Surgical Neurology International, the question was what online video service to choose. Obviously, YouTube (http://youtube.com) is the most well known. It is easy to use, and at that moment it had the best player for mobile devices available. Besides, it was the first video service that seriously started testing with HTML5. This is an upcoming web standard that will play an important role in the future, especially for mobile and tablet devices. But we did not choose YouTube for one reason: the maximum video length is limited to 10 minutes, regardless of the account type you choose.When we started video implementation for http://vimeo.com) and we liked it from the beginning. It has good video quality, an easy-to-use video player, and includes a full-screen option. Videos can be watched on the Vimeo site, and also integrated in our Web site. Moreover, there are no important restrictions on video length, which makes this service very useful for posting lectures or longer instruction videos.After testing another video service first, we found Vimeo  as well.The famous Dutch soccer player Johan Cruijff is known for some remarkable statements, and one of them is: “Every disadvantage has its advantage” (or the other way around). To enable mobile video, we needed to redo the video integration in our website, and used that occasion to realize another improvement. Prior to this, you could only place comments or questions to videos on the Vimeo page, but you would have had to create a separate account for that. Not anymore. Now the videos have been integrated in our site in such a way that you can comment directly, in the same manner you can comment on our Posts. We hope that this improved ease of use will stimulate you to engage in our community.With the exception of the UCLA 100 Lectures Series, we are not yet offering podcasts. We did experiment with creating video podcasts, and some technical issues have been solved. At this time, we are ready to create them, but wonder if they have added value next to the mobile video version. The major advantage of a podcast is that you do not need to be online to watch the video once you have downloaded it. This is especially important for developing countries, where an Internet connection is not always available. The major advantage of the standard mobile videos (as available online) is that you can watch them directly without having to download them first. Of course, these two options are not mutually exclusive. Obviously, offering both options will require additional time when preparing the videos.What is your opinion on podcasts of our videos? Should we be offering them? Would you like to download videos on your mobile device? Or would you only watch them online?pieter@kubben.nl).We are looking forward to your opinion, either on our social networks  or by E-mail (


Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease with few treatment options other than renal replacement therapy. p21, a cyclin kinase inhibitor which has pleiotropic effects on the cell cycle, in many cases acts to suppress cell cycle progression and to prevent apoptosis. Because defects in cell cycle arrest and apoptosis of renal tubular epithelial cells occur in PKD, and in light of earlier reports that polycystin-1 upregulates p21 and that the cyclin-dependent kinase inhibitor roscovitine arrests progression in a mouse model, we asked whether (1) p21 deficiency might underlie ADPKD and (2) the mechanism of the salutary roscovitine effect on PKD involves p21.p21 levels in human and animal tissue samples as well as cell lines were examined by immunoblotting and/or immunohistochemisty. Apoptosis was assessed by PARP cleavage. p21 expression was attenuated in a renal tubular epithelial cell line by antisense methods, and proliferation in response to p21 attenuation and to roscovitine was assessed by the MTT assay.in vitro. Thus, levels of p21 are inversely correlated with renal tubular epithelial cell proliferation. Roscovitine, which has been shown to arrest progression in a murine model of PKD, increases p21 levels and decreases renal tubular epithelial cell proliferation, with no affect on apoptosis.We show that p21 is decreased in human as well as a non-transgenic rat model of ADPKD. In addition, hepatocyte growth factor, which induces transition from a cystic to a tubular phenotype, increases p21 levels. Furthermore, attenuation of p21 results in augmentation of cell cycle transit in vivo in humans and rat models of a decrement of p21 in cystic kidneys as compared to non-cystic kidneys. Validation of a potential pathogenetic model of increased cyst formation due to enhanced epithelial proliferation and apoptosis mediated by p21 suggests a mechanism for the salutary effect of roscovitine in ADPKD and supports further investigation of p21 as a target for future therapy.The novelty of our study is the demonstration  Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder and, due to the absence of any currently available effective treatment, the most common genetic cause of end-stage renal disease (ESRD). While the pathogenesis of ADPKD is often viewed in light of defects in trans-epithelial fluid transport and associated channels causing massive and abundant cyst formation, it is becoming increasingly clear that ADPKD is also a disease of disordered epithelial cell cycle regulation and apoptosis. In addition, due to its monoclonality in relation to proliferating renal tubular epithelial (RTE) cells, ADPKD has been described as "a neoplasm in disguise" . In kidnThe cyclin-dependent kinase inhibitors (CKI) function in mitogenic signaling through their interaction with the cyclins and the cyclin dependent kinases , and thrPkd1 gene, polycystin-1. While these investigators also showed that p21 levels were reduced in Pkd1 knockout mice, there has to our knowledge been no published study examining the function of p21 in human tissues or in non-knockout animal models of this disease. In this study, we examine the expression of p21 in human tissue as well as in rat tissues. Very recent data has supported the role of cyclin kinase inhibition as possible treatment of PKD, using the specific inhibitor roscovitine). These homogenates were centrifuged at 12,000 × g for 30 min at 4°C and supernatants were collected. Total protein content was determined by BCA analysis .Denatured proteins were separated through a 12% SDS-polyacrylamide gel and transferred to PVDF membranes . Membranes were washed and blocked overnight with TRIS buffered saline 0.05% Tween-20 (TBS-T), containing 5% nonfat dry milk. Following blocking, membranes were again washed (TBS-T), and incubated overnight with a rabbit polyclonal anti-human p-21 , diluted 1:3000 in TBS-T. Immunodetection was accomplished by incubating membranes with a goat anti-rabbit-IgG secondary antibodies conjugated with horseradish peroxidase (HRP) for 45 minutes  in TBS-T containing 5% nonfat dry milk. Visualization was performed with enhanced chemiluminiscence (ECL) western-blotting kit  according to the manufacturer's instructions. The membranes were then stripped, re-blocked, and re-incubated for 1 hr at room temperature with goat Actin antibody , 1:4000, followed by 45-min incubation with anti-goat-IgG secondary antibody conjugated with HRP , and reaction with ECL. Resultant films  were scanned using a flatbed scanner and image analysis was performed with the ImageJ gel analysis algorithm.2O2 solution in methanol. The primary antibody was localized using the Vectastain ABC-Elite peroxidase detection system . This was followed by reaction with diaminobenzidine as chromogen and counterstaining with hematoxylin (Sigma). Sections of each polycystic kidney were processed in parallel with appropriate control tissue. Visualization occurred with a Zeiss Axioskop microscope connected to a Micropublisher 3.3 digital camera  interfaced with a Macintosh G5 computer  utilizing QCapture software (QImaging).The same antisera as described above were used for immunohistochemical detection of rat or human p21. Sections were deparaffinized in xylene, rehydrated through graded ethanols to water, and pretreated by steaming in 10% CITRA buffer . After being treated with protein-blocking solution, the slides were incubated overnight at 4°C with primary antibody (diluted 1:500) or with the same concentration of nonimmune IgG as a control. Endogenous peroxidase activity was blocked with 3% HAfter data acquisition, raw images were opened with Photoshop 7.0 for Macintosh  and images were processed with the built-in adjustments function of "auto levels," "auto contrast," and "auto color." No further image manipulation occurred.MDCK (Madin-Darby canine kidney) cells were obtained from Dr. John Payne at UC Davis. The cells were maintained in Dulbecco's media and 10% FBS and 1% Penicillin/Streptomycin.5 cells were seeded in 6 well plates 24 hr before transfection and cells were washed with sterile PBS before the transfection. The transfection reagent, GeneJuice  was diluted with OptiMEM first and then the ODNs were added in diluted GeneJuice mixture. The ODN mixture was added to the cells for 24 hr.The canine p21 antisense oligodeoxynucleotide  was synthesized by Molecula . Control ODN  was synthesized by Biognostik (Germany). For the transfection procedure, 1 × 10MDCK cells were seeded in 96 well plate 24 h before treatment with ODN or roscovitine (Sigma). For ODN transfection, 200 nM and 400 nM antisense or control ODN were added into the cells and incubated for 24 h. For roscovitine treatment, 1–10 ug/ml roscovitine was added in serum-containing media and incubated for 24 h. Media containing ODNs or roscovitine was removed and cells were incubated with 50 μg/ml MTT (Sigma) for 4 h at 37°C. Purple formazan was solubilized and samples were measured by multiwell scanning spectrophotometer at 570 nm.t values according to the method of Bonferroni (for multiple groups), as appropriate. Statistical significance was defined as p < 0.05. Values are means ± SEM.Values are reported as means ± SEM. Statistical analysis was performed by unpaired t test, or by analysis of variance followed by computation of modified PKD1, occurs in vivo in humans or in those animal models not characterized by targeted gene disruption. We tested the hypothesis that p21 is downregulated in human ADPKD tissues, and