The mean tumor size on preoperative

CT was 2.8 cm (range, 1.3–4.7) and there was no significant difference from the intraoperative measurement of 2.9 cm (range, 1.3–4.4). There has been some evidence to suggest that the cryoablation protocol is most efficacious for a tumor size of less than 4.0 cm [17]. Following the growth of our clinical experience, we were able to treat larger masses (tumor size did not exceed 5 cm). Therefore, in our study, the size of Selumetinib research buy the tumors treated with cryoablation ranged from 1.3 to 4.7 cm. Argon–helium cryoablation was successfully performed in all 32 patients. All tumors were completely ablated with a single procedure of cryoablation, except for two tumors that were ablated with two sessions of treatment. The first patient enrolled

Gefitinib in the trial had small residual enhanced nodules at the periphery of the lesion, and the cyst was detected at 24 h after the cryoablation procedure. The patient’s tumor, a 1.8 cm bladder cancer, showed residual enhancement in the portion that abutted the treated site and the patients was retreated by cryoablation. The other patient suffered a recurrence 6 months after cryoablation therapy. This patient initially had a 2.3 cm tumor mass, and was suspected to have a small residual hubble according to the image findings of the 3-month follow-up CT scan. Enhancement of the residual hubble was confirmed at the 6-month CT scan, and was Cyclin-dependent kinase 3 retreated by cryoablation at 9 months after the initial treatment. Subsequently, CT images obtained for this patient at 3 and 6 months after the second treatment did not show any evidence of another recurrence. For small tumors, a single cryoprobe was used to ablate the tumor, whereas multiple cryoprobes were used to ablate the larger tumors. CT performed within 24 h after treatment showed that all tumors were completely ablated. A total of 29 of 32 patients had 33-month follow-up (range, 6–48 months) data that was adequate for analysis. The results indicated that there was no tumor recurrence or enhancement, except

for the above two cases. Examples of the CT scans for the patients are shown in Fig. 2. Complete resolution of the treated mass or a residual small cyst without enhancement was observed in CT for all patients during the follow-up period (Fig 3), except for three patients who were lost to follow-up. There was no significant complications but no major complications associated with the cryoablation procedure. Symptoms of bladder cancer present before and within 3 days after percutaneous cryoablation are shown in Table 2. All complications had disappeared completely after 2 weeks. Radical cystectomy and transurethral resection are currently the reference standards for treating muscle-invasive bladder cancer [6] and [22].

Entrainment is a mechanism leading to the growth of the jet radius and volume flux with distance from the point of discharge through the capture of ambient fluid ( Hunt et al., 2011). At low discharge velocities Selleckchem CAL101 the jet becomes laminar, the consequence of this is that mixing with ambient fluid is significantly reduced due to the dominance of viscous forces ( Batchelor, 2001). Entrainment models for laminar jets are discussed by Morton (1967). In order to obtain optimal dilution through turbulent mixing we introduce a constraint equation(5) Re=2b0u0ν>Rec,where RecRec is a critical Reynolds number and νν is the kinematic viscosity of water. Certainly Rec=3000Rec=3000 is

sufficient for the jet to be turbulent ( McNaughton and Sinclair, 1966). We describe a mathematical model of a buoyant jet discharged horizontally and tangentially into a uniform unstratified stream in order to calculate Palbociclib mw the jet trajectory and dilution. An unstratified ambient is considered because the draught depth of merchant vessels is at most 20 m and in this range the effects of stratification are not significant. It is assumed that the issuing fluid is perfectly mixed across the width of the jet and that the dilution processes have a far longer timescale than the chemical processes that happen very rapidly (Ülpre

et al., 2013). In the ‘top-hat’ model (Morton et al., 1956), the jet is characterized by a radius b  , average

