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The global incidence of myelodysplastic syndromes (MDS) has been estimated as 0.06 to 0.26/100,000. Since their introduction, hypomethylating agents have played a central role in the treatment of MDS, with heterogeneous real-world outcomes.We assessed and synthesized clinical outcomes of azacitidine (AZA) monotherapy in treatment-naïve patients with higher-risk MDS. A systematic literature review was conducted by searching MEDLINE, Embase, and CENTRAL to identify randomized clinical trials (RCTs) and observational studies, both prospective and retrospective, reporting complete remission (CR), partial remission (PR), overall survival (OS), duration of response (DOR), time-to-response (TTR), and myelosuppressive adverse events (AEs) for patients treated with AZA monotherapy. Noncomparative meta-analyses were used to summarize effects.The search identified 3250 abstracts, of which 34 publications describing 16 studies (5 RCTs, 3 prospective, and 8 retrospective observational) were included. Across all studies, pooled CR was 16%; PR was 6%; Median OS was 16.4 months; median DOR was 10.1 months; median TTR was 4.6 months. Proportions of grade 3/4 anemia and thrombocytopenia AEs were 10% and 30%.The effectiveness and efficacy of AZA monotherapy-as measured by CR and median OS-was limited. These findings highlight a significant unmet medical need for effective treatments for patients with higher-risk MDS.

Background TP53 mutations, which are present in 5% to 10% of patients with acute myeloid leukemia (AML), are associated with treatment resistance and poor outcomes. First-line therapies for TP53-mutated (TP53m) AML consist of intensive chemotherapy (IC), hypomethylating agents (HMA), or venetoclax combined with HMA (VEN + HMA). Methods We conducted a systematic review and meta-analysis to describe and compare treatment outcomes in newly diagnosed treatment-naïve patients with TP53m AML. Randomized controlled trials, single-arm trials, prospective observational studies, and retrospective studies were included that reported on complete remission (CR), CR with incomplete hematologic recovery (CRi), overall survival (OS), event-free survival (EFS), duration of response (DoR), and overall response rate (ORR) among patients with TP53m AML receiving first-line treatment with IC, HMA, or VEN + HMA. Results Searches of EMBASE and MEDLINE identified 3006 abstracts, and 17 publications describing 12 studies met the inclusion criteria. Random-effects models were used to pool response rates, and time-related outcomes were analyzed with the median of medians method. IC was associated with the greatest CR rate of 43%, and CR rates were 33% for VEN + HMA and 13% for HMA. Rates of CR/CRi were comparable for IC (46%) and VEN + HMA (49%) but were lower for HMA (13%). Median OS was uniformly poor across treatments: IC, 6.5 months; VEN + HMA, 6.2 months; and HMA, 6.1 months. For IC, the EFS estimate was 3.7 months; EFS was not reported for VEN + HMA or HMA. The ORR was 41% for IC, 65% for VEN + HMA, and 47% for HMA. DoR was 3.5 months for IC, 5.0 months for VEN + HMA, and was not reported for HMA. Conclusions Despite improved responses seen with IC and VEN + HMA compared to HMA, survival was uniformly poor, and clinical benefits were limited across all treatments for patients with newly diagnosed, treatment-naïve TP53m AML, demonstrating a significant need for improved treatment for this difficult-to-treat population.

Background This study examined demographics, comorbidities and healthcare resource use (HCRU) and costs among Japanese patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Methods We conducted a repeated cross-sectional analysis of the Medical Data Vision (MDV) claims database, from January 2011 to March 2018. Demographics were described at index date and by calendar year; a “NASH” subpopulation included patients with ≥ 1 claim for NASH at any time. Prevalence of pre-specified comorbidities of interest and data-emergent top comorbidities were estimated. All-cause HCRU and costs were quantified by calendar year. Outcomes were compared between 2011 and 2017 using partially overlapping t tests. Results 58,958 patients (mean age 61.6 years; 55.5% male) were included. 1139 patients (2%) were in the NASH subpopulation. At baseline, comorbid cardiovascular disease (69.4%), diabetes (62.1%) and hyperlipidaemia (54.4%) were most prevalent; comorbidity prevalence increased with age. Mean outpatient visits decreased from 9.36 per patient in 2011 to 7.80 in 2017; mean inpatient admissions increased (both p p = 0.552), cost burden shifted from the outpatient to inpatient setting between 2011 and 2017. All-cause healthcare resource use/costs were generally higher for the NASH subgroup compared with the overall population. Conclusions There is a high burden of disease among Japanese NAFLD/NASH patients, including a high prevalence of comorbidities which generally increase with age. Accordingly, substantial all-cause HCRU and costs were incurred.