then further tested generalizability of the findings in a rat non-knockout model. By immunoblotting, renal expression of p21 was significantly attenuated in cystic kidneys from human ADPKD patients, as compared with kidneys from noncystic control patients  and/or by its inhibition of cyclin/cdk association ,17,18. HWe utilized an antisense ODN approach, which we have previously found to be successful in both human and rat Cell cycle progression of p21-attenuated MDCK cells was assessed by the MTT proliferation assay. Antisense p21 ODN transfection of MDCK cells at 400 and 600 nM showed increased cell proliferation as compared to cells transfected with scrambled control ODN Fig. . The incThe potent CDK inhibitor roscovitine has been recently shown to arrest PKD in a mouse model. We askeConsistent with our model of p21 decrease being associated with the cystic phenotype, we found that p21 was induced in a dose dependent fashion by roscovitine Fig. , suggestjck mice) showing that the cancer chemotherapeutic agent and CDK inhibitor, roscovitine, has long-term beneficial effects on disease progression  and Pkd2), there is a striking paucity of gene targets in this common genetic disease. Since we have now shown that p21 possesses an anti-proliferative, and hence likely anti-cystic, effect on the cystogenic MDCK cell line, and that p21 is decreased in human ADPKD, it is possible that the p21 pathway, including the p21waf1 gene, may be utilized in future therapy of this disease with or without the addition of another CDK inhibitor such as roscovitine which itself increases p21. The finding by other investigators that inhibition of apoptosis, as would be expected to occur with increase levels of p21, slows ADPKD disease progression [Other than the genes identified as mutant in PKD  declare that they have no competing interests.All authors have read and approved the final manuscript. JYP, WES, and JNL performed all experiments. TTO assisted in experimental design and execuation. SA and SPB facilitated human tissue procurement. SA helped with study design, conceived all of the rat experiments, and helped write the manuscript. RHW conceived of the study and wrote the original and final versions of the manuscript.The pre-publication history for this paper can be accessed here:


An explicit formal-ontological representation of entities existing at multiple levelsof granularity is an urgent requirement for biomedical information processing. Wediscuss some fundamental principles which can form a basis for such a representation.We also comment on some of the implicit treatments of granularity in currentlyavailable ontologies and terminologies .


Detectable shifts toward higher saturations were evident in all tumours (n = 16) immediately after the onset of carbogen breathing. The SO2 reached a new equilibrium within 1 min and remained approximately constant during 200–300 s of administration. The return to baseline saturation was more gradual when carbogen delivery was stopped. The degree to which carbogen increased SO2 was variable among tumours, with a tendency for tumours with lower initial SO2 to exhibit larger changes. Tumour haemoglobin concentrations at the time of peak enhancement were also variable. In the majority of cases, haemoglobin concentration decreased in response to carbogen, indicating that increased tumour blood volume was not responsible for the observed elevation in SO2. We observed no apparent relationship between the extent of the change in tumour haemoglobin concentration and the magnitude of the change in the saturation. Near infrared diffuse reflectance spectroscopy provides a rapid, non-invasive means of monitoring spatially averaged changes in tumour haemoglobin oxygen saturation induced by oxygen modifiers. © 1999 Cancer Research CampaignWe have evaluated the ability of steady-state, radially-resolved, broad-band near infrared diffuse reflectance spectroscopy to measure carbogen-induced changes in haemoglobin oxygen saturation (SO


College drinking is a significant public health problem. Although parental monitoring and supervision reduces the risk for alcohol consumption among younger adolescents, few studies have investigated the impact of earlier parental monitoring on later college drinking. This study examined whether parental monitoring indirectly exerts a protective effect on college drinking by reducing high school alcohol consumption.A longitudinal cohort of 1,253 male and female students, ages 17 to 19, attending a large, public, mid-Atlantic university was studied at two time points. First, data on high school parental monitoring and alcohol consumption were gathered via questionnaire during the summer prior to college entry. Second, during the first year of college, past-year alcohol consumption was measured via a personal interview. Multiple regression models tested the relationship between parental monitoring and past year alcohol use .Holding constant demographics, SAT score, and religiosity, parental monitoring had a significant protective effect on both high school and college drinking level. However, the association between parental monitoring and college drinking level became non-significant once high school drinking level was held constant.While parental monitoring did not directly influence college alcohol consumption, evidence for mediation was observed, whereby parental monitoring had an indirect influence on college drinking through reductions in high school drinking. Initiatives that promote effective parenting might be an important strategy to curb high-risk drinking among older adolescents. More research is needed to understand the nature and degree of parent-child communication that is necessary to extend the protective influence of parents into the college years. Underage alcohol consumption has received a significant amount of attention as a major public health concern . High riMonitoring the Future survey indicated that while 8.6% of male and 2.3% of female full-time college students drink every day, a much larger proportion have had five or more drinks in a row in the past two weeks  [While drinking alcohol in college is often seen as an expected rite of passage, heavy drinking among college students adversely affects students' health, safety, and academic performance ,11. The females) . Unfortufemales) . As Schufemales)  describefemales) -17.Taken together, the mass of scientific literature regarding college student drinking makes the problem appear almost intractable unless new prevention and intervention strategies are developed and embraced by college administrators, parents, and health care professionals. To this end, researchers have attempted to identify risk factors which then could become targets of interventions. Several cross-sectional studies have identified sociodemographic and other individual-level characteristics that are associated with increased risk for excessive alcohol consumption among college students. For instance, males are heavier drinkers than females , White sMonitoring the Future survey, while very useful for describing trends in drinking and identifying differences between college and non-college attending peers [In addition to sociodemographic characteristics, several studies have shown that high school drinking patterns are highly predictive of college drinking patterns; however, surprisingly few longitudinal studies have been conducted on the risk factors for escalation of drinking during the transition from high school to the first year of college. The ng peers ,19, is lng peers  observedng peers  conducteth grade at the start of the study) and found that higher levels of parental disapproval of alcohol use were associated with lower levels of alcohol use in 12th grade, as compared to students whose parents had low levels of disapproval. The results of that study also suggested that the effects of parental disapproval were mediated by lower levels of peer influence over drinking behaviors [None of the aforementioned longitudinal studies explored whether pre-college parenting practices influence the risk for drinking in college students, despite the substantial body of literature demonstrating the important influences of family characteristics, especially parental drinking behaviors, parent-child relationships, communication, and parental monitoring, on the risk for underage alcohol use -29. Usinehaviors . Additioehaviors  evaluateehaviors  studied ehaviors  found thAlthough the bulk of evidence on parental monitoring and decreased risk for alcohol consumption stems from research on young adolescents, a few studies involving college students warrant mention. First, Turrisi et al.  found evThe present study aimed to determine the extent to which the level of parental monitoring and supervision during the last year of high school might account for variation in alcohol consumption during the first year of college. Consistent with prior literature, we expected that students who experienced higher levels of parental monitoring and supervision during their last year in high school would consume less alcohol during high school. Moreover, we hypothesized that pre-college alcohol consumption levels would significantly predict the level of alcohol consumption in college. Lastly, we tested the hypothesis that parental monitoring would exert a significant protective, albeit indirect, effect on college drinking that would be mediated by reductions in high school drinking level.Data were gathered as part of the College Life Study, an ongoing longitudinal prospective investigation of college student health risk behaviors, including alcohol and other drug use. A two-stage sampling design was used to ascertain the sample. First, 3,401 incoming first-time, first-year students ages 17 to 19 completed a screening survey during new student orientation in the summer prior to entering a large, public university in the mid-Atlantic region of the United States. The first-stage response rate was 89%. The initial sample represented almost 90% of the incoming class, and did not differ significantly from the class with respect to demographic characteristics . Second,Precollege background variables were obtained from the screener survey  and from university administrative datasets  as permitted by informed consent. Race was assessed by the question "How would you describe yourself?" where the respondent was able to choose multiple racial/ethnic categories. Because of the preponderance of Whites in our sample, and the fact that very few students describing themselves as having multi-racial backgrounds, race was dichotomized as White vs. non-White for the present analyses. Mother's education level was used as a proxy for socio-economic status. The combined SAT score was used as a continuous measure representing academic achievement in high school; for ease of interpreting results in the present analyses, SAT score was arithmetically transformed by dividing by 100. Finally, religiosity was measured by a single question "How important is religion in your life?" modeled after the Monitoring the Future survey [e survey . ResponsLiving situation in college was assessed during the personal interview with the question "Since coming to college, how would you describe your living situation?" Because the presence of parental supervision was salient to the aims of this study, living situation was dichotomized as living with parents or other relatives (n = 85) versus living in other situations . The latter group consisted primarily of students living in campus housing  plus a small number living off campus (n = 18).Alcohol consumption in high school and college was measured as the typical number of drinks consumed per day, on days in which the student drank alcohol during the past 12 months. Rather than a categorical measure, we elected to use this continuous measure in order to represent the variability that occurs within the higher levels of alcohol consumption, which is sometimes obscured with categorical measures  [SD = 2.8) and 4.5 (2.9) for high school and college, respectively. We found this measure to demonstrate a high degree of concordance with more detailed measures of college drinking, including calendar data using the Timeline Followback method.per day) . This coParental monitoring during the last year of high school was measured with a slightly adapted version of the parental monitoring scale, which was developed by Capaldi and Patterson [M = 29.2; SD = 6.3), with a higher score representing a higher level of parental monitoring. Table atterson  and lateatterson . This nir2 (sr2) statistic, which represents the proportion of variance in the outcome variable uniquely explained by an explanatory variable, while holding constant the remaining explanatory variables in the model [Consistent with literature cited above, we expected that parental monitoring would have a protective effect on high school drinking and that high school drinking would correlate strongly with college drinking. We further hypothesized that parental monitoring would have an indirect protective effect on college drinking via its influence on high school drinking. To test these hypotheses, we performed a series of ordinary least squares multiple regressions predicting (1) high school drinking on the basis of parental monitoring, (2) college drinking on the basis of parental monitoring, and (3) college drinking on the basis of both parental monitoring and high school drinking. For each analysis, hypothesized effects were first evaluated at the bivariate level as were the effects of several control variables . Next, all explanatory variables were evaluated together in a series of multiple regression models. In the final model, the first-order interaction term of parental monitoring with high school drinking was included to test for a possible moderating effect. Because students were interviewed at various times during their first year in college, the combined models included time in college  to adjust for any potential confounding effects related to the timing of the interview. Effect size for each explanatory variable was evaluated using the semipartial he model .As can be seen in Table p < .001), with males, White students, and students with lower religiosity having higher levels of alcohol consumption in high school. As expected, parental monitoring was strongly negatively related to high school drinking, such that number of drinks per day decreased as the parental monitoring score increased  = -10.49, sr2 = .08, p < .0001). Interestingly, the results of the multivariate model indicate that while sex and race had significant independent effects on high school drinking level, the effect of religiosity become non-significant once sex, race and parental monitoring were held constant (p = .56). Additional post-hoc analyses suggested that the effect of religiosity in the model was reduced mainly by the addition of parental monitoring, rather than sex or race. The magnitude of the parental monitoring effect remained essentially unchanged by the addition of these covariates  = -9.26, sr2 = .07, p < .0001.Table b = -0.11, t(df) = -8.26, sr2 = .05, p < .0001), albeit less strongly than the effect on high school drinking level  = 4.27, sr2 = .01, p < .0001), whereas living with parents was negatively associated  = -7.82, sr2 = .05, p < .0001) Time in college, which was included as a control variable, did not contribute significantly to college drinking (p = .42).Table b = 0.63, t(df) = 6.01, sr2 =.02, p < .0001), whereas the effect of parental monitoring became non-significant (p = .60). The interaction between parental monitoring and high school drinking did not contribute significantly to the model (p = .62). Model estimates for race and sex were reduced appreciably from Model 1, but retained statistical significance. Finally, Model 3 excludes the interaction between parental monitoring and high school alcohol consumption, and shows that the model explains 48% of the variance in college drinking. Moreover, the effect of high school drinking accounted for a large proportion of variance in college drinking (sr2 = .27) whereas parental monitoring remained non-significant (sr2 < .01). In summary, we directly tested our mediation hypothesis in the models shown in Tables In the first multivariate model that controlled for all the covariates but did not control for high school drinking (see Model 1), the model estimates were essentially unchanged with two important exceptions. First, religiosity did not retain significance once parental monitoring and other covariates were held constant. Second, the effect of SAT score on college drinking was reduced quite substantially and became non-significant. In the second multivariate model (Model 2) where high school drinking was included, high school drinking was strongly related to college drinking  and college drinking (.78), because the proportion of non-drinkers was higher than expected in a normal distribution . However, we obtained similar results from replicating the multivariate models in a restricted sample that excluded non-drinkers. Nevertheless, results should be interpreted cautiously whenever the criterion variable in a regression model is not normally distributed. Third, although a standard measure of parental monitoring was used in this study, the construct being measured might be highly correlated with positive child characteristics and not simply parent behaviors. For example, the item pertaining to leaving a note is both a reflection of the child's willingness to conform to prosocial behavior and perhaps the expectation set by parents about the need to leave a note. Future studies should attempt to disentangle the relative effects that are more child-driven from behaviors that are under the parents' control, such as taking away privileges if a student comes home past curfew. Fourth, it is important to recognize that the measure of parental monitoring used in the present study is limited to only one facet of effective parenting, namely the student's perception of parental monitoring, and may not necessarily reflect actual parent behavior. Moreover, our measure may be a proxy for the presence of other parenting behaviors, such as parental disapproval of underage drinking , and effFifth, the observed protective effect of parental monitoring during the last year of high school could be interpreted to be a marker of effective parenting throughout adolescence. Unfortunately, the current study did not measure parent monitoring and supervision during earlier developmental periods.This study is also limited in its ability to explain the mechanism by which parental monitoring exerts its protective effects. Several studies have suggested that parental monitoring might limit affiliation with deviant peers -47, or mDespite the above limitations, the present findings have implications for both prevention and future research. Based on our findings, we speculate that with regard to prevention, the results extend support for parental monitoring and supervision during the high school years as a strategy to reduce adolescent drinking. An interesting policy debate exists around the degree to which parents should be involved in monitoring their college student's behavior related to alcohol consumption, since, legally their children are adults. There is more, but not unanimous, agreement pertaining to involving parents when there is a life-threatening situation involving their child. For example, not all universities have mandatory parental notification policies in cases of alcohol poisoning. The issue raised by the results of this study is whether it might be useful to engage parents at an earlier stage – namely, in prevention strategies to reduce underage drinking during college. While the results of this study showed that parental monitoring during the last year of high school was associated with reduced levels of high school drinking, and high school drinking levels in turn predicted college drinking levels, it would be important to know whether continued parental involvement in college had additional benefits on reductions in college student drinking over and above the effects of high school drinking levels. Evaluations of programs that focus on modifying parenting practices have shown promising results in reducing risk among younger adolescents. Providing consistent discipline, setting rules, monitoring adolescents' activities, providing positive reinforcement, and communicating with adolescents are all parenting tools that have proven efficacious in reducing and delaying adolescent drinking and risk-taking behaviors -33,52-54To our