Heroin trafficking and consumption has increased steadily over the past decade in Tanzania, but limited information regarding HIV and drug use exists for the city of Mwanza. Our study investigates the epidemiology of drug use, and HIV risk behaviors among drug users in the northwestern city of Mwanza. Using a combination of targeted sampling and participant referral, we recruited 480 participants in Mwanza between June and August 2014. The sample was 92% male. Seventy-nine (16.4%) participants reported injecting heroin, while 434 (90.4%) reported smoking heroin. Unstable housing and cohabitation status were the only socioeconomic characteristics significantly associated with heroin injection. More than half of heroin injectors left syringes in common locations, and half reported sharing needles and syringes. Other risk behaviors such as lack of condom use during sex, and the use of illicit drugs during sex was widely reported as well. Among the study sample, there was poor awareness of health risks posed by needle/syringe sharing and drug use. Our results show that heroin use and HIV risk related behaviors are pressing problems that should not be ignored in Mwanza. Harm reduction programs are urgently needed in this population. The dual epidemic of HIV and substance use—specifically heroin injection—is a growing public health problem in Tanzania. It is well established that the injection of drugs is associated with HIV acquisition. Specifically, several studies conducted in Eastern Europe, China22, South In the past decade, the increase in the number of heroin users has fueled a rise in HIV infections among PWID in Tanzania. While HILimited data on heroin use in Tanzania and associated HIV risk factors is available mainly from Dar es Salaam and Zanzibar. Currently, 22 tons of heroin is trafficked through East Africa annually with 2.5 tons consumed locally. It is estimated that there are 30,000 PWID in mainland Tanzania. . AnecdotFrom June to August 2014, 480 participants were recruited and interviewed about their substance use and associated risk behaviors. With this sample size, the study was estimated to have 90% statistical power to detect a difference of 0.04 using a two-sided binomial test with 95% confidence. Substance users were recruited based on a combination of targeted sampling and participant referral. The sampThis information was then used to target certain neighborhoods in the city that were known as ‘hotspots.’ Neighborhood selection was then confirmed by direct observation of drug use by the interviewers. In total, 12 study areas were selected and 50–60 people were interviewed per area. Study areas were determined according to local administrative areas (wards) and then further divided according to street names where drug users were reported to congregate. We selected 7 wards, and out of these 7 wards, 12 streets. Data collection began at the street closest to the primary investigator’s office, and ended in the area furthest away.Two outreach workers, who were trained by the investigators AXT and SK for a 5-day period prior to the start of data collection, conducted the interviews. Verbal consent was obtained for this study. Before conducting the interview, participants were read an information sheet in Swahili that contained all the details of the interview, and were informed of their right to not answer any question. The information sheet was also made available to the participants to read. Written consent was not obtained to protect the identities of the participants. Each participant was assigned a unique identification number and full confidentiality was maintained. Interviews were conducted individually in Swahili in various private, enclosed locations along the street where participants gathered.The study and consent procedure was reviewed and approved by the institutional review boards for the protection of human subjects at Yale University, USA (HSC #1404013808) and at the National Institute of Medical Research (NIMR) in Tanzania in May 2014.Eligible participants were those who self-reported to be above the age of 18, had injected drugs in the past 12 months or used any other kind of drug in the past 12 months. Many of those approached on the streets were preparing to use illicit drugs. Screening measures for drug use included self-report and visual inspection for injection marks on the arms, feet or legs. Illicit drug users were typically found in groups in alleyways, in rented rooms, abandoned homes, or common congregation areas such as football fields. Some participants also showed us their injection equipment and drugs voluntarily, as proof that they were drug injectors. Participants who completed the interview were provided a small meal, drink and/or snack after the interview. On average, each meal cost 958 TSH (USD$0.50).Data were collected in Swahili using a structured questionnaire written by the investigators based on instruments employed by the World Health Organization (AUDIT survey), Tanzanian AIDS Prevention Program (MAT Pilot Program Client Assessment form) as well as previous instruments used in an alcohol study that have yielded promising results. The quesData were entered into an OpenClinica  database and analyzed with the statistical analysis software R . Data from all 480 participants were available for analysis. A key outcome of interest was heroin injection, defined as either yes or no. We fitted two logistic models to heroin injection use: socioeconomic characteristics and HIV risk related behaviors.Predictors measured at continuous integer levels were recoded into discrete categories that reflected the distribution of data. Information collected via open-ended questions was coded and stratified as non-ordinal categories for use as independent variables. The reference category for each predictor was the one that had the lowest perceived HIV risk. We assessed correlations between each independent variable and the likelihood of injection. Predictors with the highest level of correlation and significance (p<0.2) were included in the multivariate models. Akaike Information Criterion (AIC) and deviance tests were used to compare models to one that included all independent significant variables associated with injection. The model with the lowest AIC value was used as the final reduced model. Incomplete data were omitted from the model.To determine the best reduced multivariate model, we conducted factor analysis to find the strongest predictors for heroin injection. Factor analysis removes redundancy from a set of correlated variables, such that the final model is one that contains the most significant and highly correlated predictors.Predictors were analyzed for independence, i.e., to examine potential significant interactions among the terms. All predictors were found to be independent. Interaction terms were not included in the final model as none were found to be significant.Results are presented in the form of odds ratios with 95% confidence intervals. Significance of odds ratios was assessed using 95% confidence intervals and chi-squared tests. We used chi-squared tests to assess differences in socioeconomic characteristics and risk behaviors between PWID and non-PWID.In our sample of 480 participants, we interviewed 442 males (92%) and 38 (8%) females. The overall mean age of our study sample was 28.8 years. The mean age among PWID was 29.0 years, while the mean age among those who had never injected drugs was 28.3 years. More than a tenth of the study population (10.4%) were living on the streets or considered themselves homeless, whereas170 (42.3%) rented rooms. A substantial fraction (69.4%) reported having a job as a primary source of income, where slightly less than a third (27.7%) reported stealing or pickpocketing as a primary source of income. Having a job, however, often included illicit means such as sex work or selling stolen goods.Among our study population, 65 (13.5%) reported currently injecting drugs. A majority of those who had a history of injection use remained injectors (82.3%). Almost everyone interviewed (99.4%) reported using drugs 7 days a week. Self-reported daily frequency of any kind of drug use ranged from once a day to a maximum of 25 times a day. The most commonly reported frequencies were: 3 times a day (20.8%), 5 times (20.0%), and 4 times (18.8%).We found that many current injectors reported engaging in HIV-risk related injecting behaviors. For example, 44/65 (66.7%) reported sharing needles, 31/65 (47.7%) shared injection equipment and 41/65 (63.1%) left syringes in public locations. Although 58/65 (89.2%) of the current injectors reported cleaning injection equipment, only 32.7% cleaned their equipment with bleach. Most of the other PWID (43.1%) used potable water, a non-effective method of sterilization.We next explored the relationship between socioeconomic status and type of drug use. To assess socioeconomic status, we used the following measures: age, gender, education level, marital status, living arrangement and income source. However, we found that these factors were not significantly associated with heroin injection (summarized in A majority of PWID was in the 21–25 (31.1%) and 26–30 (28.4%) age groups. Similarly for non-PWID, a majority was in the 21–25 (29.3%) and 26–30 (30.4%) age groups. PWID included more females than non-PWID . Fewer males were PWID than non-PWID . More PWID had never gone to school compared to non-PWID . A greater proportion of PWID reported some form of higher secondary education  and post-secondary education compared to non-PWID . More PWID lived without a spouse/partner compared to non-PWID . Those who were separated or divorced were approximately 6 times  more likely to inject heroin compared to those who are married with one spouse.Room rental was the most common living arrangement among both PWID and non-PWID . Living on the streets was slightly less prevalent among PWID than non-PWID . Income sources differed very little between PWID and non-PWID (p>0.05). More than half of PWID and non-PWID have jobs as their main source of income . Those who had jobs mostly reported that they sold household items, were drivers or engaged in sex work.kokteli (translated to “cocktail”) and 86% of individuals reported smoking these. Less commonly reported among the study population was the combination of marijuana, non-injection heroin and pharmaceutical drugs (12.5%).In addition to injecting heroin, smoking heroin was most commonly reported (83.0%) as a concurrent behavior, followed by smoking marijuana (77.2%). PWID also often engaged in smoking marijuana and heroin (63.3%). PWID also reported engaging in smoking heroin, marijuana and pharmaceutical drugs simultaneously (15.2%). These combinations of risky behaviors are not independent of each other.We show in Peer pressure, defined as influence from members of his/her social circle, was one of the most commonly cited reasons for starting drug use among PWID and non-PWID . Both PWID and non-PWID cited family problems as the reason for starting drugs .Risky sexual behaviors were found to be different between PWID and non-PWID, although these were not statistically significant. The proportion of both PWID and non-PWID that had their first sexual experience at a very young age was quite high: 43.1% and 40.3% respectively. More PWID than non-PWID reported having more than 5 sex partners in the past 30 days . The use of condoms all of the time was less common among PWID than non-PWID .We investigated HIV-related injection risk behaviors among injectors. A majority of those with a history of heroin injection are still current PWID (82.2%). Of the 65 current PWID, 67.7% have ever shared needles. Approximately half of PWID (47.7%) in our sample reported having shared injection equipment. A majority of the PWID (89.2%) reported cleaning their injection equipment and needles using soap (6.2%), alcohol (9.2%), bleach (29.2%), boiling water (4.6%), and cold water (38.5%).The practice of flashblood was known among the study population, but rarely practiced. Flashblood is the practice that occurs when a PWID, after self-injecting heroin, draws blood back into the syringe. This blood is then injected by another PWID with the hope of having enough heroin in that blood sample to stave off withdrawal.  