e19062 Background: AZA is a standard of care for patients who have HR-MDS. Given the limited availability of large datasets describing outcomes in the current treatment paradigm of HR-MDS, this analysis aimed to aggregate clinical outcomes associated with AZA monotherapy for treatment-naïve HR-MDS. Methods: CENTRAL, EMBASE, and MEDLINE were searched to identify interventional, prospective, and retrospective observational studies in treatment-naïve HR-MDS (defined as intermediate-2 or high risk by IPSS or intermediate to very high risk by IPSS-R) using AZA monotherapy. Inclusion of observational studies was limited to those with n >20 in the AZA arm. Responses according to IWG 2000 or IWG 2006 including complete remission (CR) rate, overall response rate (ORR; defined as CR, marrow CR [mCR], partial response, and hematologic improvement), overall survival (OS), duration of response (DOR), and time to response (TTR) were extracted. Response rates were synthesized using random-effects models; median of medians was used for OS, DOR, and TTR. Results: Of 3250 abstracts identified, 34 publications describing 16 studies met inclusion criteria: 5 randomized controlled trials (RCTs), 3 prospective studies, and 8 retrospective studies. None of the response endpoints were reported in all studies (see Table). The pooled ORR ranged from 44% to 55% across RCTs, prospective, and retrospective studies. The pooled CR rates, reported in 2 RCTs (n=55), 1 prospective study (n=27), and 3 retrospective studies (n=509), were 14%, 11%, and 16%, respectively. The pooled CR rate across all studies (n=591) was 16% (95% CI: 13%, 19%). Pooled median OS (mOS) was 16.7 months (mo) in the 3 RCTs (n=161), 16.5 mo in a single prospective study (n=34), and 14.4 mo in the 5 retrospective studies (n=1472). Pooled mOS across all studies (n=1667) was 16.4 mo (95% CI: 12.0, 17.3). The pooled median DOR was 10.1 mo (95% CI: 9.1, 11.0), and the median TTR was 4.6 mo (95% CI: 3.0, 9.0). Conclusions: These findings provide evidence that benefit from AZA monotherapy in treatment-naïve HR-MDS patients is limited. Opportunity exists for novel therapies to increase response rates, improve the duration of responses, and prolong survival. [Table: see text]

e19020 Background: TP53 mutations are present in 10%–15% of patients with acute myeloid leukemia (AML) and are associated with resistance to therapy and poor outcomes. Currently available frontline therapies for TP53-mutated ( TP53m) AML include intensive chemotherapy (IC), hypomethylating agents (HMA), and venetoclax combined with HMA (VEN+HMA). This systematic review and meta-analysis evaluated outcomes associated with IC, HMA, and VEN+HMA in newly diagnosed, untreated TP53m AML. Methods: EMBASE and MEDLINE were searched May 20, 2021 to identify studies of interest. Single-arm data on complete remission (CR), CR with incomplete hematologic recovery (CRi), median overall survival (mOS), event-free survival (EFS), and duration of response (DoR) were extracted and pooled for each treatment. Response rates were pooled using random-effects models; the median of medians method was used for time-related outcomes. Results: Of 3006 abstracts identified, 17 publications describing 12 studies met the inclusion criteria: 6 were randomized clinical trials (RCTs), 2 were single-arm trials, and 4 were retrospective studies. Outcomes are displayed in the Table. CR rate was highest with IC at 43% (95% CI, 30%, 56%), followed by VEN+HMA, 33% (22%, 47%), and HMA alone 21% (7%, 49%). Rates of CR/CRi were 49% (37%, 60%) for VEN+HMA, 46% (39%, 53%) for IC, and 13% (2%, 48%) for HMA alone. mOS was similarly low across the 3 treatments: IC, 6.5 months (N=155; 5.1, 8.5); VEN+HMA, 6.2 (N=73; 5.2, 7.2); HMA, 6.1 (N=34; 4.9, 7.2). Conclusions: CR, CR/CRi, and mOS were low across all treatments for patients with newly diagnosed, untreated TP53m AML. Addition of venetoclax to HMA showed a trend toward improved response vs HMA alone but not for mOS. There is a significant unmet need for more effective treatment for this very difficult-to-treat population. [Table: see text]