knowledge, few interventions have focused specifically on parental engagement strategies to reduce college drinking . In theiThere are a variety of possible ways to involve parents in prevention. First, at the very least, parents can communicate with their college-age child about campus policies related to underage drinking and illicit drug use. For this to happen, campus officials must inform parents of these policies, at orientation and on an ongoing basis during the time their child is in college. CASA notes that close to 90% of colleges report that their policies are available for inspection by parents, either through direct communication, or through the college website .Second, parents could be encouraged by colleges to express disapproval of underage drinking while their child attends college. Research shows that college students who report that their parents have permissive attitudes about underage drinking and substance use are more likely to engage in these behaviors . This is"The only reason for college binge drinking is prohibition. Kids that binge drink in college are the same ones that were raised by 'responsible' parents who did not let their kids try a drop of alchohol (sic) at home.Once kids get to college and away from parents' relatively frequent control they go on a rampage. Binge drinking can easily be resolved in late teenagehood by educating kids how to drink, what it means to drink a lot, and what hangover is ."However, our study has shown that binge drinking in high school predicts college binge drinking. In addition, the CASA survey found that 70% of college students reported that their parents' concerns or expectations either somewhat or very much influenced whether or how much they drank, smoked, or used other drugs, and that parental attitudes were significantly related to the likelihood to binge drink, use marijuana, and smoke tobacco.Third, colleges could encourage parents to play an important role in recognizing early warning signs of alcohol abuse and intervening by facilitating access to services. If parental notification policies were in place when a student receives a citation from residence life for underage drinking, then parents could encourage their student to undergo a comprehensive assessment, which includes exploration of underlying mental health issues. The 1998 amendments to Part E, Section 952 of the Higher Education Act of 1965 (PL 105–244) allow institutions of higher education to notify parents of students who are under the age of 21 when the student has committed a school disciplinary violation involving alcohol or a controlled substance. The United States Department of Education clarified the ruling in 2000 by stating that "school officials may notify parents whenever they determine that a disciplinary violation has occurred, and that those determinations can be made without conducting a formal disciplinary preceding or hearing ." The poAlthough many students may be physically separated from their parents once they begin college, future studies are needed to investigate whether or not certain parental practices with college-age children  might be helpful in reducing the risk of problematic alcohol consumption. In the 2002 landmark report "A Call to Action: Changing the culture of drinking at US colleges," several potential strategies for reducing excessive drinking, such as social marketing campaigns and environmental strategies were described. Evaluation research should continue to understand the extent to which these types of prevention strategies are effective. This report offered scant information about the protective role of parents except to say that parents should be aware of campus policies on alcohol and illicit drugs . ArguablIn summary, the transition to college marks a high-risk period for escalation of alcohol consumption. Parents and prevention practitioners can benefit from evidence that points to specific parenting practices that might help reduce the risk for heavy drinking, while at the same time allow for appropriate levels of autonomy that are critical for young adult development. Colleges should invest in initiatives that involve parents as partners in communicating the message to students about the risks of heavy drinking and promote appropriate levels of parental monitoring through the college years.M: Mean; SD: Standard DeviationCASA: Center for Addiction and Substance Abuse; PL: Public Law; The author(s) declare that they have no competing interests.AA, KO'G, and EW contributed to the overall scientific direction of the project. KC and KV managed the day-to-day operational aspects of data collection. KV supervised staff involved in data collection. VK, KC and KO'G performed the statistical analyses. AA, VK, KO'G, KC, KV, and EW assisted with writing. All authors read and approved the final manuscript.


The paper considers conceptual and methodological issues in studying the scope of alcohol’s harm to others. Reasons are suggested for the relative neglect of the topic. The approaches in two relevant research traditions are considered: population surveys on alcohol problems, and economic cost of alcohol studies. Ways of conceptualizing and measuring aspects of the drinker’s effects on others are considered, in terms of main types of relationship with the other, and in terms of major societal response institutions. The main types of data tend to measure different levels of severity, with population survey data dominated by less severe problems, and response institution data by more severe problems; so both are needed for a three-dimensional view. Research questions for the field and its policy significance are noted. A traffic crash caused by a drinking driver may kill passengers, the other driver or pedestrians. An elderly couple walking home at night may be threatened by carousing teenagers. A child may be left stranded when an adult supposed to pick the child up from preschool instead overstays an after-work drinking session. A sober bystander attempting to separate two drunks fighting may himself be injured when they turn on him. An adult daughter may find herself at her wit’s end over the drinking of her live-in father. A small firm may be driven into bankruptcy by mistakes or misdeeds of its employees when they have been drinking on the job. A pregnant woman may continue her heavy drinking and harm her baby. All of these instances are examples of ways in which someone’s drinking may adversely affect someone else.As will be discussed, the literature on the scope of the harm from drinking to the social environment of the drinker is small, though there are substantial literatures on some specific areas of harm, such as from drinking driving, and from violence, including domestic violence. This paper discusses conceptual and methodological issues in studying the scope of alcohol’s harm to others.2.In the modern literature on alcohol problems the harms which are best measured are the effects of drinking on health. Estimates of the role of alcohol in each of a variety of diseases now draw on meta-analyses based in turn on dozens of prospective and case-control studies . The domBut health records usually focus on characteristics of an individual defined as the patient. The International Classification of Diseases is a catalogue built around the body of the individual patient. Even for injuries, where the environment is coded, the codes pay attention primarily to the inanimate context of the injury: the injury was from an automobile, a particular poison, a fall or a fire. The classification, and the health records in which such classifications are used, are largely blind to the condition of other humans as an element of the context of the disorder.The emphasis on harms to the drinker also arises from the general bias towards methodological individualism, with samples designed in terms of isolated individuals, in research methods and questions. Population surveys typically interview only one person per household, and sampled in such a way as to limit any cross-contamination of responses between respondents. Greater attention is often paid to the life history of the individual than to factors in the individual’s social environment. Measuring alcohol’s harm to others requires at a minimum measuring drinking and associated behaviours of one person and harm to another.There are some realms of harm to others where there is more attention to social interactions and human elements of the environment. Police reports on homicides or sexual assaults typically pay detailed attention to potential perpetrators, and in general to the human context of the crime. Child welfare investigations parse all relationships and every member in the child’s family. But the presence of drinking or intoxication is often only fitfully recorded in the case notes.This general situation differs substantially from a century ago. A marital partner’s inebriety was an accepted ground for divorce, which meant that official statistics were available. “Worker’s compensation systems collected data on findings that the claimant had been drinking…. Life insurance companies routinely collected data on an applicant’s ‘drinking habits’” . In geneWhat happened in the interim were two big social changes. By the mid-20th century, there had been a strong generational reaction against the temperance movement. Alcohol’s involvement in social problems—the adverse effects of the drunkard’s drinking upon the family, the economic loss to business from employee drinking, the idea that it was alcohol which filled the prisons—had been a staple of temperance movement campaigns and rhetoric , and in The other change was in ideas and boundaries of privacy. Among the several social trends which contributed to the move to “no-fault divorce” in the 1960s and after, and thus to the loss of statistics about alcohol’s contribution to divorce, one change was an expansion in the realm of privacy, in 1965 elevated in the USA to the state of a constitutional right , and driThese social changes have had a long persistence, even after the tide has clearly changed on recognizing the serious effects of drinking on the drinker him- or herself. One early breach in the neglect of alcohol’s effect on others was in the area of drinking driving. By the 1960s, the serious effects of drinking driving on others