumor chemotherapy.Supporting Information S1Table S1, The physiological parameters of the normal tissue used to validate our numerical method.(PDF)Click here for additional data file.


This research forms the dissertation for an MSc in Podiatry.The Intermetatarsal (IM) angle forms an integral component in the assessment of Hallux Abducto Valgus (HAV) surgery. Commonly used to assess the severity of such deformity and guide surgical selection, the degree of accuracy is debatable for both clinical and research purposes.A common fault of previously described IM angle assessment techniques is that when the shaft of the metatarsal, or the metatarsal head its self has been altered through the surgery there is inaccuracy associated with the measurement of the post operative radiograph when these reference points are used.A new method of assessment is proposed which can be applied for accurate assessment of both pre and post operative radiographs using the same method of examination. This new technique utilises the lateral most margins of the head of the metatarsal and most lateral margin of the base of the metatarsal. It is inherently applicable to all base, mid-shaft and distal osteotomy selections with or without medial eminence cheilectomy, a feature its predecessors have had difficulty in assessing accurately.All patients whom underwent a surgical procedure to change the IM angle with in our surgical department were recruited into our study. There were no restrictions on the severity of deformity, osteotomy selection or preoperative examinations.Pre and post operative radiographs were assessed blinded to the surgery three times by three different members of the surgical team. The inter- and intra-tester reliability of the new examination was compared against commonly used examination techniques.It is anticipated that this new method of IM angle assessment will provide grounding for a uniform pre- and post-operative radiographic interpretation for a variety of surgical procedures. It is hoped this simple technique will be applicable to future research and clinical settings.


In the Indian scenario, research in mental health is notably deficient, but available clinical and epidemiological data suggest a significant co-morbidity between mental diseases and cardiovascular diseases. Mental health problems do not have the precision of other biological sciences due to the complex phenotypes. In India the effects of culture and the transition in symptomatology of psychiatric patients are also important. Equally important are the family influences, traditional Indian herbal ethno-pharmacology and the community care perspective. The Indian systems of medicine give a lot of attention to visceral functioning and psychiatric research look into the metabolic substrate.


In this paper we analyse the impact of financial liberalization and reforms on the banking performance in 17 countries from CEE for the period 2004–2008 using a two-stage empirical model that involves estimating bank performance in the first stage and assessing its determinants in the second one. From our analysis it results that banks from CEE countries with higher level of liberalization and openness are able to increase cost efficiency and eventually to offer cheaper services to clients. Banks from non-member EU countries are less cost efficient but experienced much higher total productivity growth level, and large sized banks are much more cost efficient than medium and small banks, while small sized banks show the highest growth in terms of productivity. The opening to the outside and the internal structural reforms of the financial sector are two interdependent processes, both having as a purpose the development of a financially competitive and efficient system in order to facilitate economic growth and financial system stability.In the present days, in the context of recent turmoil on the financial markets, there is a dispute regarding the benefits of financial liberalization. There are opinions that the financial deregulation and the increasing of the process of globalization were the main causes what amplified the recent financial crisis. Many studies evaluate the direct impact of financial deregulation on banking performance, their empirical results are also rather controversial. Some authors, such as Combining insights from the liberalization – efficiency and financial openness – stability literatures, we develop a unified framework to assess how regulation, supervision and other institutional factors may affect the performance of banking systems in 17 countries from Central and Eastern Europe for the period 2004–2008. This study seeks to address two key questions. What variables influence the performance of banks from Central and Eastern European countries? Did the financial liberalization and reforms in the banking system have a notable influence on bank performance?Actually, we analyze the impact of financial liberalization and reforms in the banking system as well as the associated changes in the industry structure on the banking performance, measured in terms of cost efficiency and total productivity growth index. To do this, we develop a two-stage empirical model that involves estimating banks’ performance in the first stage and assessing its determinants in the second one.The importance and originality of this paper consist in assessing the CEE banking systems in a period when there were two waves of EU enlargements and the first influences of the recent international financial crises had appeared. Our sample of countries could be split into three categories: EU members, EU candidates and other potential EU candidates. The results of our papers are important in the context of the present financial turmoil; therefore, in the end of the paper, we try to develop some policy recommendations for both policy makers from CEE countries and EU ones. The evidence of our research could also be useful for banks’ strategies of internationalization.Cross-country efficiency studies in the banking industry have attracted a lot of attention. For banks, efficiency implies improved profitability, greater amount of funds channeled in, better prices and services