centre line velocity u   and a density contrast of ρ-ρaρ-ρa compared to the ambient ρaρa. These variables are combined about to form the volume flux Q  , specific momentum flux M   and specific buoyancy flux B  , which are defined as equation(6a,b,c) Q=πb2u,M=πb2u2,B=πb2ugρa-ρρa.The initial values of Q,M and B   at the point of discharge are Q0,M0 and B0B0. The conservation of mass and momentum are expressed in terms of how Q   and M   vary with distance s   along the jet trajectory. The jet is directed along the y  -axis, rises due to buoyancy along the z  -axis and is swept by an ambient flow along the x  -axis. Two forces act on the buoyant jet in the presence of an ambient flow U∞U∞, the Lamb force and buoyancy. In conclusion this gives equation(7) dQds=2πuEb,ddsMdxds=2πuEU∞b,ddsMdyds=0,ddsMdzds=πb2gρa-ρρa,where uEuE is the entrainment velocity that must be closed by an empirical relationship between the mean jet velocity and the ambient flow ( da Silva et al., 2014). We use the closure relationship applied by Woodhouse et al. (2013) equation(8) uE=αudzds+udxds-U∞+udyds,but others have also been proposed e.g.   Jirka (2004). Since the discharges are likely to be in the form of jets we can assume the empirically determined entrainment coefficient to be α=0.08α=0.08 ( Turner, 1969).

The X chromosome is full of surprises and if the future of the field is anything like the last few years, it would seem we have much to look forward to. Papers of particular interest, published within the period of review, have been highlighted as: • of special interest This work was supported by NIH/NHGRIT32 this website HG000044 and U01-HL100397. “
“Current Opinion in Genetics & Development 2013, 23:316–323 This review comes from a themed issue on Molecular and genetic bases of disease Edited by Jim Lupski and Nancy Maizels For a complete overview see the Issue and the Editorial Available online 17th April 2013 0959-437X/$

– see front matter, © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.gde.2013.02.015 Thrombocytopenia with absent radii (TAR) syndrome is characterized by a reduction in the number of platelets (the cells that make the blood clot) (generally below 50 × 109 L−1, normal range 150–350 × 109 L−1) and the absence of one of the bones in the forearm (the radius) but with preservation of the thumb. TAR syndrome was first described by Gross et al. [ 1] and Shaw and Oliver in 1959 [ 2], but Judith Hall was the first to define it as a syndrome in 1969, presenting

clinical findings in a cohort of 40 patients [ 3]. The presence of the thumbs distinguishes TAR from other syndromes that combine blood abnormalities with absence of the radius, such as Fanconi anemia [ 3, 4 and 5]. The severity of skeletal abnormalities varies from absence GSK3 inhibitor of radii to virtual absence of upper limbs (phocomelia) with or without lower limb defects, such as malformations of the hip and knee [ 3 and 5]. TAR cases have low numbers of megakaryocytes, the platelet precursor cells that reside in the bone marrow, and cases frequently present with bleeding episodes in the either first year of life [ 3 and 5]. A remarkable feature of TAR syndrome is that the platelet count can improve with

age and bleeding diminishes [ 5]. Other symptoms have been described in a series of 34 TAR patients [ 6], with renal anomalies and cardiac anomalies in respectively 23% and 15% of patients, and 47% suffering from intolerance to cow’s milk. TAR syndrome has an incidence of approximately 1 in 240 000 births [7] and was thought to be inherited as an autosomal recessive disease [8] based on finding affected siblings. There is however no clear evidence of increased incidence in consanguineous families with only one case reported [9]. On the other hand, vertical parent-to-child transmission has been reported [10], as well as the case of a male patient and maternal uncle [11]. This unusual inheritance pattern has complicated the application of classic linkage analysis methods and homozygosity mapping approaches.

6). This counters the amplification of the sink regions just to the north. MERRA forcing produces the smallest sink in the North Pacific and North Atlantic basins (Fig. 5). The weaker sink in the North Pacific can be attributed to a source region see more east of the Sea of Okhostk

(Fig. 6), and the North Atlantic to a local source in the Labrador Sea. MERRA-estimated fluxes in these two basins is about 0.15 mol C m−2 y−1 (39%) lower in the North Pacific than the strongest sink and 0.33 mol C m−2 y−1 (21%) lower in the North Atlantic. The strongest sink in both cases is produced by NCEP2. In the tropical basins, the estimates of air–sea carbon fluxes by NCEP2 produce the strongest source in 3 of the 4 major basins (Fig. 5). Sometime this is closer to the in situ estimates relative to the other forcings, as in the Equatorial Atlantic, and sometimes it is a larger departure, as in the Equatorial Indian. The large source represented by NCEP2 forcing in the Equatorial Pacific is derived from a very strong local flux along the Peru coast (Fig. 6). Although a smaller manifestation appears in NCEP1 and ECMWF forcing, it does not appear in MERRA-forcing, PLX4032 which leads to its representation of