Background: Demographic, healthcare resource utilization (HCRU), and healthcare costs of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) patients, and those progressed to liver cirrhosis (LC) and hepatocellular carcinoma (HCC) was assessed from Japan Medical Data Center (JMDC) claims database. Methods: 185,012 NAFLD or NASH patients between 1st January 2006 and 31st July 2018 were identified from JMDC database. Mean annual all-cause HCRU and costs were reported pre- and post-index date of the initial diagnosis of NAFLD/NASH, LC and HCC. Age, gender, and comorbidity influence on post-index cost was assessed with a multivariable analysis. Results: 123,379 NAFLD/NASH, 205 LC, and 96 HCC patients were selected into 3 liver severity cohorts based on the study inclusion/exclusion criteria. Majority of patients were male (70.0% to 71.7%) with comorbid hyperlipidaemia (50.2% to 61.5%), diabetes mellitus (40.0% to 60.4%), and hypertension (27.9 % to 42.7%) most prevalent across the 3 liver disease states. The mean all-cause healthcare annual cost significantly increased with liver disease severity, at ¥146,096, ¥399,425 and ¥842,875 for NAFLD/NASH, LC and HCC patients, respectively. Comorbid cardiovascular disease (CVD), following by type 2 diabetes mellitus (T2DM) had the highest influence on all-cause cost with a cost ratio of 1.77 and 1.45, respectively. Conclusions: NAFLD/NASH patients with LC or HCC have increased comorbidity burden, high HCRU, and healthcare costs, which further highlights the importance and need of timely identification and management for NAFLD and NASH patients in Japan.

For the accurate evaluation of the ship performance in actual seas, the relationship among the ship speed, the engine revolution and the engine power in calm seas is important. One method to obtain the relationship is to use the onboard monitoring data. The approximate curve is obtained by the least-square method. In this method, it is important that the number of the data is enough in the appropriate range of the engine revolution or the ship speed. However in the case of a bulk carrier, the range of the engine revolution and the ship speed is narrow in one voyage. In this paper, a new numerical model is applied to a bulk carrier in service. The data is filtered by the wind speed, the significant wave height, the difference between the ship speed through the water and over ground and the rudder angle. Moreover the corrections for the external force and the combination of the data of each voyage are carried out. The approximate curve is obtained in a numerical expression using parameters “an”, “bn”, “cn” and “dnv”, and the displacement correction model is obtained. The difference between the simulation and the monitoring data of the ship speed and the fuel oil consumption is within 2%.

Background The positive effects of wearing a mouthguard on shock absorption have been indicated in various papers. The ability of a mouthguard to protect against indirect injury, however, is not clear, and the thickness that a mouthguard would require to provide such protection remains to be determined. The primary aim of this study was to clarify the shock absorption potential of a mouthguard against forced, traumatic occlusion. The secondary objective was to compare the shock absorption ability of different thicknesses of mouthguard against this type of trauma. Materials and methods An artificial skull (ZA20; 3B Scientific International, Co. Ltd, Niigata, Japan) with two-axis strain gages applied to the right buccal aspect of the mandible and the mandibular and maxillary teeth was used to measure shock absorption ability. Three different thicknesses of EVA mouthguard (1, 2, and 3 mm at the first molar) were tested. Results and conclusions Within the limitations of this laboratory study, the following results were obtained: the results showed that increasing the thickness of the mouthguard improved its shock absorption ability.

The application of computational intelligence (CI) and artificial intelligence (AI) to games has been attempted as a typical implementation of intelligent processing on computers. Intelligence in this sense is understood as the ability to search for the best solution efficiently among multiple options, specifically in AI playing board games such as chess. As the processing ability of computers increases, CI/AI systems are outperforming humans in finding potential solutions from a tremendous number of options within a short timeframe. These days, computer games are widely prevalent. CI/AI applications in computer games are focused on animating non-player characters (NPCs), whereas CI/AI applications in the scientific fields are focused on modeling intelligent human activities. The field of computer games faces many issues, such as dealing with dynamic environments that change quickly and processing images at higher resolutions and complexity. The use of computer games as a benchmark for CI/AI technologies has been attempted, and competitions involving various kinds of games have been held to encourage innovation in the field. In this paper, we describe a learning agent that participated in a platform game CI competition held in conjunction with Fuzzy System Symposium (FSS 2012). The approach adopted in this paper is a basic method based on conventional methods. The authors hope that this presentation of our development processes would encourage many researchers to participate in competitions and that it would contribute to progress in the field.