were recognized and became arguments for policy change . In othe3.The harms from drinking are conventionally discussed in terms of health problems and social problems . In factHowever, most social problems with drinking involve some harm, perceived or tangible, to another person. Someone other than the drinker is perceived or perceives him/herself to be adversely affected by the drinking, and a social problem with drinking often involves some response by the other person which in turn adversely affects the drinker. Most social problems with drinking are thus inherently interactional.It should be noted that in most circumstances human perception and definition are thus inherently involved in whether person A’s drinking is defined as harmful to person B. A may not perceive there to be a problem for B. A may not perceive his or her drinking to have any relation to it. Or A may not know that B considers A’s drinking to have created problems for B. Naturally, B may have his or her own permutations on these possibilities. An observer may have a third set of perceptions and definitions. Thus, an old USA study of 252 domestic physical assaults where the police were called found that the putative assaulter was alleged by the complainant to have been drinking in 40% of the cases, but that the police judged that the person had been drinking in only 21% .The evidence which is commonly available on alcohol’s harm to others draws from a variety of perspectives on the occurrence of a problem and drinking’s relationship to it. Data from police or hospital records are formally recorded by professionals or the relevant organization’s clerical staff. They may represent professional observation. But they may also or instead reflect what is volunteered or answered by one or another party to a situation. Data from surveys reflect answers by a drinker or by someone adversely affected by a drinker, but built into the questions or answers may be the respondent’s report of what someone else said.A book edited by Klingemann and Gmel  is the mAs we consider the traditions of research on social harms from drinking, versions of these two underlying dimensions of organisation—by major social roles and by major societal response institutions—are a recurrent theme. One reason the major social institutions figure heavily in the conceptual organization is that they are the main avenues of societal response to social problems, and thus generate the records on which most research on serious consequences is based. The major social roles look at social consequences instead from the perspective of the individual involved—usually the drinking individual: how has the drinking impinged on major areas of his or her life? The obverse of these social roles is sets of persons in interaction with the drinker: employer and workmates; spouse/partner, household members, relatives; friends, neighbours and acquaintances. What must be added to these sets is the indefinitely large set of strangers who may be affected by the drinker: those whose sleep is disturbed by the drunkard’s noisy path home, passersby caught up in a drunken fight, owners of “lemon” automobiles supposed to be more commonly built when the weekend drinkers were missing from the assembly line. The adverse effect may come from collective acts or threats, or may come from an individual drinker. Thinking in terms of the individual drinker, many of these constituencies are affected by the drinker’s comportment as an actor in public spaces , carryin4.There are two main alcohol-specific literatures in which there have been attempts to be comprehensive about alcohol-related harms: the survey research tradition of asking about alcohol problems, and the tradition of “cost-of-illness” studies of the social costs of alcohol. The two literatures look at alcohol-related harms through very different windows.4.1.The primary strand in the survey research tradition has asked the drinker about problems from his or her own drinking. These have included a wide range of problems, personal and social. As noted above, social problems from drinking tend to be inherently interactional, so that when a drinker is answering that his drinking has harmed his marriage or home life, for instance, it is very likely there is another who considers him/herself to have been adversely affected by the drinking.etc.), are also somewhat relevant.A typical listing of problem areas relevant here would include problems related to the respondent’s drinking with a spouse/partner, with relatives, with friends or neighbours, on the job or with workmates, and with the police ,15. SomeImplicit in this survey research tradition is a conceptualization of social problems from drinking in terms of default in major social roles—the roles specified in Overlapping this tradition has been a line of analysis of patterns of informal social control of drinking—for instance, suggestions to the drinker to cut down drinking ,17. The There are also growing traditions of survey studies which focus more on specific kinds of interpersonal problems – for instance, the literature on alcohol in partner violence . In studet al. [A secondary strand in the survey research tradition has looked at alcohol-related harms specifically from the perspective of the other—whether in the role of victim or (less often) of bystander. In this strand, while the relation of the drinker to the respondent is often not clear, the focus is not on fuzzily-defined “drinking problems”, but instead squarely on harm experienced by the respondent from others’ drinking. “The focus is usually explicitly on concrete events, whereas items in own-drinking problem series often concern conditions, or are commonly interpreted as indicators of a condition” . The papet al.  is a curet al. [et al. [Analyses of the questions have often stayed at the item level ,23, with [et al.  series cIn existing studies, the questions about harm from others’ drinking have been a relatively minor part of a broad-ranging questionnaire. The range of topics to be covered has tended to mean only a shallow coverage of each one, particularly in the era of the 20-minute telephone interview. The questions typically pick up adverse effects of drinking in both the public and the private spheres.This conceptual paper is written in the context of a study which includes a population survey specifically devoted to measuring alcohol’s harm to others . In the 4.2.The other main relevant broad-ranging tradition of work derives from the “cost of illness” tradition in economics. While, as its name implies, this tradition originated specifically with respect to disease and the health system , from thIn principle, the focus is particularly on the costs to others than the drinker, defined in economic jargon as “negative externalities”: “Negative externalities occur when individuals or firms undertake actions which impose costs on other individuals or firms, while providing no, or insufficient, compensation to those who bear these extra costs.” , p. 8 Hoet al. [A small tradition within economics, critical of the general cost-of-illness tradition discussed next, has endeavoured to confine the estimated costs to strictly-defined “external costs”, that is, costs imposed on others by the alcohol consumption of the drinker ,30. HoweThe mainline cost of alcohol studies have tended to divide their estimates according to the societal response institutions from which their primary data mainly derive. The recent Swedish study categorized its main direct costs into: health care, social services, and crime , p. 71. So far we have been dealing with what economists call the “direct costs” of alcohol consumption— costs of the major societal response institutions which, at least in a welfare-state society, are primarily borne by the society. To the extent this is true, those around the drinker—family, friends, victims, bystanders—are not much out of pocket for the actual costs which are measured—though they do contribute to paying them as taxpayers. However, in the economists’ conceptualization, there are two categories of cost beyond what we have considered which do have a more direct impact on those around the drinker.One of these is the indirect costs or the productivity costs – the loss to the economy from a drinker’s early death or other incapacity to work. Typically these costs, primarily from early deaths, are the largest or second-largest component of cost of alcohol calculations , p. 95. i.e., indirect costs). Finally, early death and disability are also likely to cause distress in the family and impact one’s quality of life (intangible costs). In these senses, what is measured as “lost productivity” is also an indication of harm to others. Likewise, there are likely to be substantial intangible costs of living with a heavy drinker. One widely-used measure of intangible health costs is Quality-of-Life Years (QALYs), with a full-quality year of life scored at 1.0 and death at 0, and mental and physical health disablements scored in between. A substudy of the Swedish cost of alcohol study estimated the loss in terms of QALYs for those who reported someone close to them or living in their household having a drinking problem, finding a significant decrement among those sharing a household with someone with a drinking problem. Assigning the standard costing used in Swedish economic studies to the QALYs, the estimated intangible cost to those sharing a house was 10.9 billion Swedish crowns, compared with total net direct and indirect costs to the society  of 20.3 billion [If we consider these categories in terms of the harm of drinking to others, both have substantial implications, particularly for members of the drinker’s immediate family or household. An early death or disability due to alcohol results in the reduction of net resources  used in paying for funeral expenses, health costs or legal proceedings – in essence direct costs. But the death or disability also removes from the family budget the earnings of the drinker, often substantially reducing the family’s future earnings  even costs in the welfare system are omitted. This is partly because the proportion of welfare caseloads which could be attributed to someone’s drinking is not well measured anywhere, and not measured at all in most places. Also reflected are economists’ rules on what counts and what does not count in a cost study, which exclude “transfer costs” , including most welfare payments.et al. [Also involved in the neglect of family/social network costs is the old tradition in economics of treating the household as a consumer unit and as “the primary decision making unit in our society” . As Johaet al. , p. 17 nThe conclusion, in the context of cost of alcohol studies, must thus be that “social harms, such as problems in family life and personal friendships and relationships, have not been well measured” , p. 11. Mainstream cost of alcohol studies often provide some subdivisions of the costs. For instance, Collins and Lapsley [5.An important step in studying alcohol’s harm to others is to ascertain what data can be found or developed concerning the adverse effects of someone’s drinking on specific others. The adverse effects on the other can be in terms of mental or physical health, of safety or security, or tangible or intangible costs. The effects can be as described by the other, and noted by a bystander or interested party, or as recorded in agency records. The data can be drawn from multiple sources, which do not necessarily share common definitions or frames of reference. Thus the harms that are measured are not necessarily mutually exclusive—though an interesting question, of course, is what can be said about overlap and potential doublecounting?The fact of an occurrence, for instance, a death or a traffic crash, can be viewed as an indicator of harm for the person affected. Thus a count of deaths, or of years of life lost (YLLs) short of a full life, is one kind of metric of harm to the individual.Particularly in population survey data, the respondent’s report of an adverse occurrence—for example, something being broken or damaged that mattered to the respondent—is often used as an indication of harm to the respondent.The frequency and intensity of such harms can also be indicated by the respondent, for instance by asking how often it happened, and whether the adverse effect was a lot or a little.Another measure used of the degree of harm to the respondent can be in terms of the respondent’s report on items indicating a degree of wellbeing or of health disability , which can then be compared with the reports of others similarly situated.For harms where it is possible, a monetary measure of the amount of harm can be calculated. This can be measured in various frames of reference, depending on the harm: e.g., in terms of the wages which could have been earned in time which was lost, in terms of the loss of monetary value of something broken or damaged, in terms of the conventional monetary value assigned by econometric studies to an increment of health disability.Harm to an individual can occur in many forms, and can be measured in various metrics. Likewise, alcohol’s involvement in the harm can be established or estimated in several ways. For instance:Costs of the effect of someone’s drinking on another which are not paid by the affected person can also be estimated—costs which are paid collectively, usually by a government, such as hospitalization or policing costs.In data drawn from population surveys, alcohol’s causal involvement in the harm is commonly measured directly by the attribution of the person affected. Thus a question like “How many times in the last 12 months were you physically hurt by them because of their drinking?” has built into the question an attribution (in a “yes” response) of the occurrence to the other’s drinking.For some harms, the alcohol attribution is commonly made by the personnel of the health or social response system—for instance, a child protection worker coding that the parent’s drinking is involved in a child endangerment case. Sometimes the attribution is built into the system’s categorization of the case—for instance, a Foetal Alcohol Syndrome diagnosis, or a “drunk and disorderly” arrest.For harms measured by the health system without any routine coding of alcohol involvement, meta-analyses of special studies have often relied on to measure an “alcohol attributable fraction” (AAF). AAFs are usually concerned with the drinking of the person with the illness, but it is possible to develop analogous fractions concerning the drinking of another, for instance, in estimating the proportion of child traffic deaths where another’s drinking played a causal role.In studying the effects of others’ drinking on personal wellbeing and health disability, the alcohol attribution can be imputed from differences in wellbeing or disability scores between those similarly situated who are affected by heavy drinkers and those who are not.The definition of causation which will be commonly used in such studies is an epidemiological one : would tAll of these metrics of harm and means of assessing causality have a substantial base in the research literature. But all are the subject of continuing debate and discussion, as scientists continue to endeavour to improve concepts and measurement.6.Like the social cost studies, a study of alcohol’s harm to others will normally use data collected in two main frames. One frame is that of surveys of the general population; the other is that of agency records, such as police and ambulance files, hospitalisation and emergency department records, alcohol treatment agency casefiles, and mortality records.Each frame has its own characteristics, advantages and drawbacks. The advantage of the population survey is that in principle it is inclusive of the whole range of experience in the population, including lesser problems which would never come to official attention. The drawbacks include that really serious adverse effects are not very common, and it would take a very large sample of the population to cover them adequately. The picture of adverse effects drawn from a population survey is thus going to be dominated by the milder end of the continuum of severity of effects. A second drawback is that it is increasingly impossible to get an adequate representation of the whole population in a sample survey. Marginalised people are often missing from a sample based on households, and increasingly young adults are missing from survey samples defined by having a landline telephone. Also, response rates have fallen as populations have found themselves bombarded not only with research surveys but also with telemarketing masquerading as a survey.Agency records have the advantage that they are likely to give a good picture of the more serious end of the continuum of severity. In contrast to population studies, one drawback is that less serious cases tend not to come to an agency’s attention. A second drawback is that the data is usually collected as part of the agency staff’s routine work activities; in many cases, the staff is involved in life-and-death situations, and accurate data recording will often come lower on the priority list. Details like the involvement of someone’s drinking in the situation may not be routinely recorded. Alternatively, if there is a required tick-box concerning this, the box will be filled out, but its validity may be questionable. What is recorded may also be shaped by how the staff member wants to present their daily work to their supervisors and others who may use the records.Using data from both these two main frames gives the opportunity for what might be called a binocular view of alcohol’s harm to others. In studies of those whose drinking causes problems, one finds what has been called “two worlds of alcohol problems” . Looked The challenge for future work in the field, then, is not only to develop better measurement of problems as they are manifested both through agency windows and through the general population window, but also to develop study designs which chart and limn in the connections. When and under what circumstances does the risk increase that a minor annoyance on the street will turn into a serious event? What can be learned about prodromal signs that the wellbeing of family members is seriously threatened by another member’s drinking?7.From court records, coroner’s studies and the casefiles of emergency response agencies, we know that drinking can have very serious adverse effects on those around the drinker. From limited sets of items on population surveys, we know that others’ drinking sometimes annoys or discomforts a very large fraction of the population. We need to know more about the scope and magnitude of these problems at both ends of the spectrum of severity, and we need to know what lies between these extremes: the circumstances and prevalence of adverse effects which are not cataclysmic, but which also cannot be shrugged off. We need to know more about the natural history of relationships where the drinking of at least one person has an adverse effect on others. When do relationships persist despite heavy drinking and when do they lapse? What are the longer-term effects of one person’s heavy drinking on the other, in a particular type of relationship? To what extent and under what circumstances are drinkers responsive to efforts at social control from others in a social relationship? These kinds of questions suggest how inherently social and interactional is the study of the harmful effects of drinking on others, and of efforts by the other or by third parties to prevent or reduce the harm. Drinking is usually a social activity, and drinkers interact with and affect those in their social environment.The knowledge is of practical value in terms of designing effective resources to counsel and assist those adversely affected by others’ drinking. Generally, provisions for those seeking such help are presently an add-on to services for those with alcohol problems. A fuller and more concrete understanding of the harms to others from drinking is also important in designing prevention programs and policy initiatives to reduce the harms from drinking. It also has a potentially important role in policy debates about public health approaches to alcohol problems. Some will argue that what the drinker does to his or her own body and mind is private rather than public business. But even those who take a very restrictive view of the responsibilities of the state will commonly agree that the state should intervene to prevent harm from one person’s behaviour to another.