quality for consumers and greater safety in terms of improved capital buffer in absorbing risk Studies of the impact of deregulation upon efficiency have found different results. Evidences from Taiwan Studies focused on the case of developing countries from Central and Eastern European countries explore various issues including the impact of ownership and privatization The creation of an effective and solid financial system constituted an important objective of the process of reform and transition from a centralized economy to a market economy in CEE countries. The liberalization of prices, the liberalization of the circulation of goods, services and capital, the deregulation of financial systems, globalization and the mutations on the level of the economic, social and political environment had a significant impact on the development of the CEE banking system Most studies focused on the banking system in Central and Eastern Europe (CEE) are only performed at the level of one state and do not offer comparative information regarding the efficiency and productivity growth of banks in these states. However, in recent years, several papers have published comparative analyses highlighting the impact of banking system reform, the evolution of banking structure, competition and privatization on banks’ efficiency see e.g. ,.Fang et al. find that the institutional development, proxied by progress in banking regulatory reforms, privatization and enterprise corporate governance restructuring, has a positive impact on bank efficiency Brissimis et al. examine the relationship between banking system reform and bank performance – measured in terms of efficiency, total factor productivity growth and net interest margin – accounting for the effects through competition and bank risk-taking Pasiouras et al. uses stochastic frontier analysis to provide evidence on the impact of regulatory and supervision framework on bank efficiency based on a dataset consisting of 2853 observations from 615 publicly quoted commercial banks operating in 74 countries during the period 2000–2004 The rest of the paper is organized as follows: in section 2 we explain the methodology used to measure the impact of financial liberalization on the bank efficiency and productivity growth and we discuss the data and the variable selection. Thereafter, the results of the empirical analysis are presented and discussed in section 3. The main conclusions are drawn in section 4.In this section we discuss the empirical model used to investigate the impact of financial liberalization on bank performance. Then we explain our measures of bank performance: cost efficiency and productivity growth. The discussion of data and control variables follows afterwards.The purpose of the estimable model outlined in this section is to capture the effects of financial liberalization, reforms in the banking system and the associated changes in the industry on bank performance. We also include a range of bank-specific variables that have been used in previous empirical studies that examine the drivers of bank performance. The model is specified as:Bank performance is proxied alternatively by cost efficiency (EFF) and total productivity growth index (TFPCH). These indicators have been used widely in previous empirical literature concerned with the measurement and determinants of the bank performance in developing countries In line with ity– outputs vector; t – time component.In the estimation of the cost efficiency level of the banks in CEE countries we used the SFA Method and applied the model developed by The cost frontier indicates the minimum cost, The SFA method assumes that the inefficiency component of the error term is positive and thus the high costs are associated with a high level of inefficiency.In the order to quantify the total productivity growth we estimated the Malmquist index with the help of the DEA-type linear programming method, a method that was introduced by Färe et al. proposed in In the empirical analysis of the mutations on the level of the productivity of banks we have to calculate four distance measures that occur in The linear programming problems must be solved N times, once for each company in the ensemble. The introduction of solutions to the problems in relation (4) allows for the estimation of the Malmquist index of productivity.Because the purpose of this analysis is to analyze the connection between the performance of banks and the degree of financial liberalization of the banking system, the first set of banking system characteristics considered in the model includes the following variables: Banking reform and interest rate liberalization indicator (BREF), Financial Openness Index (KOPEN), Asset share of state-owned banks (ASSB) and Asset share of foreign-owned banks (ASFB).The Banking reform and interest rate liberalization indicator is compiled by the EBRD with the primary purpose of assessing the progress of the banking systems of formerly communist countries and quantifies and qualifies the degree of liberalization of the banking industry In order to assess the level of financial openness we use the Chinn-Ito index that measures the country’s degree of capital account openness. The index is based on the binary dummy variables that codify the tabulation of restrictions on cross-border financial transactions reported in the IMF’s Annual Report on Exchange Arrangements and Exchange Restrictions Following previous studies that focus on banks’ performance We measure bank stability using Z-score, which is a very popular indicator in recent literature concerned with the measurement and determinants of soundness and safety of banks ROA is the bank’s return on assets, E/A represents the equity to total assets ratio and The data used to quantify these indicators have been taken from EBRD and ECB reports.The economic literature pays a great deal of attention to the performance of banks, expressed in terms of efficiency, productivity, competition, concentration, soundness and profitability.The use of risk indicators in the analysis of bank performance has gained in the past decades a special attention because the control on banks’ risks is one of the