the smallest Equatorial Pacific source. ECMWF departs strongly from the other forcings in the North Indian, and is nearly 3 times the fluxes estimated by the lowest reanalysis (NCEP1), but is closer to the in situ estimates (Fig. 5). This stronger source can be attributed

to local intensification offshore of Somalia (Fig. 6), which feature is either much smaller in the other forcings (NCEP1) or non-existent (MERRA and NCEP2). Estimates of FCO2 in Reverse transcriptase the sub-polar basins are more similar among the forcings than the high latitudes and tropics (Fig. 5), exhibiting the lowest ranges of estimates of all the basins. ECMWF is the strongest sink in 4 of the 5 basins, while MERRA forcing is the lowest in 2 basins (North Central Pacific and Atlantic). All the forcings indicate a much stronger sink estimate in the South Atlantic and Pacific than the in situ estimates. Global area-weighted mean partial pressures show similar relationships among the four reanalysis forcings and with the data (Fig. 7). The deviations from data are much smaller than the flux estimates: all are within 1% of data global means, with ECMWF the outlier at 0.6%. NCEP1 pCO2 is closest to the data, with a difference < 1 μatm, or −0.1%. All forcings also show positive and statistically significant correlations across basins, with values similar to the fluxes. On basin scales the pCO2 mean differences between the forcings and data are smaller, and more consistent with one another than for the basin fluxes (Fig. 7). The South Atlantic is a notable exception, which exhibits a departure from the data for all forcings similar to the fluxes. NCEP2 forcing is noticeably closer to the data pCO2 but it is still low by 26 μatm (about 7%).

The CD spectra were measured on MOS-450/AF-CD-STP-A (Bio-Logic, France) at a protein concentration of 0.1 mg/mL in 50 mM Tris/HCl buffer (pH 8.6) using a 1 cm path-length

quartz cuvette. To minimize the signal baseline drift, the spectropolarimeter and xenon lamp were warmed up at least 30 min prior to each experiment. The enzyme data in the 190–240 nm bands were collected, and which the spectrum obtained for a buffer blank was subtracted from these data. The assay to determine the kinetic parameters were performed using different concentrations of l-phenylalanine (1–20 mM) (Sigma–Aldrich, Germany). The reactions were initiated by the addition of an appropriate quantity of RgPAL to each reaction system. The reaction was conducted at 40 °C and selleck stopped by addition of 0.5 mL of methanol. The formation of

trans-cinnamic acid was Selleckchem Olaparib measured by HPLC (Hitachi, Japan) at 290 nm, the mobile phase contained 50% methanol. The obtained experimental dependences of the initial catalytic rates on the substrate concentrations were fitted to Michaelis–Menten equation through nonlinear regression analysis using Origin (7.5 versions). One enzyme activity unit was defined as the amount of enzyme that produced 1 μmol trans-cinnamic acid per minute at 40 °C. The effects of the pH were determined at 40 °C using a series of buffers with various pH values (pH 5.0–7.0, 50 mM sodium acetate buffer; pH 7.0–9.0, 50 mM Tris–HCl buffer; pH 9.0–12.0, 50 mM sodium carbonate buffer). The chiral resolutions of dl-phenylalanine using RgPAL and RgPAL-Q137E were performed at pH 7 and pH 9, respectively. The experiments were carried out in

500 mL batch conical flasks with lid in a rotating shaker and contained 300 mL of dl-phenylalanine (100 mM) and 250 μg of pure enzyme at 40 °C. The conversion rate of l-phenylalanine and the eeD value of d-phenylalanine were calculated by the following equations: conversion rate=[(Lphe,in−Lphe,out)Lphe,in]×100%eeD=[(Dphe−Lphe,out)(Dphe+Lphe,out)]×100%;where the eeD is the enantiomeric excess of d-phenylalanine; the Lphe, in is the initial concentration of l-phenylalanine; the Lphe,out is the residual concentration of l-phenylalanine Rebamipide after resolution; the Dphe is the concentration of d-phenylalanine. The d-phenylalanine and l-phenylalanine are detected through HPLC (Hitachi, Japan) at 205 nm according to the method described by Fukuhara [7]. The mobile phase contained 20% methanol and a complex of optically active L-Pro-Cu(II) (1.5 mM L-Pro and 0.75 mM CuSO4). The “mutational effect” was determined by dividing the kcat value of the mutant enzyme by that of the wild type, and the free energy (ΔΔG‡) was calculated from the following equation: ΔΔG‡ = −RTln (mutational effect) as described by Olucha (2011, 2012) [17] and [18].