Purpose. Rhabdomyosarcoma (RMS) is an embryonal tumor thought to arise from skeletal muscle cells that fail todifferentiate terminally. The majority of RMSs express MyoD, a protein essential to the differentiation of skeletal muscle.It was recently shown that during myogenesis, MyoD activates the expression of the cyclin-dependent kinase inhibitor(CDKi), p21, which itself plays a critical role in normal muscle development. To investigate the integrity of the MyoD/p21pathway in RMS, we analyzed p21 and its relationship to MyoD expression in RMS.            Methods. A panel of RMS samples was assembled from primary biopsies and from cell lines. Integrity of p21 was analyzedby single-strand conformation polymorphism (SSCP) and sequencing. Expression of p21 and MyoD was determined byNorthern blot analysis, and the ability of exogenous p21 to arrest the cell cycle of RMS cell line was determined bytransfection studies.            Results. Our analysis indicates that although p21 is wild type in RMS, there is an inverse correlation between the levelsof p21 and MyoD in these tumors. Tumors that express significant amounts of MyoD fail to express p21. This does notappear to be the result of mutations within the potential CACGTG sites present in the p21 promoter region or in thecoding region of p21. An additional group of RMSs express very high levels of p21 but express little, if any, MyoD.Furthermore, RD, a RMS cell line which expresses high levels of endogenous p21, undergoes withdrawal from the cellcycle following forced expression of p21, suggesting that the pathway which would lead to G1 arrest from endogenous p21 activity is defective.            Discussion. These data suggest that the interaction between p21 and MyoD is defective in RMS although the precisenature of the defect remains to be elucidated.


A video of introductory information about inherited susceptibility to breast cancer was made in consultation with clinicians in four Scottish cancer family clinics. One hundred and twenty-eight women, newly referred for breast cancer risk counselling were randomized to receive the video before (n = 66) or after (n = 62) counselling. Data were collected before randomization at clinic and by postal follow-up at 1 month. The Video Before group had shorter consultations with the breast surgeon (mean = 11.8 min+/-5.4 vs 14.6+/-7.2 for the Video After group). There was no difference between the groups in the accuracy of their risk estimate after counselling, although the Video Before group scored higher for self-reported  and objectively assessed understanding . At 1 month follow-up, the Video Before group were less likely to underestimate their risk estimate , but there was then no difference between the groups in subjective or objective understanding. Use of the video was not associated with increased distress  and was associated with greater satisfaction with the information given at the clinic. This study supports the value of videotape as a method of giving information to prepare women for breast cancer risk counselling. Observations of misunderstandings and distress emphasize the video should be seen as an aid to, not a substitute, for communications at the clinic.


Plasmodium knowlesi, a simian malaria parasite, are more common than previously thought. They have been detected by molecular detection methods in various countries in Southeast Asia, where they were initially diagnosed by microscopy mainly as Plasmodium malariae and at times, as Plasmodium falciparum. There is a paucity of information on the morphology of P. knowlesi parasites and proportion of each erythrocytic stage in naturally acquired human infections. Therefore, detailed descriptions of the morphological characteristics and differential counts of the erythrocytic stages of P. knowlesi parasites in human infections were made, photographs were taken, and morphological features were compared with those of P. malariae and P. falciparum.Human infections with Thick and thin blood films were made prior to administration of anti-malarial treatment in patients who were subsequently confirmed as having single species knowlesi infections by PCR assays. Giemsa-stained blood films, prepared from 10 randomly selected patients with a parasitaemia ranging from 610 to 236,000 parasites per μl blood, were examined.P. knowlesi infection was highly synchronous in only one patient, where 97% of the parasites were at the late trophozoite stage. Early, late and mature trophozoites and schizonts were observed in films from all patients except three; where schizonts and early trophozoites were absent in two and one patient, respectively. Gametocytes were observed in four patients, comprising only between 1.2 to 2.8% of infected erythrocytes. The early trophozoites of P. knowlesi morphologically resemble those of P. falciparum. The late and mature trophozoites, schizonts and gametocytes appear very similar to those of P. malariae. Careful examinations revealed that some minor morphological differences existed between P. knowlesi and P. malariae. These include trophozoites of knowlesi with double chromatin dots and at times with two or three parasites per erythrocyte and mature schizonts of P. knowlesi having 16 merozoites, compared with 12 for P. malariae.The Plasmodium knowlesi infections in humans are not highly synchronous. The morphological resemblance of early trophozoites of P. knowlesi to P. falciparum and later erythrocytic stages to P. malariae makes it extremely difficult to identify P. knowlesi infections by microscopy alone. Plasmodium knowlesi, a malaria parasite species commonly found in long-tailed and pig-tailed macaques  is the only malaria parasite of primates with a 24-hour erythrocytic cycle [P. knowlesi by blood passage soon after the parasite was first isolated in 1932 [P. knowlesi were thought to be extremely rare. However, following a number of reports of human knowlesi malaria infections detected by molecular methods in various countries in Southeast Asia [P. knowlesi is now recognized as the fifth species of Plasmodium infecting humans [ic cycle ,2. Humang humans .Plasmodium species for rational decisions on appropriate patient treatment and management. The parasite species is identified by morphological characteristics and for the diagnosis of human malaria, detailed morphological descriptions for Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale are given in medical text books and malaria diagnostic reference literature [P. knowlesi in the parasitology literature are largely based on experimental infections of rhesus macaques, since P. knowlesi causes a high parasitaemia in these hosts, as opposed to low parasitaemia in its natural macaque hosts [P. knowlesi in naturally-acquired human infections other than the description by Singh et al [P. falciparum while the other stages are similar to those of P. malariae. These morphological similarities between P. knowlesi, P. malariae and P. falciparum have been noted previously by other workers but without accompanying detailed accounts with coloured photographs [P. knowlesi parasite stages in human erythrocytes are truly indistinguishable from P. falciparum and P. malariae infections by microscopy. Therefore, the morphology of the different blood stages of P. knowlesi parasites observed in human erythrocytes from knowlesi malaria patients is described, together with quantitative estimates of the different erythrocytic stages, and compared with those of the other malaria parasites causing human disease.Malaria diagnosis relies heavily on examination of stained blood films by microscopy, leading to parasite detection, enumeration and identification of terature ,12. Morpue hosts ,14. Thergh et al  in whichtographs ,16. It rP. knowlesi infections were randomly selected from films that had been prepared from 83 knowlesi malaria patients admitted to Kapit Hospital [Thick and thin blood films from ten patients admitted to Kapit hospital and subsequently confirmed by nested PCR assays  as havinHospital . These p® buffered water, pH 7.2  for 30 minutes, as described previously [Thin blood films were fixed with absolute methanol  for 10 seconds and were allowed to dry at room temperature before staining. Thick and thin blood films were stained with 3% and 10% Giemsa  respectively, in Gurreviously . All thiP. knowlesi parasite developmental stages was scored according to the descriptions by Garnham [et al [The parasitaemia of each patient in the study was calculated from thick blood films by counting