most important factors the profitability of the bank depends on Following the empirical literature, we use the Return on Assets (ROA) to reflect the bank’s management ability to use the resources the bank disposes of for the purpose of optimizing profit. Bank capital adequacy is measured as the equity to assets ratio, quantified as the value of total equity divided by the value of total assets.To express the risk profile of the banks we use two different types of risk: credit risk measured as ratio of loan-loss provisions to total loans (LLR_GL) and liquidity risk measured as ratio of liquid assets to total deposits and borrowing funds (LA_TD). Another variable used in the analysis is the bank’s size measured as logarithm of total assets (TAL).The data used in the analysis are taken from the annual reports of the banks and from the Fitch IBCA’s BankScope database.In line with the previous literature In order to quantify the effects of structural reforms, we also use two governance indicators developed by Kaufmann et al. to proxy institutional differences: rule of law (ROL) and regulatory quality (RQ) Improvements in the regulatory quality help banks if it is accompanied by more adequate banking supervision. The quality of the rule of law affects cost efficiency through the effectiveness and predictability of the judiciary. There is a growing literature that points to the importance of institutions for an efficient operation of the financial system. This literature argues that better institutions positively affect bank efficiency see also . The datThis study seeks to undertake this assessment by examining banking efficiency and productivity growth in 17 countries from Central and Eastern Europe . We omit Belarus and Ukraine from our study because we could not obtain sufficient data. All bank-level data used are obtained from the BankScope database and are reported in Euros. To be included in our sample, a bank has to have a minimum of 3 years of continuous data to obtain reliable efficiency estimates In the literature in the field there is no consensus regarding the inputs and outputs that must be used in the analysis of the efficiency and productivity growth of commercial banks When analyzing the means of determinants of efficiency value we can observe that the degree of financial liberalization of the banking system has continuously increased during the assessed period. Thus the level of the banking reform and interest rate liberalization indicator (BREF), Financial Openness Index (KOPEN) and asset share of foreign-owned banks (ASFB) increased and the level of asset share of state-owned banks (ASSB) due to the privatization process and the increase of foreign capital (the last two determinants are correlated). The number of banks was relatively stable, the concentration ratio of the first 3 banks continuously grew, but the evolutions of HHI denote a moderate competition towards high competition, being relatively stable. The stability of the entire banking systems, from the perspective of insolvency probability, has increased continuously as Z-score relieves. The explanations could be the process of harmonization with the EU acquis, which implies a better banking regulation framework. We consider that the evolutions of these determinants were influenced by the process of European integrations, because some of the countries assessed are EU members, some of them are EU candidates and others potential EU candidates.The bank-specific variables had different evolutions. Thus we can observe a decrease of ROA in the context of an ample growth of total bank assets. The risk profile of the banks evaluated as following: the ratio of loan-loss provisions to total loans (LLR_GL) and liquidity risk measured as ratio of liquid assets to total deposits and borrowing funds (LA_TD) have decreased, indicating a loss in bank liquidity, but a better credit risk situation.The empirical models used in the specialty literature use a two-stage procedure: in the first stage the level of cost efficiency and total productivity growth is estimated and in the second stage the regression analysis is applied in which the levels of cost efficiency and total productivity index are dependent variables.The empirical model specified in the equation is estimated using the panel least square fixed effects methodology. We use the fixed effects model, since we focus on a limited number of countries, for which we want to assess country-specific differences with respect to the relationship between financial liberalization and bank performance. For this purpose, performance scores are regressed on a set of common explanatory variables; a positive coefficient implies efficiency increase whereas a negative coefficient means an association with an efficiency decreases. The empirical model is tested for each of the two measures of banking performance, i.e. cost efficiency and total productivity growth.The research strategy follows the specific-to-general approach. We start by investigating the relationship among cost efficiency and Banking reform and interest rate liberalization indicator (BREF) and Financial Openness Index (KOPEN). Next, we include all other banking system characteristics, bank-specific variables and macroeconomic variables one by one to test the stability of the main independent variables BREF and KOPEN. A second set of models is estimated using total productivity growth index as dependent variable.From empirical results we see that the average cost efficiency of banks in Central and Eastern European countries grew in the period analyzed, from an average value of 0.8866 in 2004 to 0.9099 in 2008, but there is significant variation across the banking systems of the Central and Eastern European countries in terms of cost efficiency level. Similar to Table no. 4 also shows the average cost efficiency and productivity growth results for banks of different size. Following Thus the results show that, on average, banks from a non-member country are less cost efficient but experienced much higher total productivity growth level during 2004–2008 period. In non-member countries, these productivity gains could be due to technological progress, rather