Overall,Knowledge and awareness about the risks posed by using and sharing syringes is crucial to HIV prevention see . ApproxiAfter adjusting for knowledge of other diseases, the adjusted multivariate model demonstrated that “not knowing” and knowledge of TB were the two main knowledge factors associated with heroin injection. The odds of injection among those who were not aware of any problems (“not knowing”) was 10.4 times (95% CI: 5.88–18.97) that of those who do know.A reduced multivariate model demonstrated that housing and co-habitation status were significantly associated with heroin injection. However, after adjustment, housing status was no longer significantly associated with heroin injection. The odds of heroin injection among those who do not live with a spouse are 2.25 times (95% CI: 1.05–5.44) those who do live with a spouse. These results reinforce that results from Further, as shown in To our knowledge, this is the first study to describe the epidemiology of substance use in general and substance injection in particular, and associated HIV related risk behaviors in Mwanza, Tanzania. Using a survey of 480 drug users, we found high numbers of heroin use, and HIV risk behaviors amongst current substance users in Mwanza. We also found marginal differences between PWID and non-PWID in terms of socioeconomic status. These results suggest that the population in these two sub-groups of drug users is similar and that their backgrounds are not confined to any one particular socioeconomic stratum.Approximately one fifth of the study population had a history of heroin injection, and 13.5% were current heroin injectors. Very few people reported injection with other types of drugs besides heroin and combinations of smoking heroin and marijuana were also commonly reported. Given that the overwhelming majority of individuals with a history of injection are current injectors, this highlights the urgent need to establish harm-reduction oriented programs, including methadone maintenance, which are currently absent in Mwanza.,,, eve eve,[24], Our data, These re, hav hav,[27],Deciphering the start of the heroin epidemic among our study population is difficult. The type of drug that was first used was not specified. Among our study participants, the mean length of drug use is 7.9 years. The most common year that people began to use drugs was in 2006, implying a recent uptick in heroin imports in the region. This is also consistent with UNODC reports that cite an increase in heroin seizures over the past decade, which also imply that there could be many more undetected shipments. Heroin u, Amon Amon,[7], However,,,33 With , , Needle-related risk behaviors were widely reported among PWID. More than half the PWID leave syringes in common locations and half the PWID shared injection equipment. The general availability of syringes—which consists of a 2ml syringe and 23 gauge needle and is sold in a pack—facilitaDespite the widespread sharing of injection equipment, cleaning injection equipment was widely reported among PWID. The most commonly used cleaning agent is cold water, which is ineffective to sterilize the syringe. Ideally, PWID should clean their needles with bleach adequately to kill viruses, which is,,,[, Flashblo,[In Mwanza, awareness about health risks posed by using and sharing needles is poor. A third of PWID were not able to list any health risks posed by using and sharing needles. Previous prevention efforts conducted in the Mbeya region of Tanzania have shown that information, education and communication about HIV is integral to the reduction of HIV prevalence. However,, In agreeThe results of this study should be used to catalyze the implementation of methadone clinics as well as other forms of harm reduction programs that provide access to sterile injection equipment in Mwanza and cities beyond Dar es Salaam and Zanzibar. Our results have highlighted that there is a sizable population of heroin drug users in Mwanza, and that many PWID are engaging in high-risk behaviors. However, we must not exclude the non-PWID as well. Given the large number of non-PWID who use heroin in our study sample, there is a high chance that non-PWID will make the transition to injection later on in life. Research has shown that non-PWID exposed to treatment such as methadone maintenance and rehabilitation are less likely to initiate injection.These results should be interpreted in light of the following limitations. Firstly, although great care was taken to ensure that we had a sizable and diverse sample of drug users, obtaining a random representative sample of hidden population is extremely difficult. We were also not able to recruit many female drug users, which may have skewed results. The nature of our study is also heavily reliant on self-report, which may have resulted in underreporting of risky behaviors that are not socially acceptable. However, self-report was and is still the main measure of risky behavior. Further,The results of this study highlight that heroin use is a significant problem in a major city outside Dar es Salaam and Zanzibar, suggesting that this urban center has now become a consumer hub of heroin, and may be a transit hub for heroin to other parts of East Africa. We find that housing status and living arrangements are the strongest predictors of heroin injection, and that many users began using drugs due to peer pressure, underscoring the fact that family stability and home life should be taken into consideration in HIV and drug prevention efforts in Tanzania. Many PWID were also reported to engage in needle sharing and reported improper methods of cleaning needles. A significant proportion of the study population exhibited a lack of awareness of the risks involved in needle sharing and drug use. However, even among those who are knowledgeable about risks, the odds of heroin injection are high. This suggests that HIV prevention must extend beyond education campaigns, such as ensuring that students stay in schools, engaging in productive after school activities and encouraging family counseling. Failing to recognize heroin injection in Mwanza may derail the work that has been done to address the HIV epidemic in Tanzania. Furthermore, the high prevalence of heroin use in Mwanza should sound the public health alarm in neighboring countries. If heroin use is active in Mwanza, it is likely crossing Lake Victoria to Uganda and western Kenya, as well as continuing on the road to Kigali, Rwanda. The prevalence of heroin in Mwanza needs a broad response.S1 Questionnaire(PDF)Click here for additional data file.


In this paper, case study on outlet cracking is first conducted for the Goupitan and Xiaowan arch dams. A nonlinear FEM method is then implemented to study effects of the outlets on integral stability of the Xiluodu arch dam under two loading conditions, i.e., normal loading and overloading conditions. On the basis of the case study and the numerical modelling, the outlet cracking mechanism, risk, and corresponding reinforcement measures are discussed. Furthermore, the numerical simulation reveals that (1) under the normal loading conditions, the optimal distribution of the outlets will contribute to the tensile stress release in the local zone of the dam stream surface and decrease the outlet cracking risk during the operation period. (2) Under the overloading conditions, the cracks initiate around the outlets, then propagate along the horizontal direction, and finally coalesce with those in adjacent outlets, where the yield zone of the dam has a shape of butterfly. Throughout this study, a dam outlet cracking risk control and reinforcement principle is proposed to optimize the outlet design, select the appropriate concrete material, strengthen the temperature control during construction period, design reasonable impounding scheme, and repair the cracks according to their classification. Arch dam has been constructed for water storage reservoir since early times such as the Kurit dam constructed in Iran in the 13th century, the Elche dam in Spain in the 17th century, and the Pontalto dam in Italy in the 17th century . Since tMoreover, the super-high arch dams tend to layout more ancillary structures such as outlets for various purposes, for example, flood discharging, sediment removal, silt scouring, and reservoir emptying, which are usually distributed in a relatively high density in the dam body, as shown in Three kinds of theoretical analysis are adopted in literatures to analyze effects of outlet cracking on the integral stability of the super-high arch dams. (1) Plane stress analysis: if the outlet opening is relatively small compared with the whole dam body and the minimum distance between the centre of the outlet and the dam foundation is not less than three times of the width of the outlet, only local stress distributions of the dam will be affected by the outlet. Thus, appropriate two-dimensional (2D) section of the outlet may be selected for plane stress analysis. (2) Linear elastic analysis: in the area where tensile stress exceeds the strength of concrete, it is assumed that the concrete completely cracks and reinforcement bar bears all the tensile stress. Linear elastic analysis is usually suggested for the preliminary design of the concrete dam and its components and usually leads to a large safety factor in design , 18, whiHowever, most of the analyses available in literatures are conducted for the dams without sufficient considerations of outlets, which lead to a large gap between the obtained and actual stresses and/or displacements for the dams and may adversely affect the dam design, construction, and optimization processes. In sum, the effect of the outlets on working condition of the super-high arch dam is still a blank area worthy of further studies.In this study, the status, reason, and consequence of the outlet cracking in the Goupitan and Xiaowan super-high arch dams are first discussed. The effects of the outlets on the deformation, stress, cracking risk, and overall stability of the Xiluodu super-high dam are then analyzed using a finite element method. Finally, a dam outlet cracking risk control method is proposed on the basis of the outlet cracking mechanism identified above to ensure the safety and stability of the super-high arch dams.The Goupitan high arch dam  is constThree groups of defects were discovered in the Goupitan concrete arch dam at the end of May 2008. The first one was the peripheral fractures observed near the number 1 reservoir empting bottom outlets, as shown in Furthermore, the status of the peripheral fractures near the reservoir emptying bottom outlets is highlighted here. The first series of cracks appeared at the end of November 2006 in the surfaces of the number 13 dam monolith at EL 491 m for the number 1 reservoir emptying bottom outlet and the number 14 dam monolith at EL 497 m for the number 2 bottom outlet, as shown in Moreover, there are local cracks in the numbers 1, 2, and 4 diversion bottom outlets which coalesce with the transverse joints at a distance of about 10 m from the upstream surface. These cracks are rather long but the width is about 0.2 mm. The depth of the cracks in the floor and roof of the bottom outlets is shallow, and the majorities of them are less than 1 m. However, the cracks in the side wall are somehow deeper and the greatest depth is larger than 2.8 m.In sum, the number of cracks in the different outlets ranges from 13 to 21 and the majority of them is longitudinal  accordinFollowing the design requirements, the reservoir emptying and diversion bottom outlets are constructed with the C50 concrete so as to improve their abrasion-resistance capacity. As we know that the concrete has poor conductivity, high temperature gradients may be resulting in between the interior and the surface of the concrete structural elements or between parts of a concrete element during the sequential pouring phases. The temperature gradients may lead to tensile