Wang et al. have discussed these processes in detail [ 3••]. Here we summarise recent advances in both passive and active delivery of platinum-based anticancer complexes. Utilizing nanotechnology

to improve drug delivery is a well-known concept, however innovative designs of nano-vectors to achieve efficient drug delivery and their complexity are emerging [4•]. Carbon nanotubes (CNTs) are the most studied. Pristine CNTs are insoluble in most solvents and bear structural resemblance to carcinogenic asbestos fibres. However, coating CNTs with linear and/or branched poly(ethylene glycol) (PEG) units (1 and 2, Figure 1a) renders them more hydrophilic and more suitable for biomedical applications [5]. The toxic nature of pristine (non-functionalised) multi-walled and single-walled CNTs and ability to induce mesothelioma have been demonstrated. Bianco et al. have shown that mono-functionalisation, see more bi-functionalisation, and tri-functionalisation of CNTs (3–5, Figure 1b) give enhanced biocompatibility click here and can be translocated directly into the cytoplasm of cells. Non-biodegradable CNTs have the potential to accumulate in various tissues and organs [ 6], however the oxidative enzyme horseradish peroxidase (HRP) can catalytically degrade f-CNTs [ 7]. Tripisciano et al. have encapsulated CDDP into functionalised single-walled carbon nanotubes (SWCNTs). CDDP-SWCNTs are more cytotoxic than free CDDP towards

PC3 cancer cells, but less potent than CDDP towards DU145 cells [ 8]. Recently, Li et al. capped multi-walled carbon nanotubes (MWCNTs) with functionalized 1-octadecanethiol (ODT) gold nanoparticles (f-GNPs) to facilitate the effective delivery of CDDP (6). The presence

of the f-GNP at the tip of the MWCNTs hinders the encapsulated CDDP from leaving the narrow passage of the MWCNTs. The in vivo activity of CDDP in capped CDDP-MWCNTs towards MCF-7 breast cancer cells was enhanced (IC50 7.7 μM), compared to uncapped CDDP-MWCNTs (IC50 11.7 μM). These results suggest that f-GNP MWCNTs may be effective drug depots [ 9]. Reducing the size of the CNTs renders them more likely to pass into the cell, as seen for SWCNTs of 1–2 nm diameter. Guven et al. have synthesised ultra-short Progesterone carbon nanotubes (USCNTs) of ca. 1.4 nm diameter in which CDDP was encapsulated (7) and then wrapped with a surfactant. The CDDP-USCNTs were more potent than free CDDP in two breast cancer cell lines (MCF7 and MDA-MB-231) after 24 hours. Wrapping of USCNTs with a surfactant retards release of CDDP resulting in its higher cytotoxicity. For in vivo use, the surfactant molecules could be replaced with a cancer-specific protein [ 10]. Li et al. have entrapped a hydrophobic PtIV complex (8) within the inner cavity of MWCNTs. Chemical reduction converted the PtIV prodrug to its hydrophilic and cytotoxic PtII form triggering its release from the MWCNTs.

, 2007 and Kotak et al., 2007). Two hypotheses may explain the lack of HSP up-regulation in N. noltii. First, HSP expression may have been up-regulated earlier in the heat wave experiment and decreased while

the selleck chemicals stress-temperatures continued; or secondly, the critical temperature threshold was not reached. Evidence supporting the first hypothesis has been found in N. noltii (and A. thaliana) at 38 °C, where HSP expression returned to pre-stress levels within several hours or days after heat stress was initiated (but before it was removed) ( Massa et al., 2011). Conversely, HSP up-regulation in Z. marina can persist for 1–3 weeks with a constant applied stress at only 26 °C ( Bergmann et al., 2010 and Franssen et al., 2011a). The mechanisms behind recovery to pre-stress Alectinib solubility dmso HSP expression levels during stress exposure vs. ongoing induction are not well studied and it is not known to what extent this effect depends on the strength of the applied heat stress. Regarding the second hypothesis, the lack