than to an improvement in efficiency. Large sized banks are much more cost efficient than medium and small banks, while small sized banks show the highest growth in terms of productivity. This suggests that small sized banks are able to generate strong profits possibly by operating in the high value added segments of the markets while incurring higher costs at the same time.As for the effect of banking system characteristics, we found that a higher level of the Banking reform and interest rate liberalization indicator (BREF) and Financial Openness Index (KOPEN) improves cost efficiency, suggesting that banks in countries with higher level of liberalization and openness are able to increase cost efficiency and finally to offer cheaper services to clients. Our results are in line with The results show that the level of Banking reform and interest rate liberalization indicator (BREF) and Financial Openness Index (KOPEN) have a positive impact on the total productivity growth. The Z-score is positively correlated with total productivity, demonstrating that the total productivity depends on the soundness and safety of banks.With regard to the impact of structure of banking systems, results show that higher concentration quantified by means of the Herfindahl-Hirschmann index (HHI) improves cost efficiency, while the percentage share of the three largest banks (CR3) has a negative impact on the cost efficiency level. The mean value for these two indicators during the period assessed does not prove significant changes in the banking structure and level of competition. This evidence could suggest that the competition was not one of the most important factors of improving cost efficiency, being in contradiction with the traditional view and previous results As regards the impact of bank-specific variables, the results show that the level of Return on Assets (ROA) has a statistically significant and negative impact on both cost efficiency and total productivity growth. The level of credit risk measured as the ratio of loan-loss provisions to total loans (LLR_GL) negatively influences cost efficiency.Turning to the effect of macroeconomic variables, we observe that GDP growth rate had a negative impact on cost efficiency, maybe because under expansive demand conditions, managers are less focused on the expenditure control and therefore become less cost efficient. Another explanation could be that the increase in credit markets involves higher capital cost, an increase in operating expenses and cost with fixed assets. This results are in line with From another point of view, the decrease of GDP growth rate improves the total productivity of banks. This could be a reason for foreign-owned banks to maintain their exposure on these markets in case of economic decrease, but with the condition of maintaining the soundness and safety of banks. We also found a negative and significant relationship among Inflation rate (IR), Interest rate spread (IRS) and level of Rule of law (ROL) and bank cost efficiency.Our results show that the level of Financial intermediation has a positive effect on the bank performance, meaning that a low level of financial intermediation hampers banking performance.From our analysis it results that the Financial liberalization improves cost efficiency of banks from Central and Eastern European countries with higher level of liberalization and openness are able to increase cost efficiency and finally to offer cheaper services to clients. These facts are in compliance with the Single European Market principles and demonstrate that EU new member states, candidate states and potential candidate states banking market mechanisms could achieve their objective of lowering and harmonization of banking services prices. In this case, from a banking policy perspective, we consider that the EU enlargement could continue in Central and Eastern European countries and could add benefits for the EU banking market.In exchange, the level of Asset share of foreign-owned banks has no statistically significant impact on the level of bank cost efficiency. This could mean that the dominance of foreign banks on the market does not increase cost efficiency, but the best practices that they brought in the banking systems. From the policy perspectives, these results suggest that, in the case of new member countries, foreign-owned banks have no influence on increasing cost efficiency by means of their own activity and dominance on the market, but perhaps by means of their best practices that domestic banks must adopt for competing them.In what concerns the effect of financial reform on the total productivity growth of banks from CEE countries, the results show that the level of Banking reform and interest rate liberalization indicator has a positive impact on the total productivity growth. Also, the results suggest that the important factors shaping the total productivity are merely the banking system characteristics and bank-specific variables, and the only macroeconomic variable with impact is the GDP growth rate.Overall, in order to promote efficiency and productivity, monetary authorities from CEE countries should enhance their efforts to continue the reform of the financial services regulatory and supervisory framework. At the same time, banking markets should remain open, encouraging the entry of foreign banks for improving best practices and for increasing the benefit from technological spillovers brought by them. For a sustainable improvement of cost efficiency and total productivity of banks, the focus should be on the improvements of managerial practices, especially in domestic small and medium banks. Policy makers should also be concerned about improving the liquidity level.Furthermore, our results indicate that policy makers in EU could take into account the follow-up of the process of enlargement in some countries from CEE, because their banking markets have a good potential in adapting the Single European Markets principles. Foreign banks could maintain their exposures or enter the CEE markets because there is a good perspective for total productivity growth and the stability of the banking systems has increased.