stresses, which may result in the young concrete cracking. In the Goupitan arch dam, the large amount of cements, the high temperature of hydration, and the hot weather in July during the construction of the bottom outlets lead to high temperatures inside the concrete. As the temperature of the concrete drops down sharply later, stress due to the temperature gradient of the concrete from inside to outside creates several cracks. As the time passes, the temperature of the concrete decreases continually and more and more cracks are appeared. In addition, if the conservation measures are not perfect; for example, the external concrete has not been supplied with sufficient water; the concrete surface will shrink generating further cracks. Actually, even if the upstream water level reaches EL 590.0 m, the resultant stresses at the reservoir discharging bottom outlets in the Goupitan arch dam are not more than the tensile or shear strengths of the C50 concrete. Thus, it is not necessary to use the C50 concrete during the construction of the abrasion-resistant layers of the bottom outlet from the point of view of the actual diversion capacity of the bottom outlets in the Goupitan arch dam.KIC of the concrete, illustrating that the crack will not continue to propagate.In addition, the C35 concrete is used to construct the dams in the transition zone from the C50 to C18035 concretes. The shrinkage coefficients of the concretes differ from each other, which further contribute to the outlet cracking. The 3D finite element method was conducted by the design institute to analyze the stress and deformation of the Goupitan arch dam during the operation phases with and without outlet cracking. It is found that the integral stability of the dam is affected by the outlet cracking. The analysis results show that the existence of the cracks in the bottom outlets has little effects on the dam stress and displacement. During the operation phase, compressive and shear stress of crack is small, which indicates that the cracks will be closed and shearing slip will not occur. Even if water pressures and external loads are applied, the stress intensity factor at the tip of the cracks surrounding the outlets is still smaller than the fracture toughness 3/s. The maximum average water flow speed is 45 m/s but it is 38 m/s at the centre of the middle diversion outlet. Taking the high speed and large amount of the diversion flow, the middle diversion outlets should be reinforced with fiber concrete. Below EL 1051 m, surfaces of the outlets are built with 0.6-metre-thick abrasion-resistant C2840W9010F90150 concrete.The Xiaowan arch dam  is constThe outlet cracking mainly occurs in the middle diversion outlets in the Xiaowan arch dam. Correspondingly, only the outlet cracking characteristics and reinforcement measures of the middle diversion outlets are summarized into Because of the large displacement toward the upstream side of the arch dam when the water through the diversion outlets exceeds the designed amount, the large tensile stress near the upstream surface may be the main cause of the outlet cracking in the arch dam.Cracks near the middle diversion outlets coalesce with those thermal cracks due to temperature gradient, which become the main source of water leakage. Our studies have shown that if the pore water pressure in the crack reaches 0.5 MPa, the crack may propagate. The bigger the aspect ratio, the smaller the pore water pressure needed for the crack to propagate. Currently the pore water pressure of 1.1 MPa in the cracks has led to a large amount of water leakage through the numbers 22 and 23 dam monoliths. If appropriate measures could not be taken timely to cut off the water source, the irregular cracks in the side wall of the outlets may propagate continually under the repeated pressing of the pore water in the cracks, which may harm the overall instability of the arch dam. The correspondingly crack reinforcement measures are listed in In this section, effects of outlets on the working status of a 300 m high arch dam in the Xiluodu hydropower station are studied. The Xiluodu hydropower station is located on the Jinshajiang River, Leibo county, Sichuan Province, southwestern China. It is the second largest power station in the world and can produce 13.86 million kW of power, which is close to the capacity of the largest power station, that is, the Three Gorges hydroelectric power station. The principal structures consist of a double-curvature arch dam with a height of 285.5 m and a crest length of 603 m, spillway, underground powerhouse, and logway. The thickness of the dam is 14 m at crest and 60 m at the lowest foundation. There are 7 surface outlets, 8 deep outlets, and 10 diversion bottom outlets placed in the numbers 12~19 dam monoliths. The volume of the outlets counts for 2% of that of the whole dam.β1 and P2β2) with an average thickness of about 25~40 m. The main weak zones are the interstrata bedding planes C9, C8, C7, C3, C2, and C1 and the intrastrata rupture belts Lc6 and Lc5 [The rock mass strata in the reservoir basin are clastic rock, carbonate rock, and basalt of Paleozoic, a small amount of metamorphic rock of Presinian and dolomite of Sinian , 34. The and Lc5 , 33. TheIn this section, three-dimensional nonlinear finite element method is implemented to study the integral stability of the Xiluodu super-high arch dam with and without outlets under normal loading and overloading conditions. Some preliminary results from these analyses were reported previously in a conference paper  to exchI1 is the first invariant stress, J2 is the second invariant stress, and α and H are material constants, which can be determined according toc is cohesion and φ is friction angle. Equations  yield criterion, which can be expressed inf=αI1+J21σ0 and ε0 and f(σ0) ≤ 0. For a given load step or iteration, the strain increment Δε of the point can be obtained by displacement method and correspondingly the stress can be calculated usingD is the elasticity tensor. If f(σ1) > 0, then the stress needs adjustment. If plastic strain increment of the loading step or iteration is Δεp, then the stress after adjusting can be written usingThe stress adjustment process in the nonlinear finite element analysis with the D-P criterion can be listed as in the following: stress and strain of the initial point is set to be f/∂σ by σ1 usingJ2, I1, and f can all be determined by σ and λ and μ are Lame constants, which can be expressed usingE and ν are Young's modulus and Poisson's ratio, respectively. Stress increment of each incremental step or iteration can be written inTransform the AC flow rule to incremental form approximately, which can be written intoCase A: the whole dam under usual loads  and overloads .Case B: dam without outlets, under usual loads and overloads.It should be noted that in the analysis case A, the existence of sluice is not considered and there is no hydrostatic pressure in the area of the outlets. The 3D finite element nonlinear analysis was executed for the Xiluodu arch dam in the following analysis cases.For the analysis cases A and B, the displacement distribution in the upstream sides of the dam under normal loads is illustrated in Figures It is known from the numerical results that (1) under the normal loading conditions, the maximum displacements of the dam crown decrease slightly when the outlets are taken into account. The maximum displacement decrease is about 1.6 mm, as shown in In the design of the dam outlets, it is vitally important to investigate clearly the stress distributions in both dam and outlet, especially in the tensile zone at the roof, floor, and side walls of the outlets. Correspondingly, the distributions of the major and minor principal stresses at the upstream and downstream surface of the dam are depicted in It can be seen from Figures The yield process of the arch dam at ultimate limit states is predicted by applying overloads on the dam in the analysis cases A and B. Figures For the analysis case A under normal loads, there is no yield zone occurring in either the upstream or downstream surfaces. The factor of safety at various locations of the upstream surface is between 2.0 and 5.0. It is discovered from the sequentially overloading process that when the applied load is two times the normal load, a small yield zone appears in the heel of the upstream surface. As for the downstream surface, the yield zone spreads quickly under overload conditions and a large area becomes yield when the applied load reaches 4 times the normal water load.For the analysis case B under normal loads, there is again no yield zone in either the upstream or downstream surfaces. The factor of safety at various locations of the upstream surface is between 2.0 and 5.0, too. The sequential overloading process in the analysis case B shows that when the applied load is two times the normal load, a small yield zone appears in the dam heel while some big yield zone appears in the downstream surface. As the times of the applied overload increase, the yield zone in the downstream surface spreads quickly. When the applied load reaches 3 or 4 times the normal water load, large yield zone appears in the downstream surface and the arch dam enters into nonlinear deformation stage, which indicates the beginning of the dam destruction.It can be seen from the analysis cases A and B that the outlets are integral and help dam shoulder some load although they relatively weaken the carrying capacity of the arch dam. The initial cracking overload coefficient K1 is 2 and the ultimate overload coefficient is 6.5~7. It is obvious from above analyses that, under the overloading conditions, the cracks initiate around the outlets, propagate along the horizontal direction, and then coalesce in the area between the adjacent outlets. The yield zone generated in the dam under overloading conditions looks like a butterfly.Based on the case studies on the outlet cracking in the Goupitan arch dam and the Xiaowan arch dam presented in 1) Concrete Materials. Outlets are always part of the hydraulic structures, which are usually built with stronger concrete so as to improve the abrasion-resistant ability. However, the stronger the concrete is, the more the cement is used, which may generate the larger amount of hydration heat and the higher temperature. All these factors set higher requirements for the construction environment, temperature control, and maintenance measures. Cracking may easily occur once the temperature in the construction environment changes sharply, for example, the drop of the temperature in the late maintenance phase. In addition, if the concrete used in the bottom outlets differs sharply from that used in the surrounding dam body, that is, the shrinkage coefficients of the two kinds of concretes vary greatly, the risk of cracking still increase even if several different kinds of concretes are used in the transition zone.(2) Temperature Control and Maintenance. Temperature control and maintenance of the concretes used to construct the outlets are relatively more complex than the other factors. In addition to conventional measures of the temperature control, the surface of the outlets has to be closed so as to prevent them from impact of low temperatures caused by cavern drafts flowing and water is kept to flow on the surfaces of the dam body concrete. If the measures of the temperature control and maintenance are not carried out properly, thermal cracking may easily occur in the outlet concrete due to temperature gradients.(3) Impounding Scheme. During the construction phase, the water pressure in the reservoir influences the stress distribution in the dam. If the reservoir water is stored too early or too much, large tensile stresses may be induced in the upstream surface, heel, and shoulder of the dam. If the water storage is delayed, cracking may easily be caused by the tensile stress in the upstream face of the crown cantilever, which has large upstream-tend displacement. Thus, reasonable storage scheme should be figured out. During the construction phase of the arch dam, the concrete structure above a certain elevation belongs to a beam structure instead of an arch beam structure since the joints grouting of the arch dam only happens after the temperature of the dam body drops to a specified temperature.