We propose a statistical MOSFET model using the α-power equation for the I D –V GS curves of a transistor to make it easier to deal with transistor variations using hand calculations. We evaluated the impact of the transistor variation (mismatch) on the harmonic distortion (HD) in a differential amplifier using the statistical α-power model along with a sensitivity simulation using SPICE. We found that the driver transistor variation majorly impacted on the 2nd HD in the differential gain, which was approximately proportional to the transistor current mismatch, whether the mismatch was induced by the threshold voltage variation or by the current factor variation. We further evaluated the HD by directly using the experimental I D –V GS curves to obtain more accurate values. The α-power model, fitted to g m –V GS curves, described the HD more precisely, to make it more agreeable with the results obtained from the experimental data, when we used the differential current equation as a function of the transconductance (g m ), its derivative $$ \left(g_{m}^{\prime}\right) $$ and their variations (Δg m and Δ $$g_{m}^{\prime}\, $$ ).

The variation characteristics of the inverter delay time in a large-scale integrated (LSI) chip were evaluated by using an analytical model equation combined with the statistical simulation program with integrated circuit emphasis (SPICE) simulation as well as the experimental data obtained from a device matrix array (DMA) test vehicle [11]. We demonstrate that the variation in the two-stage delay time t d (t d = t dLH + t dHL ) is linearly proportional to the variation of the effective peak operating current of the two-stage inverter I D (7) expressed as Δt d /t d = -ΔI D /I D . This remains constant whether or not the current variation was induced by the threshold voltage variation (Δ V th ), the current factor variation (Δβ), or both, even for unbalanced transistor width ratios between the p-type metal oxide semiconductor (PMOS) and the n-type metal oxide semiconductor (NMOS) (W P /W N = 0.5-5). Thus ΔI D /I D can be regarded as a measure of the inverter delay time variation. The relative variation in the delay time increases dramatically when the supply voltage is decreased, which we attribute to the specific gate voltage dependence of the MOS drain current variation induced by the threshold voltage variation ΔV th . .

International audience; Aussi surprenant que cela puisse paraître, le Japon comprend un grand nombre de juristes francophones et francophiles, notamment chez les spécialistes de droit constitutionnel (mais pas seulement). Depuis les années 60, les échanges ont toujours existé. Ils ont été renforcés par la création dans les années 90 du Groupe d’études francojaponais de droit public formé par une nouvelle génération de juristes partageant le même désir de renouveler les modes d’approche du droit. Ce Groupe d’études organise à un rythme régulier des colloques autour d’un thème qui ouvre des perspectives de recherche nouvelles en droit public et en droit comparé. La rencontre qui a eu lieu à Kyoto en septembre 2012 portait sur « les transferts de concepts juridiques ». Elle a associé des juristes de droit public et de droit privé conscients que la confrontation des points de vue enrichit plus qu’elle ne contrarie. Les contributions réunies dans le volume témoignent de la richesse et de la variété des sujets abordés. Elles permettent de prendre la mesure d’une communauté de méthodes pour approcher le phénomène juridique, tant dans sa dimensioncomparative qu’en ce qui concerne l’exercice du pouvoir et la protection des droit fondamentaux. Elles sont signées par quelques unes des figures actuelles importantes du droit public ou privé en France et au Japon. L’ouvrage a été coordonné par Pierre Brunet, Professeur de droit public à l’Université Paris Ouest Nanterre (Vouloir pour la nation. Le concept de représentation dans la théorie de l’Etat, LGDJ, 2004 ; Questions contemporaines de théorie analytique du droit, Marcial Pons, 2011), Ken Hasegawa, Professeur de droit public à l’Université Kogakuin de Tokyo et Hajime Yamamoto, Professeur de droit public à l’Université Keio de Tokyo. (Résumé éditeur)