of HSP induction for N. noltii is due to a higher temperature threshold for HSP up-regulation relative to Z. marina. This correlation between habitat temperature and HSP up-regulation might be an indicator for different ecological niches, a phenomenon commonly observed between species pairs (summarized in Feder and Hofmann, 1999). Numerous examples include fucoid seaweeds ( Jueterbock et al., 2014), mussels (Mytilus), marine snails (Tegula), fruit flies (Drosophila), ants (Cataglyphis and Formica), yeast (Saccharomyces) ( Feder Ribose-5-phosphate isomerase and Hofmann, 1999), lizards ( Ulmasov et al., 1992) and shrubs (Prunus and Ceanothus) ( Knight, 2010), where congeners and/or related species occur in different ecological niches such as upper vs. lower intertidal areas ( Feder and Hofmann, 1999), south vs. north facing slopes ( Knight, 2010) or different climatic zones ( Ulmasov et al., 1992, Gehring and

Wehner, 1995, Hofmann and Somero, 1996 and Krebs, 1999). In each case, the species naturally occurring in the environment with higher temperatures have higher HSP induction thresholds, which usually differ by 2–7 °C ( Ulmasov et al., 1992, Hofmann and Somero, 1996 and Feder and Hofmann, 1999). For the Z. marina and N. noltii species pair, where long term heat treatment at 25 °C showed over-expression of HSPs in Z. marina (also see Bergmann et al., 2010; Franssen et al., 2011a), but not in N. noltii, the only additional study on N. noltii showed HSP up-regulation in response to a simulated low tide at ~ 38 °C ( Massa et al., 2011). Thus, the exact difference in HSP induction thresholds in Z. marina and N. noltii remains unknown. The lack of HSP induction in N. noltii at 26 °C, in contrast to Z. marina, may be adaptive.

The behavioural results replicate the findings of previous reports. We found shorter interval estimations in an active condition in which the

participant caused the tone through their action, compared to a passive control condition (cf. Engbert et al., 2007; Wenke and Haggard, 2009). Ebert and Wegner (2010) recently showed that both implicit binding effects and explicit agency judgements show a similar sensitivity to temporal delays. This suggests that our measure, though clearly implicit, does capture a core aspect of the phenomenology of agency. We focussed on changes in time perception that accompany the sense of agency by using parametric analyses and a contrastive design. This analysis was designed to focus on the associative core of the implicit MDV3100 sense of agency, i.e., changes in perceived timing due to the ‘constant conjunction’ of motor and sensory events (Hume, 1763). Thus we parametrically modulated the BOLD response with the judgement error of the perceived interval between action and tone in the active condition, and then subtracted the similarly calculated parametric regressor in the passive condition. This procedure removes variations in time estimation due to non-specific causes, leaving

only activations related to agency-related variability in time perception. That is, the contrast between the two parametric analyses is assumed to capture the variation in temporal experience that is specifically associated with the context in which the participant’s voluntary action caused the tone. Our results highlight the involvement of SMA proper in agency-related intentional binding. Vorinostat nmr We had a prior hypothesis that the posterior frontomedian cortex might underlie the association between action and effect from a previous PET study (Elsner et al., 2002) and a TMS study (Moore et al., 2010). However, the former study did not include a subjective measure of agency, and the latter

study did not explore effects of stimulating different subregions within the SMA complex. Thus, our previous study may be the first aiming to find the specific brain areas correlating with the implicit feeling of agency. Our results showed a cluster in the Digestive enzyme left SMA proper, extending into the dorsal premotor cortex, whose activation correlated more strongly with judgement errors in the active than in the passive condition. Some care is needed in interpreting this result, since it is based on a single neuroimaging experiment. However, the number of participants (17) in our study is roughly comparable with other recent neuroimaging studies of agency and volition (De Luca et al., 2010: n = 12; Farrer et al., 2008: n = 15; Miele et al., 2011: n = 11; Nahab et al., 2011: n = 20). Moreover, dismissing a positive finding on the basis of a small sample does not follow the standard logic of statistical inference ( Friston, 2012).