(4) Design Scheme. Since the outlets may experience obvious deformation and are prone to tensile stress, reinforcement design is often required. Because of the complex structure and the big size difference from the dam body to the outlets and the effects on the outlets caused by the dam weight, water pressure, temperature gradient, concrete creep behaviour, and so on, the accurate analysis of stresses on the outlets becomes very difficult. So, the design scheme itself alone could not reduce the cracking risk effectively.(5) Concrete Fracture Characteristics. According to the experiment on fracture properties of full graded concrete used in Xiluodu high arch dam, the initial fracture toughness of the concrete with one month age is 0.3 MPam1/2 in average, the unstable fracture toughness is 1.225 MPam1/2 in average, and the cracking toughness is 448.257 N/m in average. The corresponding values of the concrete with three months of age are 0.655 MPam1/2, 1.387 MPam1/2, and 470.600 N/m, respectively. Because of the low cracking-resistance ability of the early concrete and the complex conditions in the construction sites, the concrete dam is prone to generate initial microscopic cracks, especially around stress concentrated area like the outlets. The analysis conducted above shows that the cracks around the outlets have little impact on the dam integral stress and displacement but these cracks may propagate to coalesce with the interior temperature cracks and traverse joints and become the main source of the water leakage. The irregular cracks on the wall of the outlet corridors may propagate under the high pore water pressure in the cracks. Once these cracks propagate into deep depth or through the foundation and their direction is parallel to the axis of the dam, the consequences may be unbearable. In this case, these cracks may harm the dam structural integrity, change the stress condition of the concrete structure, and damage some local dam structures. Moreover, the durability of the concrete may be weakened. Thus, the effects of the superposition of the thermal and structural stresses on the integral stability of the dam allow no ignorance.(6) Outlet Cracking Risk. Based on the case studies on outlet cracking in the Goupitan and Xiaowan arch dams, the diversion outlet is prone to local stress concentration and crack initiation due to hydration heat associated with the exothermic chemical reactions in the fresh concrete. Thus, the local reinforcement design is needed for the diversion outlet, which will be discussed in the next section. During the operation period, the stress and deformation distribution around the outlet generally satisfy the operation requirement of the dam under normal loading conditions. The outlets mainly affect the overall stability of the dam under overload conditions, especially when the yield zones occur around the outlets under the overloading conditions. The shallow processing is involved in sealing and backfilling the cracks with preshrunk mortar and filling the grooved part of cracks with imperial materials during the inspection. (3) The deep processing is used to repair deep cracks, that is, to use chemical grouting method to reinforce the crack. After the chemical grouting, a site investigation should be done to inspect the surfaces of the repaired cracks. Moreover, the grouting quality should be examined by core-sample drilling and hydraulic pressure tests in 28 days after the chemical grouting. The samples from the core drilling should be tested to obtain the compressive resistant capacity and splitting resistant capacity besides the visual inspections. The testing results of the Goupitan arch dam show that the compressive resistant capacity of the sample taken from the core drilling after the chemical grouting is more than 40 MPa and the splitting resistant capacity is more than 2.0 MPa. The hydraulic pressure tests are conducted using the holes from the core drilling or those drilled alone and the pressure of the injected water during the inspection is 0.2 MPa. It is found that the results from the hydraulic pressure tests satisfy the judgment standard, which allows no more than 0.1 Lu permeation rate. In addition, the deep sonic wave tests are also conducted after the grouting is completed, whose results are compared with those from the visual inspection and the tests mentioned above so as to have a further examination of the grouting quality.(1)The outlet cracking in the Xiaowan arch dam has been reinforced in two times. The reinforcement measure in the first time is intended to repair the cracks in the middle diversion outlets which happened before August 2008. At that time, the cracks due to the temperature gradients have not been observed and the cracks in the middle diversion outlets have not coalesced with those due to the temperature gradients yet. The reinforcement measures include grooving the cracks and spraying impervious materials on the surfaces of the cracks.The reinforcements in the second time happened in May 2009, when several cracks in the middle diversion outlets had been found to coalesce with the cracks due to the temperature gradients. The main reinforcement measures include chemical grouting and grooving and spraying impervious materials on the surface of the cracks, which can be detailed as follows: (1) grooving and backfilling with preshrunk mortar immediately. (2) For the water leakage cracks, a 4 mm thick polyurea coating is sprayed in the scope of 2 meters around the cracks. For the area with dense cracks, the 2 m scope is determined from the crack located in the edge of the area. (3) Chemical grouting is applied in the cracks, which coalesce with the thermal cracks due to the temperature gradients inside the dam.In this section, a reinforcement principle is proposed to control the outlet cracking risk based on the reinforcement experiences of the outlet cracking in the Goupitan and Xiaowan arch dams in Sections 1) Selection of Appropriate Concrete Materials. The dam outlets are a hydraulic structure for water diversion, which should be designed using the concretes with appropriate strengths according to their flow rate. The concrete with high strengths should not be used blindly. If the abrasion-resistant capacity of the concrete is only to be improved, the fibre-reinforced concrete may be used, which may reduce the use of the cement then lower down the hydration heat and alleviate the pressure from the temperature control. If the outlet must be constructed using the high strength concrete, whose expansion coefficient is much different from that of the concrete used to construct the dam body, a transition area must be constructed between the outlets and the dam body using various types of concretes and the expansion coefficients of the adjacent concretes should not differ significantly.(2) Strengthening Temperature Control during Construction Period. The routine temperature control measures should make sure that the temperature of the concrete in each procedure satisfies the requirement including the concrete mixing and pouring temperatures, the highest temperature inside the concrete, and the temperature difference between the inner and external surfaces of the concrete. The concrete may be poured under low ambient temperatures such as nighttime. Special temperature control measures may be adopted for the bottom diversion outlets: (1) the concrete started to pour from the outlets. The surfaces of the outlets may be closed using curtain-style closed doors to prevent the surface of the concrete from the wind blowing through them, which may reduce the temperature of the concrete, result in too high temperature gradient, and induce thermal cracking. (2) When the mould at the sidewalls of the outlet is dismantled, thermal insulation quilt with 2 cm thickness should be installed to maintain the temperatures there. (3) Canvas insulation frame is installed at the upstream and downstream sides of the outlets to maintain the temperatures when the outlets are formed. (4) When the construction of the floor of the bottom diversion outlet is finished, water flow is used to maintain the temperatures there, which may be replaced with watering in 1 or 2 days after the highest temperature of the poured concrete appears.(3) Reasonable Impounding Scheme. The impounding scheme should make sure that the reservoir is impounded with water as early as possible when the stress state and the point factor of safety of the dam body and the outlets satisfy the design requirements. In this case, the height of the cofferdam can be reduced as low as possible and the electricity can be generated as early as possible.(4) Optimizing Outlet Design. The outlets should be designed to reduce the size of the tensile stress, which may appear near the outlets, and the area of the outlet, which may be under tension, in order to reduce the reinforcement as far as possible. The potential engineering measures may include changing the shape of the outlets, grouting the transverse joints, filling and pressuring the transverse joints, and preloading and grouting aggregates. Moreover, physical model testing and numerical modelling may be conducted to study the stress and strain characteristics of the outlets, the progressive development of the outlet crack initiation, propagation and coalescence, and the nonlinear reinforcement method for the outlets.(5) Outlet Cracking Classification and Reinforcement. Based on the case studies and numerical simulations conducted above and the arch dam design code, the outlet cracking can be classified and reinforced according to the following engineering procedure: cracking investigation → causes of cracking and cracking category analysis → hazard evaluation and classification → patching treatment → inspection and acceptance.(Special attention should be paid to the effects of the outlets on the working conditions of the super-high arch dam. It is found that the outlets decrease the upstream pressure of water and sand/silt and the dam stress, longitudinal displacement, and transverse displacement. The maximum reduction ratio can be 35%. Thus the outlets may harm the structural continuity of the arch dam, weaken the carrying capacity, and decrease the load pressing on the dam surface.Under normal loading conditions, the optimal distribution of the outlets will contribute to the tensile stress release in the local zone of the stream surface and decrease the cracking risk under operation period. Under overloading conditions, cracks initiate around the outlet then propagate along horizontal direction, and finally coalesce with the adjacent outlet cracks. The yield zone of the dam has a shape of a butterfly. The integral bearing capacity of the dam may increase about 20% if the elastic modulus of the concrete used for the outlet increases.The outlet cracking is caused by many factors including the concrete materials, temperature control and maintenance, impounding scheme, and dam design scheme.A reinforcement principle is proposed to control the outlet cracking risk through selecting the appropriate concrete materials, strengthening the temperature control during construction period, designing reasonable impounding scheme, optimizing the outlet design, and classifying the outlet cracking for various reinforcement measures.This paper first conducts two case studies on the outlet cracking in the Goupitan and Xiaowan arch dams by focusing on the current statuses, reasons, and potential consequences of the dam outlet cracking. Then, effect of outlets on the integral stability of the Xiluodu super-high arch dam under normal loading and overloading conditions is studied using 3D nonlinear finite element method. After that, the outlet cracking mechanism and risk control are discussed on the basis of the two case studies and numerical modelling. Finally, a reinforcement principal is proposed to control the dam outlet cracking risk. The following conclusions can be drawn.