To clarify the nature of cation sites, such as the strength of the electric field exerted by them, their location, etc., in zeolite pores, adsorption of methane on a series of ion (Li, Na, K and Rb) exchanged zeolites (FAU, FER and MOR) with different Si/Al ratios was discussed based on IR spectroscopy and adsorption thermodynamics. The interaction energy of methane with the zeolites was strongly correlated with the micropore size of the main channel rather than the cation content in the zeolites. On the contrary, the strength of the electric field in the vicinity of Na sites increased with the increase in the Si/Al ratio of the zeolite in spite of the decrease in the amount of cations. All of the cations incorporated in the zeolites studied were not always available for methane adsorption since cations in the zeolites are distributed into deep (methane inaccessible) sites and surface (methane accessible) sites, and the amount of inaccessible sites often increased with the decrease in the size of the cation.

BACKGROUND: Concussions are common among athletes, with the potential to cause memory-related, physical, cognitive, emotional, and behavioral damage. A concussion is an acceleration/deceleration injury resulting from direct and indirect biomechanical forces transmitted to the cerebral tissues. From a sports dentistry viewpoint, increased mastication muscle activity or clenching due to the presence of a mouthguard may enhance cervical muscle activity, thereby reducing damage following impact. This relationship has not been previously investigated in the context of rugby. The purpose of this study was to investigate the effect of voluntary clenching on indirect head acceleration during attack- and defense-related drills. MATERIALS AND METHODS: A total of 12 high school rugby players participated in the study. Linear acceleration of the head was measured using an accelerometer that took measurements in three axes. Masseter and sternocleidomastoid muscle activities were measured using wireless electromyography. These data were synchronized using digital video imaging software for analysis. The study protocol was approved by the Tokyo Dental College Ethics Committee. RESULTS AND CONCLUSIONS: Within the limitations of this study, the following results were obtained: the activities performed during rugby practice involved relatively small indirect head acceleration and masseter and sternocleidomastoid muscle activities. After the young male rugby players were instructed to clench their masseter muscles, a marked decrease in head acceleration was observed. Language: en

A rugby player who had frequently experienced soft tissue injuries while playing rugby and wearing a conventional custom-made mouthguard came to the hospital clinic. The patient had suffered traumatic soft tissue injuries such as lip lacerations and bite trauma. Severe crowding due to ectopic maxillary and mandibular canines was observed. In response to the patient's request for better protection, a set of maxillary and mandibular mouthguards was designed: one covering the entire maxillary dentition and the other the mandibular front teeth only. The mouthguards were to be worn simultaneously. In this paper, we describe how these mouthguards were fabricated and discuss the results. The patient has experienced no injury to the stomatognathic system, including the lips, for five seasons since he began wearing this set of mouthguards. This new pairing of mouthguards appears to offer sufficient protection against injury, despite severe malalignment. We believe that this new type of paired maxillary and mandibular mouthguards has the potential to reduce sports-related dental injuries.

The separation process of various molecules in inorganic membranes was investigated by using molecular dynamics, quantum chemical calculation, and computer graphics. It was indicated that an inorganic membrane with the high selective affinity to CO2 molecules is effective and efficient to separate CO2 molecules from the industrial exhaust gas even at high temperatures. The affinity of various membranes to CO2 and N2 molecules was quantitatively evaluated by quantum chemical calculations. The separation mechanism of water and various alcohol, such as methanol, ethanol, 1-propanol, and 2-propanol, in zeolite membranes was suggested. Moreover, the applicability of carbon nanotubes for the separation of organic molecules, such as 2, 6-dimetyl naphthalene and 2, 7-dimetyl naphthalene was also demonstrated.

Power Reactor and Nuclear Fuel Davelopment Corporation (PNC) has been developing techniques of evaluating groundwater flow in granitic rock. In a link of this purpose, PNC introduced the borehole radar system (RAMAC) which was developed by Swedish Nuclear Fuel and Waste Management Co., because it is critical to investigate the spatial extent and dimensions of fracture zones.This report describes the results of crosshole measurements which were performed with RAMAC system at the Kamaishi Mine in-situ Experiment Site in the northern part of Honsyu Island, Japan.The results are summarized as follows:(1) Spatial extent of some low velocity zones and high velocity zones of electromagnetic waves were delineated.(2) Almost of the seeping points observed by borehole TV lies in the low velocity zones.(3) The fracture concentrated zones or fracture zones with groundwater recognized by observing the wall of the gallery, which was dug along the borehole used for crosshole measurements, corresponded to the low velocity zones.These results indicate that the low velocity zone obtained by the borehole radar measurements corresponds with the fracture concentrated zone or fracture zones with groundwater.