The growing number of large-scale neuronal network models has created a need for standards and guidelines to ease model sharing and facilitate the replication of results across different simulators. To foster community efforts towards such standards, the International Neuroinformatics Coordinating Facility (INCF) has formed its Multiscale Modeling program, and has assembled a task force of simulator developers to propose a declarative computer language for descriptions of large-scale neuronal networks.The name of the proposed language is "Network Interchange for Neuroscience Modeling Language" (NineML) and its initial focus is restricted to point neuron models.The INCF Multiscale Modeling task force has identified the key concepts of network modeling to be 1) spiking neurons 2) synapses 3) populations of neurons and 4) connectivity patterns across populations of neurons. Accordingly, the definition of NineML includes a set of mathematical abstractions to represent these concepts.NineML aims to provide tool support for explicit declarative definition of spiking neuronal network models both conceptually and mathematically in a simulator independent manner. In addition, NineML is designed to be self-consistent and highly flexible, allowing addition of new models and mathematical descriptions without modification of the previous structure and organization of the language. To achieve these goals, the language is being iteratively designed using several representative models with various levels of complexity as test cases.The design of NineML is divided in two semantic layers: the Abstraction Layer, which consists of core mathematical concepts necessary to express neuronal and synaptic dynamics and network connectivity patterns, and the User Layer, which provides constructs to specify the instantiation of a network model in terms that are familiar to computational neuroscience modelers.As part of the Abstraction Layer, NineML includes a flexible block diagram notation for describing spiking dynamics. The notation represents continuous and discrete variables, their evolution according to a set of rules such as a system of ordinary differential equations, and the conditions that induce a regime change, such as the transition from subthreshold mode to spiking and refractory modes.The User Layer provides syntax for specifying the structure of the elements of a spiking neuronal network. This includes parameters for each of the individual elements  and the grouping of these entities into networks. In addition, the user layer defines the syntax for supplying parameter values to abstract connectivity patterns.The NineML specification is defined as an implementation-neutral object model representing all the concepts in the User and Abstraction Layers. Libraries for creating, manipulating, querying and serializing the NineML object model to a standard XML representation will be delivered for a variety of languages. The first priority of the task force is to deliver a publicly available Python implementation to support the wide range of simulators which provide a Python user interface . These libraries will allow simulator developers to quickly add support for NineML, and will thus catalyze the emergence of a broad software ecosystem supporting model definition interoperability around NineML.


Upon publication of the article entitled “Heat stress-induced response of the proteomes of leaves from Salvia splendens Vista and King”  the authThe co-authors would like to apologise for this omission. All authors have agreed to the addition of Dr Hen-Mu Zhang to the revised author list as shown above, for his provision of the original raw experimental materials, contribution to the design of the experimental procedure and quantitative experiments of the plant physiology and biochemistry index.