The objective of the study is to investigate the effect of introducing jute yarn on the mechanical properties of concrete. Jute fibre is produced abundantly in Bangladesh and hence, very cheap. The investigation on the enhancement of mechanical properties of concrete with jute yarn as reinforcement, if enhanced, will not only explore a way to improve the properties of concrete, it will also explore the use of jute and restrict the utilization of polymer which is environmentally detrimental. To accomplish the objective, an experimental investigation of the compressive, flexural and tensile strengths of Jute Yarn Reinforced Concrete composites (JYRCC) has been conducted. Cylinders, prisms and cubes of standard dimensions have been made to introducing jute yarn varying the mix ratio of the ingredients in concrete, water cement ratio, length and volume of yarn to know the effect of parameters as mentioned. Compressive, flexural and tensile strength tests had been conducted on the prepared samples by appropriate testing apparatus following Standards of tests. Mechanical properties of JYRCC were observed to be enhanced for a particular range of lengths of cut  and volume content of jute yarn . The maximum increment of compressive, flexural and tensile strengths observed in the investigation are 33, 23 and 38 %, respectively with respect to concrete without jute yarn. The necessity of sustainable, non-hazardous and cost effective materials in the construction industry is inevitable. Concrete being popularly used all over the world is characterised by low strength-strain capacity in tension, and low fracture toughness. To overcome the shortcomings of plain concrete (PC), the use of reinforcing fibre has been found very effective  shown in Fig. Mix design is the selection of mix ingredients and their proportions required in a concrete mix. The mix design involves that amount of cement, fine aggregate, and coarse aggregate be available and the relation between water/cement ratio and target strength must be known. Since, the objective of the study is to investigate the effect of incorporating jute yarn on the mechanical properties of concrete, the mix design with target strength was not accomplished in the study. Rather, the commonly practised mix ratio used in Bangladesh and other neighbouring countries like parts of India and Pakistan was used. To this end, in the present study, two different mix ratios, cement: sand: brick chips (by volume) = 1:2:4 and 1:1.5:3 and water/cement ratio (by weight) 0.60 and 0.55 were cautiously maintained. In concrete mix preparation, initially different jute yarn cut length and volumetric content were applied in the concrete mix and observed the mixing performance to obtain better arrangement of jute. And finally jute yarn of 10, 15, 20 and 25 mm lengths with 0, 0.1, 0.25, 0.50 and 0.75 % volume dosing were selected; and lastly samples were prepared for a particular set of parameters.Table The different parameters of the concrete composites, the length and volume fraction of the jute yarn content were used. The different lengths of yarn 10, 15, 20 and 25 mm and the contents 0, 0.1, 0.25, 0.50 and 0.75 % were used. Three different specimens; cubes (150 mm × 150 mm × 150 mm), prisms (450 mm × 150 mm × 150 mm) and cylinders (150 mm × 300 mm) were cast to determine the compressive, flexural and tensile strength of the composites, respectively. The yarns were cut to the mentioned length manually by a hand scissor. The mixing of the ingredients were done by a pan mixer accordingly jute yarns were added slowly and evenly to the concrete mix, so that, a uniform distribution of yarns throughout of the concrete could be confirmed. Cement was added into the mixer and mixing was conducted followed by the addition of water, until uniformity was achieved. This way of concrete mixing was continued for about 3 min. Then the freshly mixed concrete was poured in the moulds of cube, prism and cylinder. After that the specimens were left 24 h for de-moulding. They were then cured in water for at least 28 days. At the end of curing period the specimens were allowed to be dried in air for 24 h before testing.The present study consists of determining the flexural, compressive and tensile strength of concrete composites with jute yarn and was compared to that of plain concrete. A Universal Testing Machine  for tensile test and an Automatic Compression Testing Machine  shown in Fig. Compressive strength of a concrete is a measure of its ability to resist static load, when the later one tends to crush it. Testing of compressive strength is the most common, many desirable characteristics of concrete are related to its strength, and hence the compressive strength of concrete in structural design is of utmost importance. Additionally, the compressive strength gives a good and clear indication that how the strength is affected with the increase of fibre volume dosage rate in the test specimens. In AS 1012, it is mentioned that the specimens for compressive strength should be 150 mm diameter and 300 mm height, but this only applies to the maximum aggregate size more than 20 mm while the cube specimen with 150 mm in each side (AS l) is 133 mm and the supporting point (L) is 400 mm whereas the load was applied continuously and without any shock at a constant rate to the breaking point. Apply the load at a rate that constantly increases the extreme fibre stress 1.21 MPa./min. Finally, results were obtained in the form of total load in KN and intensity of load in MPa.Flexural strength of a concrete is a measure of its ability to resist bending and it can be expressed in terms of modulus of rupture. Therefore, the two point loading method was used in making flexural strength tests of concrete employing bearing blocks which ensured that forces applied to the beam was perpendicular to the face of the specimen and was applied without eccentricity. During test the reaction was always parallel to the direction of applied force. The test procedure was carried out following the test method ASTM C 78-00. The distance of the loading point  are well known indirect tests used for determining the tensile strength of concrete. The test procedure consists of applying a compressive line load along the opposite generators of a concrete cylinder placed with its axis horizontal between the compressive planes. The splitting tensile strength test was conducted according to the test method ASTM C 496/M496.The mechanical behaviour of fibre-cement composite, which basically accounts for the bond between fibre and surrounding concrete, largely depends on many factors like the physical characteristics of the fibres such as geometry, type and surface characteristics, fibre orientation, fibre volume ratio and fibre distribution, the chemical composition of the fibre and so on. Tests were conducted to evaluate the effect of jute yarn and results are presented diagrammatically in figures Figs. , 7, 8, 9Figure Figures Figures The variation of tensile strength with respect to yarn content  and yarn lengths  are shown in Figs. Microscopic images of failed JYRCC specimen were taken and shown in Figs. In the experimental investigations conducted in the study, it was found that, the addition of jute yarn contributes enriched results for mechanical properties of concrete composites for a particular yarn length and yarn content. More specifically, compressive, flexural, and tensile strength are found to enhance significantly for volume content of 0.1 and 0.25 % and the yarn cut length of 10 and 15 mm. However, with larger yarn length and content the mechanical properties were found to affect adversely. Finally the jute yarn shows the positive contribution to minimize irregular mixing disabilities of concrete composites that creates major problem regarding fibre reinforcement. So JYRCC can be developed with locally fabricated jute yarn in Bangladesh. The least cost of jute yarn, its being renewable resources, the reduced weight of the JYRCC and the environmental compatibility would clearly show the socioeconomic viability of JYRCC. This diversified use of jute may redeem the lost glory of jute in Bangladesh.