It was found that when Escherichia coli is grown in the presence of 0.2-0.3 mM menadione (2-methyl-1,4-naphthoquinone), an FMN-dependent NADH-quinone reductase increases more than 20-fold in the cytoplasmic fraction. The menadione-induced quinone reductase was isolated from the cytoplasmic fraction of induced cells. The purified enzyme had an Mr of 24 kDa on SDS-polyacrylamide gel electrophoresis. The enzyme required flavin as a cofactor and a half-maximum activity was obtained with 0.54 microM FMN or 16.5 microM FAD. The enzyme had a broad pH optimum at pH 7.0-8.0 and reacted with NADH, but not with NADPH. The reaction followed a ping-pong mechanism and the intrinsic Km values for NADH and menadione were estimated to be 132 microM and 2.0 microM, respectively. Dicoumarol was a simple competitive inhibitor with respect to NADH with a Ki value of 0.22 microM. The electron acceptor specificity of this enzyme was very similar to that of NAD(P)H: (quinone acceptor) oxidoreductase (EC 1.6.99.2, DT-diaphorase) from rat liver. Since menadione is reduced by the two-electron reduction pathway to menadiol, the induction of this enzyme is likely to be an adaptive response of E. coli to partially alleviate the toxicity of menadione.

Ranula is a term to indicate rather roughly a mucous retention cyst occurring in the floor of mouth, which is caused by passing disorder of saliva in the submaxillary duct or sublingul one. The developmental mechanism of the most of ranula is known to be salivary extravasation from an injured duct, whose cause is most commonoly described as trauma, followed by inflammation, foreign body.This report describes a case of ranula whose development should be concerned with sialolithiasis.The patient, a 40-year-old man, visited us with a chief complaint of a swelling on left side of the floor of mouth. Radiographic examination revealed sialoliths in the left submaxillary duct and gland. The fenestration of ranula was carried out, the sialoliths were extirpated.It should be thought, in this case, that saliva was extravasated into the connective tissue of the floor of mouth by the perforation of the submaxillary duct to which sialoliths were an injury.

Presently, there is general agreement that, while odontogenic keratocyst may be of varied origin, one clinical feature warrants its recognition and separation as a distinctive entity: the exceedingly high recurrence rate.We reported a case of odontogenic keratocyst extending from the second molar to the ramus of the right mandible with an impacted tooth in the mandibular condyle region.The patient, a 20-year-old woman, visited our hospital to examine the ramus of the right mandible.In radiological findings, from the 7 position to the ramus of mandible, a unilocular shadow with a scalloped periphery was observed.We operated on the mandibular resection from the 7 position to the ramus of mandible of the right side with mandibular condyle. Then we performed an immediate reconstructive operation of the mandible by autogeneus illiac bone grafting.The lingual cortical plate of the ramus of mandible was perforated.In histological findings, the lining epithelium of cyst wall was stratified squamous with parakeratosis. Epithelium was consisting of 6 or 8 ros of the cells, and showed dental laminalike epithelium.There is the cyst wall between the impacted tooth in the mandibular condyle region and the lumen of this cyst. The lumen of this cyst was filled with a thicker creamy material.Two years have passed since the operation and the prognosis is favorable without recurrence.

Alkanediyl bis(alkyl trithiocarbonate)s were conveniently synthesized by treating alkanedithiols with alkyl halides and carbon disulfide in the presence of a phase-transfer catalyst.

Change in small intestinal brush border membranes of rats following methotrexate administration was monitored by the fluorescence spectra and polarization of the cationic fluorescent probe, safranin 0. Total protein content of brush border membranes of treated rats was less than that of control rats, whereas no significant difference in total sialic acid content of brush border membranes was observed between them. Thus, an apparent increase in the electronegative charge of brush border membrane vesicles per unit of membrane protein following methotrexate administration may possibly cause the change in fluorescence spectra and polarization of safranin 0.