The increasing trend of atypical form of FMF among the Armenian population is one of the actual problems in the Armenian medicine. Hence, it induced and promoted the necessity of studying molecular mechanisms for correction of disturbed metabolic processes and for elaboration of new methods at pathogenic therapy of FMF. The specific features of the clinical symptoms in atypical forms of FMF give the rise of complications at differential diagnosis.In this research the informativity of clinical-laboratory and biochemical indicators has been studied. Also the relations between individual phospholipids of biomembranes and leuko/erythroid cells during atypical FMF were investigated.The intensity of 14C-glycerol and 14C-glucose incorporation was studied in vitro in the contents of individual phospholipids of erythrocytes and lymphocytes membranes at children with atypical FMF. The phospholipids were fractionated by thin layer chromatography.14C-glucose incorporation rate in the lysophosphatidylcholines (LPC) with simultaneous decrease of rate for incorporation in the contents of phosphatidylcholines (PC) and sphyngomyelines. It is observed an increase of activity of phospholipase A2 and the reduction of the activity of glycerolkinase and glycerol phosphate dehydrogenase. Also an increase of LPC/PC relation coefficient and decrease of PC/phosphatic acid relation were established.The substantial increment in the myeloid cell number was observed in all investigated patients. The leuko/erytroid sells relation was 4:1 instead of normal 3:1. The erythroid cell maturation index was low. The number of leukocytes was high in all patients. The basophilic erythronormoblasts predominated over polychromatic and oxyphilic ones. In all patients the expressed thrombocytosis and megakaryocytosis accompanied with active platelet formation were described. It is established that FMF is characterized by a sharp increase of Apparently the revealed changes are inherent atypical FMF. The membrane aspects of hemostasis disorders mechanisms at atypical FMF are discussed.None declared.


The advent of sensitive laboratory tools to detect and study the genetic evolution of these viruses has uncovered their critical role in the etiology of AGE. The flow of information is now so great that in each year since 2008, >800 scientific papers have been published on this topic as determined by a search of PubMed using the term acute gastroenteritis.The field of viral gastroenteritis is in the midst of an extraordinary period of rapid development and transition. Vaccines to prevent rotavirus, the leading cause of severe childhood AGE worldwide, are being rolled out globally and have already achieved remarkable success in reducing the burden of this pathogen in many countries, including the United States. In addition, the application of sensitive molecular assays is reaffirming the central etiologic role of noroviruses in both endemic and epidemic AGE, and vaccines against this pathogen are undergoing clinical testing. This issue of Emerging Infectious Diseases highlights recent developments in the field with a collection of timely findings from domestic viral gastroenteritis surveillance, which will further our understanding of disease effects, viral evolution and structure, implications of vaccination, and progress with other preventive measures.


The mechanosensitive channel of large conductance (MscL) is capable of transducing mechanical stimuli such as membrane tension into an electrochemical response. MscL provides a widely-studied model system for mechanotransduction and, more generally, for how bilayer mechanical properties regulate protein conformational changes. Much effort has been expended on the detailed experimental characterization of the molecular structure and biological function of MscL. However, despite its central significance, even basic issues such as the physiologically relevant oligomeric states and molecular structures of MscL remain a matter of debate. In particular, tetrameric, pentameric, and hexameric oligomeric states of MscL have been proposed, together with a range of detailed molecular structures of MscL in the closed and open channel states. Previous theoretical work has shown that the basic phenomenology of MscL gating can be understood using an elastic model describing the energetic cost of the thickness deformations induced by MscL in the surrounding lipid bilayer. Here, we generalize this elastic model to account for the proposed oligomeric states and hydrophobic shapes of MscL. We find that the oligomeric state and hydrophobic shape of MscL are reflected in the energetic cost of lipid bilayer deformations. We make quantitative predictions pertaining to the gating characteristics associated with various structural models of MscL and, in particular, show that different oligomeric states and hydrophobic shapes of MscL yield distinct membrane contributions to the gating energy and gating tension. Thus, the functional properties of MscL provide a signature of the oligomeric state and hydrophobic shape of MscL. Our results suggest that, in addition to the hydrophobic mismatch between membrane proteins and the surrounding lipid bilayer, the symmetry and shape of the hydrophobic surfaces of membrane proteins play an important role in the regulation of protein function by bilayer membranes. A fundamental property of living cells is their ability to detect mechanical stimuli. Microbes, in particular, often transition between different chemical environments, leading to osmotic shock and concurrent changes in membrane tension. The tension of microbial cell membranes is detected and controlled by membrane molecules such as the widely-studied