This process is critical to cell migration in normal and pathological conditions. In the present study, the function of c-Met in the process of EMT was investigated in prostate cancer. Initially, a c-Met stable expression cell line was constructed using EMT- and c-Met-negative LNCaP prostate cancer cells. Following the identification of c-Met in the transfected cells, the changes in EMT, phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase pathway biomarkers were determined by western blot analysis. MTT, soft agar and Transwell assays, and xenograft studies were used to investigate the effects of c-Met on the proliferation, migration and tumorigenicity of LNCaP cells. The results of the present study revealed downregulation of E-cadherin and upregulation of vimentin in LNCaP-Met cells. The results demonstrated that c-Met enhanced proliferation, migration and tumorigenicity capacity when compared with LNCaP and LNCaP-pcDNA3.1 cells. Furthermore, these EMT-like changes were mediated via the PI3K and mitogen-activated protein kinase signaling pathways. The present study clearly demonstrates a crucial function for c-Met in EMT development in prostate cancer. c-Met-targeted treatment may be an effective adjuvant therapy for improving survival rates in patients with prostate cancer. The natural ligand for c-Met is hepatocyte growth factor (HGF)/scatter factor, which is produced by stromal and mesenchymal cells . The phoA dysfunctional HGF/c-Met axis has been implicated in the development, invasion and angiogenesis of cancers , and an HGF induces the disassembly adhesion of epithelial cancer cells, thereby increasing motility and invasiveness, in a process termed epithelial-mesenchymal transition (EMT). EMT is important in cancer metastasis as it promotes the detachment of cancer cells from the primary tumor areas, leading to invasion of the vasculature and colonization of distant organs with secondary tumors .Although EMT induced by HGF has been investigated in various types of cancer ,16, the 2 humidified incubator at 37°C.An EMT- and c-Met-negative human prostate cancer cell line, LNCaP, was cultured in Dulbecco’s modified Eagle’s medium  supplemented with 10% fetal bovine serum , 100 U/ml penicillin and 100 μg/ml streptomycin. Cells were cultured in a 5% COThe full-length cDNA encoding human c-Met was amplified and the recombinant plasmid, pcDN- A3.1/c-Met was constructed . LNCaP cells at 75% confluency were transfected with pcDNA3.1/c-Met (LNCaP-Met cells) using Lipofectamine 2000 (Invitrogen Life Technologies) in a six-well plate for 48 h, and transfection with pcDNA3.1(−) alone was performed for the control group (LNCaP-pcDNA3.1 cells). Cells were then trypsinized and seeded onto a 10-cm dish. Stable LNCaP-Met and LNCaP-pcDNA3.1 cells were subjected to G418 selection (400 mg/ml), and after two weeks single-cell clones were selected and expanded. After G418 selection, five LNCaP-Met and three LNCaP-pcDNA3.1 cell clones were selected. Identification of c-Met was performed in all these cell clones and one clone in each group was selected to be used in the subsequent study.To identify the c-Met expression, cells were fixed in 4% paraformaldehyde for 10 min and blocked with goat serum  for 30 min, then incubated at 37°C for 1 h with rabbit anti-c-Met primary antibody . Following three washes with phosphate-buffered saline, the cells were incubated with tetramethylrhodamine isothiocyanate-conjugated secondary antibody  at 37°C for 1 h and stained with 4′,6-diamidino-2-phenylindole for five min. The fluorescence staining intensity and intercellular location were examined using a fluorescence-inverted microscope .Total cellular proteins were extracted. A 30-μg protein extract was separated by 12% SDS-PAGE. The separated proteins were subsequently transferred to nitrocellulose membranes , and the membrane was blocked with 5% non-fat milk in Tris-buffered saline for 1.5 h. The membranes were incubated for 1.5 h with the primary antibodies, polyclonal rabbit anti-human C-met, polyclonal rabbit anti-human p-C-met, polyclonal rabbit anti-human E-cadherin, polyclonal rabbit anti-human ERK and polyclonal rabbit anti-human AKT, and monoclonal mouse anti-human vimentin, monoclonal mouse anti-human p-ERK and monoclonal mouse anti-human p-AKT  at various dilutions and hybridized for 1 h with secondary antibodies, horseradish peroxidase-conjugated goat anti-rabbit and goat anti-mouse IgG. (Boshide Biotech Co. Ltd.). Imaging was performed using the electrochemiluminescence detection system  and protein loading equivalence was assessed by the expression of glyceraldehyde 3-phosphate dehydrogenase.4 cells/well were plated into 96-well tissue culture plates in DMEM containing 10% FBS to a final volume of 0.2 ml. Following incubation for 24, 48 and 72 h, cells were incubated with 20 μl MTT to a final concentration of 0.5 mg/ml at 37°C for 4 h. Next, the medium was removed and the precipitated formazan was dissolved by adding 200 μl of dimethyl sulfoxide (Sigma-Aldrich). Following agitation for 10 min, the samples were lysed and the absorbance was detected at a wavelength of 570 nm using a microplate reader .Cell growth was evaluated by MTT assay . A total of 1×102 of reconstituted Matrigel (Sigma-Aldrich). A total of 5×103 cells in 300 μl of serum-free growth medium were then seeded into the upper chamber. Cells were incubated under normoxic conditions and allowed to migrate towards the complete growth medium for 24 or 48 h. Non-invading cells were removed mechanically using cotton swabs. The inserts were stained with crystal violet and the invasive cells on the lower surface were counted under a microscope .Polycarbonate filters  were coated with 50 μg/cmCells were resuspended in top agar medium , and overlaid onto bottom agar medium  in six-well culture plates. After two-three weeks, colonies >0.1 mm in diameter were scored as positive. Colony formation efficiency was counted under a light microscope .7 cells/ml, and injected subcutaneously into the flank of each mouse. The tumor volume was measured weekly using the following formula: Tumor volume = (length × width2) × π/6. The mice were sacrificed after eight weeks. All experiments performed complied with the Guidelines of Animal Care of Capital Medical University .A total of 30 six-week-old male athymic nude mice, weighing 30 g  were divided into three groups: LNCaP , LNCaP-pcDNA3.1 , and LNCaP-Met . The mice were maintained under specific pathogen-free conditions and provided with sterile food and water. Cells were harvested, washed and resuspended in serum-free DMEM at a concentration of 1×10All data are presented as the mean ± standard deviation. Student’s t-test was performed and P<0.05 was considered to indicate a statistically significant difference. All statistical tests were performed using SPSS version 11.0 software .To identify the increased expression of c-Met in the LNCaP-Met cell line, c-Met was examined using immunofluorescence staining and western blot analysis. Immunocytochemistry indicated significant immunofluorescence staining in the membrane of the LNCaP-Met cells, which, by contrast, was particularly weak in the membranes of the control LNCaP cells and the LNCaP-pcDNA3.1 cells . IncreasThe development of EMT is characterized by the loss of epithelial markers, such as E-cadherin and the gain of mesenchymal markers, such as vimentin. To investigate changes in epithelial and mesenchymal markers, western blot analysis was used to determine the effect of c-Met on E-cadherin and vimentin in LNCaP-Met cells, compared with the control cells. In LNCaP-Met cells, the overexpression of c-Met downregulated E-cadherin, but upregulated vimentin , which ic-Met promotes the migration of cancer cells, which is critical for metastasis. To determine the effect of increased c-Met expression on LNCaP-Met cell migration, cells migrating to the bottom of the insert were counted at 24 and 48 h. As shown in To examine the effect of c-Met on LNCaP cell proliferation, the growth rate of the c-Met-transfected, control and parental LNCaP cells was determined. The LNCaP-Met cells exhibited a significantly higher growth rate than the LNCaP-pcDNA3.1 and LNCaP cells P<0.05;. HoweverThe increased expression of c-Met resulted in a significant increase in the number of LNCaP-Met cell colonies formed when compared with the number of colonies formed in the parental LNCaP or LNCaP-pcDNA3.1 cells P<0.05; . By contin vivo. Tumor xenografts were established via subcutaneous injection into athymic nude mice. Subcutaneous tumors developed in five mice from the LNCaP-Met cells group, however, only grew in two mice from the LNCaP and LNCaP-pcDNA3.1 cell groups. Metastasis was not observed in any of the groups. The mean tumor volumes on days 14, 21, 28, 35, 42, 49 and 56 are shown in in vivo.To corroborate the observation that the upregulation of c-Met increased the invasive capacity of prostate cancer cells, the growth rates and metastatic behavior were analyzed To investigate the mechanisms involved in c-Met-induced EMT development, the levels of ERK and AKT signaling pathway components were determined by western blot analysis. ERK and AKT are two typical signaling pathways of c-Met. The results indicated that the increased expression of c-Met promotes EMT by upregulating the levels of ERK, phospho-ERK, AKT and phospho-AKT in LNCaP-Met cells .EMT is a process during which cancer cells lose their epithelial phenotype and acquire a mesenchymal phenotype, thus promoting the loosening of intercellular adhesions, detachment from the tumor mass and invasion of neighboring tissue, blood or lymph vessels, leading to the development of secondary tumors. Previous studies have indicated that EMT is implicated in cancer metastasis and invasion ,25.A number of factors, which induce EMT have been identified, including transforming growth factor-β, HGF, epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, insulin-like growth factor, microRNA, hypoxia as well as transcription factors –27. Amonin vitro and in vivo. The results clearly demonstrated that by inducing EMT, c-Met overexpression enhances the invasion, migration and proliferation capability of LNCaP cells.In the present study, the effect of c-Met on the invasiveness of human prostate cancer was examined in LNCaP cells c-Met stable expression cell lines were constructed in c-Met- and HGF-negative LNCaP prostate cancer cells by cell transfection. Western blot analysis revealed that the expression of phospho-c-Met, as well as c-Met, was enhanced, which indicates that c-Met may be activated in an HGF-independent manner. A similar study demonstrated that c-Met may be activated via an HGF-independent signaling pathway, following transfection, in lung cancer . In addiin vitro and in vivo studies demonstrated that the LNCaP-Met cell lines exhibited the greatest proliferative, migratory and tumorigenic potential, indicating a potential association between c-Met-mediated signaling pathways, EMT and prostate cancer aggressiveness. These results are consistent with a study showing that the acquisition of EMT characteristics is associated with the upregulation of c-Met mRNA and increased responsiveness to HGF in breast cancer (Furthermore, activation of c-Met was found to activate the downstream signaling pathways PI3K and ERK, which resulted in the downregulation of E-cadherin and upregulation of vimentin. E-cadherin downregulation is regarded as a characteristic change of EMT . As intet cancer .To investigate the mechanism of EMT induction involving c-Met, the PI3K and ERK signaling pathways were examined. The two signaling pathways are considered to be typical c-Met-mediated signaling pathways  as well in vitro and in vivo. All of these results demonstrated the potential association between c-Met, EMT and invasiveness in prostate cancer. Similarly, in other solid human tumors, various studies have shown that c-Met-mediated signaling activation drives EMT and cancer cell migration, invasion and metastasis (Abnormal c-Met activation may occur in certain cancer types due to gene amplification, mutation or transactivation . Howevertastasis –45.In conclusion, the present study demonstrates that EMT induced by c-Met expression is involved in prostate cancer metastasis. Through the process of EMT, LNCaP prostate cancer cells acquire an increased proliferative, migrative and tumorigenic capability. Thus far, the role of c-Met in the progression and metastasis of numerous cancers has been described and a number of c-Met inhibitors have been investigated in clinical trials –48. Ther