Subsequently, the time series of spatially averaged HS − AV and TP − AV values were calculated along with the corresponding time series for λOW. The time series for λOW, obtained using equation 12, and the time series for DD/ρW, obtained using expression 10b, are compared in Figure 4. Using the expression for DD suggested by Mackay et al. (1980) rather than that of Tkalich & Chan (2002) will result in an average overestimation of the natural dispersion process by 4%. The heat exchange between air and oil, and between oil and sea, is based on the works of Duffie & Beckmann (2006)

and Bird et al. (1960). The dependence of viscosity on temperature, aqueous phase learn more participation and evaporation is solved as suggested by CONCAWE (1983) and Hossain & Mackay (1980). The evaporation pressure at an arbitrary temperature was defined according to GSK126 Yang & Wang (1977) and changes in the fluidization point according to CMFMWOS (1985). The atmospheric and sea properties, relevant to the process of oil transformation, are taken directly from the sea circulation model. The spilled oil may be deposited along the shoreline and afterwards re-entrained into the water column. Numerical modelling of oil behaviour at the shoreline relies primarily

on empirical formulations, because of the very complex processes and interactions involved (Guo & Wang 2009). Incorporating all these factors into the model routine is almost impossible owing to the limited data available (Owens et al. 2008). The oil transport model uses the perfect reflection algorithm in situations where a particle encounters land, assuming zero kinetic energy loss on impact and equality of the angles of incidence

and reflection. For modelling purposes, the partial constituents of oil are divided into eight fractions; their chemical structure and distillation characteristics are shown in Table 1. The adopted initial temperature of the spilled oil is 25 °C in every simulation. TCL The occurrence of oil pollution due to ship failure is modelled as a continuous and steady input discharge Qspill = 18.5 kg s− 1 into the model surface layer for a period of 12 hours, resulting in a total amount of 800 tons of spilled oil. Specifying that 200 Lagrangian particles are released at each time step in the oil transport model ∆t = 200 s, and that a constant source flux of 18.5 kg s− 1 is defined, then each released particle has a mass of 18.5 kg. The thickness of the slick is calculated at the end of a time step ∆t by counting the particles in the grid cells and then, for each grid cell, dividing the total volume of the particles present in the cell by the area of the cell. Calibration of the Mike 3 model is based on the measurement data sets obtained in the ‘Adriatic Sea monitoring programme’, which was conducted in the territorial waters of the Republic of Croatia (Andročec et al. 2009). The Mike 3 results were compared with CTD and ADCP measurements.

Thereafter, Process improvements can be derived from those best practices best practices. Combining this methodology with intelligent approaches for simulation, prioritization between different improvement measures becomes possible. Because industrial maturity models are based on a virtual best practice combination composed of real-world practice elements from various organizations, the question arises how this principle can be applied to healthcare systems. In our clinical maturity model named “Act

on Stroke”, we implemented all relevant clinical guidelines, as well as latest results in stroke research based on clinical and scientific evidence. We performed best practice visits in institutions well known for their excellent stroke Talazoparib see more service and included experience from more than 400 consulting projects in healthcare. In the end, our data resulted in a clinical maturity model addressing optimized stroke care. Best practice visits and pilot projects in hospitals with experienced department heads in stroke care were performed and provided further promising results which again were introduced into the methodology. Indeed, heads of the departments certified that all relevant strengths and weaknesses of their services have been identified

by using this clinical maturity model. Proposals for process improvements have also been helpful to them. Meanwhile, the first regular projects have been carried out successfully, and the results are currently in preparation for publication. For more than 40 years, maturity models have been helpful in software industry in order to improve processes and, as a consequence, leading to better outcomes. This principle has been used for the optimization of clinical processes, as well. Healthcare is dealing with human beings, however, has and the applicability of industrial processes had to be discussed carefully. The content for the definition of the virtual best practice is of clinical and scientific relevance, and it has to Adenosine triphosphate be specified who defines it. From our point

of view this should be done as a joint venture by experienced stroke physicians in cooperation with specialists experienced in process optimization. Care has to be taken that the patient’s needs and the adherence to clinical guidelines are the most important and that the maturity level is respecting this. A not yet fully solved problem is how to deal with improvement measures to processes or requirements not yet based on clinical evidence. It has been shown [16] and [17] that improvement of key measures lead to better outcome even if they are as such not based on large randomized trials. The fact that some requirements are based on clinical evidence while others are not, has to be met by the particular methodology of “Act on Stroke” and a solution for this issue has been implemented.