mechanosensitive channels which, depending on the tension exerted by the surrounding lipid bilayer, switch between closed and open states. Thus, the biological function of mechanosensitive channels relies on an interplay between bilayer mechanical properties and protein structure. Using a physical model of cell membranes it was shown previously that the basic phenomenology of mechanosensitive gating can be understood in terms of the bilayer deformations induced by mechanosensitive channels. We have generalized this physical model to allow for the molecular structures of mechanosensitive channels reported in recent experiments. Our methodology allows the calculation of protein-induced membrane deformations for arbitrary oligomeric states of membrane proteins. We predict that distinct oligomeric states and hydrophobic shapes of mechanosensitive channels lead to distinct functional responses to membrane tension. Our results suggest that the shape of membrane proteins, and resulting structure of membrane deformations, plays a crucial role in the regulation of protein function by bilayer membranes. The biological function of membrane proteins is determined by a complex interplay between protein structure and the properties of the surrounding lipid bilayer Acinetobacter baumanniiA paradigm of mechanosensation is the prokaryotic mechanosensitive channel of large conductance (MscL) In this article we address the above questions on the basis of the continuum elasticity theory of lipid bilayer membranes The basic experimental phenomenology of mechanosensitive gating is captured by a two-state Boltzmann model A deeper understanding of The continuum elasticity theory of membranes As mentioned above, the determination of the oligomeric state and, more generally, molecular structure of MscL in different conformational states is a problem of intense experimental interest Staphylococcus aureus (SaMscL) and Myobacterium tubercolosis (MtMscL). In particular, Escherichia coli (EcoMscL), hexameric A variety of different approaches have been employed The contour lines approximating the cross sections of the transmembrane domains in Following the approach summarized in et al.In In addition, The left-hand panel of We now turn to the dependence of the channel opening probability in In order to facilitate the systematic investigation of the connection between the oligomeric state and the gating energy of MscL in In analogy to Inspired by structural studies of MscL Our mathematical approach for determining the energetic cost of membrane deformations associated with different oligomeric states and hydrophobic shapes of MscL is general and directly applicable to other membrane proteins. Thus, the methodology developed here establishes a quantitative relationship between the oligomeric state and hydrophobic shape of a membrane protein and the elastic energy required to accommodate the membrane protein within the lipid bilayer membrane. However, the quantitative details of our predictions depend on the parameter values characterizing the hydrophobic shape of the membrane protein under consideration. In particular, crucial inputs for our model are the hydrophobic thickness and cross section of membrane proteins. Recent experimental results The physiologically relevant oligomeric states and molecular structures of MscL remain a matter of debate In accordance with the standard framework for describing elastic bilayer-protein interactions The terms The specific properties of MscL enter The membrane-mechanical model of bilayer-MscL interactions outlined above yields a qualitative framework for understanding MscL gating, is in broad agreement While the elastic model in We follow Refs. Boundary curves are obtained by fitting the Fourier representation of The molecular structures in The clover-leaf shapes in In general, Thus, using The membrane deformation energy associated with the equilibrium deformation profile in To evaluate the integrals in The deformation profiles in The primary accession numbers (in parentheses) from the Protein Data Bank are: Pentameric MscL Click here for additional data file.Figure S2Membrane deformation energy of model inclusion shapes. Thickness deformation energy in (EPS)Click here for additional data file.Figure S3Gating energy of model inclusion shapes. Difference in thickness deformation energy between the open and closed states of generalized shapes of MscL obtained from (EPS)Click here for additional data file.Figure S4Gating probability of model inclusion shapes. Membrane contribution to the opening probability of generalized shapes of MscL obtained from (EPS)Click here for additional data file.


The authors measured the results of three oxidative stress markers in blood serum, not plasma. In the second sentence of the "Methods" section of the Abstract, "Plasma levels" should be "Serum levels." In the penultimate sentence of the last paragraph of the "Recording Clinical Parameters and Collecting Blood Samples" section of the "Subjects and Methods", "Plasma samples" should be "Serum samples." In the last sentence of the first paragraph of the "Oxidative Stress Measurements" section of the "Subjects and Methods", "plasma levels" should be "serum levels." In the first sentence of the third paragraph of that same section, "blood plasma" should be "blood." In the first sentence of the second paragraph of the "Results", "plasma" should be "serum." Lastly, in the first sentence of the second paragraph of the "Discussion", "plasma" should be "serum." Since the measurement system the authors used is compatible with both plasma and serum, any data presented and conclusions described in the article are not affected by the correction.