Purpose. To explore the potential of diffusion-weighted (DW) magnetic resonance imaging (MRI) using apparent diffusion coefficient (ADC) for predicting the response to neoadjuvant chemotherapy in nasopharyngeal carcinoma (NPC). Methods and Materials. Ninety-two consecutive patients with NPC who underwent three cycles of neoadjuvant chemotherapy were retrospectively analyzed. DW and anatomical MRI were performed before and after neoadjuvant chemotherapy prior to radiotherapy. Pretreatment ADCs and percentage increases in ADC after chemotherapy were calculated for the primary lesions and metastatic adenopathies. Receiver operating characteristic curve analysis was used to select optimal pretreatment ADCs. Results. Pretreatment mean ADCs were significantly lower for responders than for nonresponders . Mean percentage increases in ADC were higher for responders than for nonresponders . The optimal pretreatment primary lesion and metastatic adenopathy ADCs for differentiating responders from nonresponders were 0.897 × 10−3 mm2/sec and 1.031 × 10−3 mm2/sec, respectively. Conclusions. NPC patients with low pretreatment ADCs tend to respond better to neoadjuvant chemotherapy. Pretreatment ADCs could be used as a new pretreatment imaging biomarker of response to neoadjuvant chemotherapy. Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in Southeast Asia, especially in the southern provinces of China . In pati18F-fluorodeoxyglucose positron emission tomography (FDG-PET) with respect to predicting tumor response is often hampered by its false-positive and expensive check cost /b, where b is the diffusion weighting factor and SI(b) and SI(0) are the signal intensities with and without diffusion-sensitizing gradients, respectively  × 10−3 mm2/sec, P = 0.012; metastatic adenopathies: [0.964 ± 0.010] × 10−3 mm2/sec versus [1.135 ± 0.042] × 10−3 mm2/sec, P = 0.013). After completion of neoadjuvant chemotherapy, no significant difference in the mean ADCs was observed between responders and nonresponders . However, the mean percentage increases in the ADCs were significantly greater in responders than in nonresponders  . Furthermore, a strong negative correlation was observed between the mean pretreatment tumor ADC and percentage change in tumor volume after chemotherapy .Before neoadjuvant chemotherapy, the mean ADCs of responders were significantly lower than that of nonresponders , specificity of 76.9% , and area under the empirical ROC curve of 0.821 . The optimal pretreatment metastatic adenopathy ADC cutoff value for differentiating responders from nonresponders was 1.031 × 10−3 mm2/sec, which yielded a sensitivity of 85.7% , specificity of 80.0% , and area under the empirical ROC curve of 0.830   .This study demonstrated that, in patients with NPC, responders to neoadjuvant chemotherapy have significantly lower pretreatment ADCs than nonresponders, and a strong negative correlation exists between the mean pretreatment ADCs and percentage change in tumor volume on follow-up MRI. The patients with lower pretreatment ADCs had a better response to neoadjuvant chemotherapy compared to those with higher pretreatment ADCs, in accordance with other clinical studies –27. In rAfter completion of neoadjuvant chemotherapy, the percentage increases in the ADCs of responders were significantly greater than that of nonresponders, and the changes in the ADCs correlated with the change in tumor volume at follow-up MRI. Previous studies have shown that low pretreatment ADCs indicate viable tumor tissue with a high cellularity, whereas high ADCs reflect less metabolic tumor tissue with a low cellularity , 29. TumOver the last 10 years or so, DW MRI has been successfully employed in head and neck cancer to distinguish between residual disease or tumor recurrence and inflammation or necrosis after completion of (chemo)radiotherapy . AdditioIt should be stressed that DW MRI was not performed after each cycle of neoadjuvant chemotherapy in this study. Other studies reported that changes in ADCs after the first cycle of neoadjuvant chemotherapy could provide more detailed information on tumor response . FurtherIn NPC, patients with low pretreatment ADCs tended to respond better to neoadjuvant chemotherapy. Pretreatment ADCs have potential as a novel imaging marker to predict the response to neoadjuvant chemotherapy, which could facilitate individual therapeutic approaches and allow some patients with NPC to avoid ineffective chemotherapy and unnecessary treatment toxicities.


Parkinson’s disease (PD) is a neurodegenerative disorder that is hallmarked by pathological changes associated with the death of dopaminergic neurons, particularly in the extrapyramidal system  of the brain. Although the causes of slow neuronal death in PD are unknown, both genetic and environmental factors are likely involved. Endogenous isoquinolines, such as 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), present in the human brain have been previously reported to participate in the pathogenesis of PD. The chronic administration of 1BnTIQ induced parkinsonism in primates, and this effect might be associated with idiopathic PD. However, another endogenous derivative of tetrahydroisoquinoline, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), displays clear neuroprotective properties in the brain. In the present study, we investigated the neuroprotective effects of 1MeTIQ (25 and 50 mg/kg) in an animal model of PD after the chronic administration of 1BnTIQ (25 mg/kg). Behavioral analyses demonstrate that both acute and repeated treatment with 1MeTIQ completely antagonized 1BnTIQ-induced changes in rat locomotor activity. Neurochemical experiments indicate that 1MeTIQ co-administered with 1BnTIQ completely antagonized 1BnTIQ-induced reduction in the dopamine (DA) concentration in rat brain structures. In conclusion, the results demonstrate that 1MeTIQ possesses important neuroprotective properties in the animal model of PD and that the rats did not develop tolerance after its chronic administration. O-methylation. This mechanism might be important for the neuroprotective activity of 1MeTIQ , are a group of endogenous compounds with neurotoxic properties. However, one derivative from this group, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), exhibits neuroprotective properties. It has previously been shown that 1MeTIQ acts as a reversible inhibitor of monoamino oxidase (MAO) activity, blocks both the formation of 3,4-dihydroxyphenylacetic acid (DOPAC) and the production of free radicals and shifts dopamine (DA) catabolism toward COMT-dependent The aim of the present study was to investigate the neuroprotective effects of 1MeTIQ in an animal model of PD after the chronic administration of 1BnTIQ. Using behavioral tests, we analyzed the influence of acute and chronic treatment with 1MeTIQ on changes in rat locomotor activity induced through the repeated administration of 1BnTIQ.In neurochemical experiments, using high-performance liquid chromatography (HPLC) methodology with electrochemical detection, we investigated the effect of 1MeTIQ on disturbances in brain DA metabolism evoked through 1BnTIQ. Additionally, the concentration of excitatory amino acids (EAA) in the frontal cortex and the level of α-synuclein and tyrosine hydroxylase (TH) in the substantia nigra were also detected.All experiments were performed in male Wistar rats with an initial body weight of 220–240 g. All animals had free access to standard laboratory food and tap water and were kept at room temperature (22°C) under an artificial light/dark cycle .1BnTIQ was intraperitoneally (i.p.) administered at a dose of 25 mg/kg chronically for 14 consecutive days. In the mixed group, a single or chronic dose of 1MeTIQ (25 or 50 mg/kg i.p.) was administered 20 min before 1BnTIQ administration. Control rats were treated with the appropriate vehicle. Rats were sacrificed through decapitation at 2 h after the last drug injections, and different brain structures were dissected for further analysis. The experiments were performed between 9:00 and 16:00.All experimental procedures were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved through the Bioethics Commission as compliant with Polish Law. All experimental procedures were approved through the Local Bioethics Commission of the Institute of Pharmacology, Polish Academy of Sciences in Kraków.1MeTIQ hydrochloride and 1BnTIQ hydrochloride were synthesized  linked on-line to a compatible IBM PC. Each cage (43 × 44 × 25 cm) perimeter was lined with an array of 15 × 15 photocell beams located 3 cm from the floor surface. Interruptions of the photocell beams were counted as a measure of horizontal locomotor activity and defined as the distance traveled (in cm). The rats were administered an acute dose of 25 or 50 mg/kg (i.p.) 1MeTIQ (expression treatment group) or as the last dose  at 20 min before the last dose of 1BnTIQ . Subsequently, the animals were transferred to experimental cages, and locomotor activity  and rearing  were recorded for 90 min and analyzed using the Auto-Track Software Program . Each group comprised seven animals.g for 5 min), the supernatants were filtered through RC 58 0.2-im cellulose membranes . The HP 1050 chromatograph  was equipped with C18 columns. The electrochemical cell potential was 800 mV. The mobile phase comprised 0.05 M citrate–phosphate buffer (pH 3.5), 0.1 mM EDTA, 1 mM sodium octyl sulfonate, and 3.5 % methanol. The flow rate was maintained at 1 ml/min. Dopamine and its metabolites were quantified based on the chromatograph peak height compared with standards run on the day of analysis. Each group comprised seven animals.The rats were sacrificed through decapitation 2 h after the last 1BnTIQ injection, and the nucleus accumbens and striatum were immediately dissected. The tissue was frozen on dry ice (−70  C) until further use in a biochemical assay. The levels of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA), were assayed through high-performance liquid chromatography (HPLC) with electrochemical detection (Hewlett Packard 1049A). The tissue samples were weighed and homogenized in ice-cold 0.1 M perchloroacetic acid containing 0.05 mM ascorbic acid. After centrifugation . The analyte was separated on an analytical Hypersil C18 column  manufactured in Germany. The mobile phase comprised a mixture of acetonitrile–phosphate buffer  filtered through a 0.45-µm nylon filter and degassed under ultrasound and vacuum for 30 min. The mobile phase was delivered at a flow rate of 1.0 ml/min, and the column temperature was set to 30 °C.The rats were sacrificed through decapitation 2 h after the last 1BnTIQ injection, and the frontal cortex was immediately dissected. The tissue was frozen on dry ice (−70 °C) until further use in a biochemical assay. The tissue was weighed, and subsequently homogenized in 4 ml of chilled saline solution (0.9 %). The homogenate was centrifuged at 22.000g for 20 min at 4 °C.The resulting supernatants were collected and subjected to protein analysis using the Bicinchoninic Acid Assay Kit . Equal amounts of protein extracts (12 µg) were boiled in Laemmli buffer containing 5 % β-mercaptoethanol for 5 min, separated through SDS-PAGE (4–15 %), and transferred to nitrocellulose membranes. The membranes were blocked with 5 % non-fat dry milk in Tris-buffered saline containing Tween-20  for 1 h at room temperature and incubated with a primary antibody against tyrosine hydroxylase  or α-synuclein  overnight at 4 °C. After three washes with blocking solution, the membranes were incubated with the appropriate secondary antibodies for 1 h at room temperature, followed by three washes with TBST. Antibody binding was detected using an enhanced chemiluminescence kit . Equal loading proteins were further confirmed after probing with anti-calnexin antiserum  or anti-β-actin antiserum . All Western blot analyses were performed at least twice to confirm the results. The chemiluminescence signal was visualized using a Luminescent Image Analyzer Fuji-Las 4000 . Immunoreactive bands were quantified using an image analyzer .Protein was extracted through high-speed shaking in plastic tubes with stainless steel beads in a tissuelyser with 100 μl of ice-cold RIPA lysis buffer , containing complete mini protease inhibitor . After incubation for 30 min, the homogenates were centrifuged at 10,000Two-way analysis of variance (ANOVA) for repeated measures was used to analyze the results of the behavioral test (locomotor activity). Differences between the control and experimental groups were assessed using Duncan’s post hoc test.n = 6–7).The comparison of the effects of acute and multiple administration of 1BnTIQ and the effect of chronic 1MeTIQ administration on 1BnTIQ-produced changes in the concentration of EAA were analyzed by one-way ANOVA, followed by Duncan’s post hoc test. The results of the biochemical experiments were analyzed using two-way ANOVA, followed by Duncan’s post hoc test, when appropriate. These indices were calculated using the concentrations of individual tissue samples (P < 0.01). In addition, the chronic administration of 1BnTIQ (25 mg/kg i.p.) produced a significant (P < 0.05) elevation of exploratory activity  induced a significant reduction in the horizontal exploratory activity of rats (P < 0.01) decrease in exploratory activity. The multiple (14-day) administration of 1BnTIQ at a low dose of 25 mg/kg (i.p.) significantly increased (P < 0.05) the exploratory activity during the first 30 min of measurement. In the mixed group, 1MeTIQ completely antagonized 1BnTIQ-induced hyperactivity  on the level of DA in the striatum (Table P < 0.01). The statistical analysis indicated no effect of 1BnTIQ treatment  on DOPAC concentration  on the level of 3-MT in the striatum (Table P < 0.05). The statistical analysis indicated a significant effect of 1BnTIQ treatment  on the HVA concentration (Table P < 0.05).One-way ANOVA demonstrated a significant effect of 1BnTIQ treatment  on the level of DA in the nucleus accumbens (Table P < 0.01). Treatment with 1BnTIQ  significantly affected the DOPAC concentration in the nucleus accumbens (Table P < 0.01). One-way ANOVA indicated a significant effect of 1BnTIQ treatment  on the 3-MT concentration in the nucleus accumbens (Table P < 0.01). The statistical analysis indicated a significant effect of 1BnTIQ treatment  on the HVA concentration (Table P < 0.05).One-way ANOVA indicated a significant effect of 1BnTIQ treatment  and an acute dose of 1MeTIQ  on the DA concentration in the striatum . Duncan’s post hoc analysis demonstrated that the multiple administration of 1BnTIQ significantly decreased the level of DA . In contrast, 1MeTIQ co-administered with the last dose of 1BnTIQ completely antagonized the 1BnTIQ-induced reduction in DA (the DA level remained similar to the control level)  and 1MeTIQ  on the DOPAC concentration in the striatum . The post hoc analysis indicated that the acute administration of 1MeTIQ (at both doses examined) decreased the DOPAC concentration  and that this effect was enhanced in the mixed groups (approximately 40 and 55 %)  or the interaction between 1BnTIQ and 1MeTIQ  on the levels of 3-MT in the rat striatum. In contrast, the effect of 1MeTIQ was significant  (Table P < 0.01), and similar effects were observed in the mixed groups  and 1MeTIQ  significantly affected the HVA concentration in the striatum . The post hoc analysis showed that the chronic administration of 1BnTIQ significantly increased the level of HVA , and this effect was completely blocked through the administration of both concentrations of 1MeTIQ . This effect was completely inhibited through the acute administration of 1MeTIQ at both doses examined  increased after the multiple administration of 1BnTIQ, and this effect was antagonized with a single dose of 1MeTIQ  and 1MeTIQ  treatments on the DA concentration in the nucleus accumbens . Duncan’s post hoc test showed that the chronic administration of 1BnTIQ decreased the DA concentration . Both concentrations of 1MeTIQ partially antagonized this effect  and 1MeTIQ  treatments on the DOPAC levels. In contrast, the interaction between 1BnTIQ and 1MeTIQ  was not significant  on the 3-MT concentration in the nucleus accumbens  and the interaction between 1BnTIQ and 1MeTIQ were significant . Duncan’s post hoc test showed that chronic treatment with 1BnTIQ (25 mg/kg) reduced the levels of 3-MT (approximately 30 %), and this effect was completely blocked using both doses of 1MeTIQ  and 1MeTIQ  treatments on the HVA levels, but the interaction between 1BnTIQ and 1MeTIQ  was not significant. The post hoc analysis showed that treatment with 1BnTIQ concomitant with 1MeTIQ significantly reduced the HVA levels (approximately 35 %)  and the chronic administration of 1MeTIQ  on the DA concentration in the striatum . Duncan’s post hoc test showed that the chronic administration of 1BnTIQ reduced the DA concentration , while the multiple administration of 1MeTIQ (in both doses) increased neurotransmitter . Additionally, when the chronic administration of 1BnTIQ (25 mg/kg) was coupled with the chronic administration of 1MeTIQ, the concentration of dopamine returned to the control level  and the multiple administration of 1MeTIQ  on the DOPAC concentration in the striatum . The post hoc analysis showed that chronic 1MeTIQ administration strongly decreased the DOPAC concentration ; this effect was enhanced in the mixed group   on the level of 3-MT  significantly affected the 3-MT concentration. There was no interaction between the chronic administration of 1BnTIQ and the multiple administration of 1MeTIQ . Duncan’s post hoc test showed that chronic treatment with 1MeTIQ (in both doses) increased the 3-MT concentration . A similar effect was observed with the chronic administration of 1BnTIQ (25 mg/kg) coupled with the chronic administration of 1MeTIQ,  on the HVA concentration in the striatum  significantly affected the level of HVA. An interaction between 1BnTIQ and 1MeTIQ was also detected . The post hoc analysis showed that 1BnTIQ increased the HVA concentration ; this effect was completely blocked through chronic treatment with both concentrations of 1MeTIQ . This effect was completely inhibited through the chronic administration of 1MeTIQ at both doses examined  increased through the multiple administration of 1BnTIQ, and this effect was antagonized through the chronic administration of 1MeTIQ  on the DA concentration in the nucleus accumbens . The statistical analysis revealed a significant interaction between the chronic administration of 1BnTIQ and 1MeTIQ . The post hoc test indicated that the multiple injection of 1BnTIQ decreased the level of DA  and that this effect was antagonized after chronic treatment with 1MeTIQ  and the multiple administration of 1MeTIQ  on the DOPAC concentration in rat nucleus accumbens . The post hoc analysis showed that chronic injections of both 1BnTIQ and 1MeTIQ reduced the DOPAC concentration ; this effect was intensified in the mixed groups   on the level of 3-MT in the nucleus accumbens. The same statistical analysis indicated that chronic treatment with 1MeTIQ  significantly affected the 3-MT concentration . Duncan’s post hoc test showed that multiple treatment with 1BnTIQ decreased the level of 3-MT , and this effect was reversed through chronic treatment at both concentrations of 1MeTIQ  and 1MeTIQ  on the HVA concentration in the nucleus accumbens . The post hoc analysis demonstrated that chronic treatment with both doses of 1MeTIQ strongly decreased the HVA concentration ; this effect was intensified in the mixed groups (approximately 50 %)  on the concentration of aspartate in the frontal cortex (Table P < 0.01) and that this effect was completely inhibited through the chronic administration of 1MeTIQ (P < 0.01). The statistical analysis revealed no effect of treatment  on the level of glutamate in the frontal cortex (Table P < 0.05) and that this effect was blocked through the multiple administration of 1MeTIQ (25 mg/kg i.p.)   decreases the endogenous 1BnTIQ content in the mouse brain  and mesolimbic (nucleus accumbens) dopamine structures in the rat brain Table .The toxiAdditionally, we showed that the chronic administration of 1BnTIQ increased the concentration of both ASP and GLU in the rat frontal cortex Table . In thisThe potential neuroprotective activity of 1MeTIQ is of obvious interest because this compound is present in mammalian brains (Yamakawa and Ohta In conclusion, the results obtained in the present study clearly confirm that 1MeTIQ possesses essential neuroprotective properties in an animal model of Parkinson`s disease. Additionally, the neuroprotective effect of 1MeTIQ did not induce the development of tolerance after chronic administration and might restore the function of dopamine neurons, even after partial damage, which suggests their clinical relevance.