the number of parasitized red blood cells per white blood cells in over 100 fields and calculated using the actual white blood cell count of each patient. The percentage of each of the parasite developmental stages was determined based on the number of early trophozoites, late and mature trophozoites, schizonts, and gametocytes in thin blood films. A total of 500 parasitized erythrocytes were counted for each of the 10 patients except for patients KH328 and KH422 where 50 parasitized erythrocytes were counted due to the low parasitaemia. The morphology of each of m [et al  as folloP. knowlesi, with a parasitaemia between 610 to 236,000 parasites per μl blood . They were characterized by the appearance of a ring-like cytoplasm enclosing a vacuole with a dot of round nuclear chromatin projecting from the cytoplasm  of the infected erythrocyte  had a highly synchronous infection with 97% of infected erythrocytes containing late trophozoites.Detailed observations of Giemsa-stained thin blood films from 10 patients with varying degree of parasite load, showed that human infections were generally asynchronous at the time of admission with all stages of the erythrocytic cycle of P. knowlesi appeared as ring forms within the infected erythrocyte and possessed characteristics that resembled the early trophozoites of P. falciparum such as double chromatin dots, multiply-infected erythrocytes and appliqué forms. The resemblance of the early trophozoites of P. knowlesi to those of P. falciparum has also been noted previously in human P. knowlesi infections [P. knowlesi can be easily mistaken for falciparum malaria when the infecting parasites are predominantly at the early trophozoite or ring form developmental stage. If the blood film had been prepared earlier from the patient with the highly synchronous infection, most of the trophozoites would have appeared as ring forms and the infection would have been diagnosed by microscopy as P. falciparum.Early trophozoites of fections ,15 and ifections ,14. HumaP. knowlesi in human infections were generally indistinguishable from those of P. malariae. There were no specific features of the cytoplasm, nucleus and pigment of the parasites or the infected erythrocytes that could easily distinguish P. knowlesi from P. malariae, other than the presence of very amoeboid cytoplasm. However, this was observed in only some late trophozoites of P. knowlesi. Moreover, 'band form' trophozoites, which are a characteristic feature for P. malariae parasites [Late and mature trophozoites, schizonts and gametocytes of arasites ,16,17 weP. knowlesi schizonts in infections of rhesus macaques [P. malariae [P. knowlesi were observed with symmetrical arranged merozoites surrounding clumps of malaria pigments or "rosette pattern," which was often described as a characteristic of schizonts of P. malariae [In agreement with previous descriptions of the number of merozoites in mature macaques ,14,16, amalariae . In addimalariae .P. falciparum and P. malariae. Distorted infected erythrocytes, which are a common feature in P. knowlesi infections of rhesus macaques [P. knowlesi infections in the present study. No stippling was apparent that resembled Schüffner's dots, which are observed in P. vivax infected erythrocytes. However, faint stippling that appeared as light irregular dots were evident in only some of the infected erythrocytes with mature trophozoite and schizont stages. This type of stippling in erythrocytes infected with P. knowlesi is referred to as 'Sinton and Mulligan's stippling' and was noted previously in infections in rhesus monkeys [P. malariae infections, the infected erythrocytes are not enlarged or distorted and may display some form of irregular fine stippling in blood films with intense staining [The infected erythrocytes for all stages were generally not enlarged, a feature that is shared with erythrocytic stages of macaques ,14, were monkeys  and huma monkeys . Accordi monkeys  was usedP. knowlesi and P. malariae or P. falciparum using routine microscopy methods for malaria diagnosis. This lack of distinguishing features accounts for P. knowlesi infections being overlooked, despite major differences in the pathogenesis of each of these different lineage parasites [P. knowlesi as P. malariae by microscopy is largely unavoidable, although it is difficult to rationalize how a parasitaemia greater than 100,000 per μl blood, together with signs of severe malaria, could clinically be mistaken for a P. malariae infection, except that until recently, such infections would have been relatively rare and on a background of P. falciparum transmission. Until the application of DNA based technology, the definitive identification test for P. knowlesi parasites was to inject infected blood into rhesus monkey and observe for a fatal outcome [P. knowlesi-specific PCR assay [P. knowlesi [P. knowlesi infects humans, would benefit from a PCR screening exercise to estimate the relative proportion of P. knowlesi to P. malariae infections. This information would be valuable to prime local healthcare professionals to recognize severe knowlesi malaria in ill patients with a laboratory report of P. malariae.Morphologically, and depending on the predominant circulating parasite stage, it was not possible to identify robust morphological differences to distinguish between arasites ,20. Labo outcome . ClearlyCR assay , provideknowlesi ,6-9. Molknowlesi . Areas oP. malariae, there are other clinical and parasitological parameters such as presentation with one or more of the WHO clinical criteria for severe malaria and a parasitaemia greater than 5,000/μl blood, that, together with a history of time spent in the forest and forest fringe areas of Southeast Asia, should strongly implicate a P. knowlesi rather than a P. malariae infection [Despite morphological similarities with nfection ,20. GiveP. knowlesi parasites in human infections closely resembled those of P. falciparum in the early trophozoite stage and P. malariae in the later stages of the erythrocytic cycle. Although there were some minor morphological differences between the blood stages of P. knowlesi and P. malariae, it would be difficult to positively identify knowlesi malaria based on morphology alone. However, even in the absence of PCR facilities, severe symptoms, a parasitaemia >5,000/μl blood, with P. malariae parasite morphology and a recent history of time spent in the forest fringe areas of Southeast Asia should be enough to make a diagnosis of knowlesi malaria. In view of what is now known of the distribution and severe manifestation of knowlesi malaria, continued misdiagnosis of this important pathogen is no longer acceptable.The morphology of The authors declare that they have no competing interests.KSL, BS and JCS wrote the paper, BS and JCS conceived the study, KSL stained and examined the slides by microscopy.


Thecomplex, [CuL(ClO4)2].2H2O is found to undergo axial ligand substitution reactions with SCN-, NO3  and Cl- to give a variety of substitution derivatives: [CuL(ClO4)mXn] where X = NCS, NO3 and Cl; m = 0 or 1, and n = 1 or 2. The complexes .have been characterised on the basis of analytical,spectroscopic, magnetic and conductance data. The anti-fungal activities of the ligand and itscomplexes have been investigated against a range of phytopathogenic fungi.The ligand Me


Plasmodium knowlesi, the PhilippinesHuman Infections with  Plasmodium knowlesi from Palawan, the Philippines, were confirmed by nested PCR. This study suggests that this zoonotic infection is found across a relatively wide area in Palawan and documents autochthonous cases in the country.Five human cases of infection with the simian malaria parasite  Plasmodium falciparum, P. vivax, P. malariae, and P. ovale. However, a large focus of human infections with the simian malaria parasite, P. knowlesi  were P. vivax, 430 (3%) were P. malariae, and the remainder  were mixed-species infections.Palawan is an island province lying southwest of the main islands of the Philippines. One of its smaller islands, Balabac, located off the southern tip, is separated from Borneo by the Balabac Strait . MalariaP. malariae at a local laboratory in Palawan, were sent to the malaria national reference laboratory of the Research Institute for Tropical Medicine (RITM) in Manila. Microscopy showed mature trophozoites indistinguishable from P. malariae and young ring forms of P. falciparum. This observation, and the fact that macaques in the Philippines can harbor P. knowlesi , for confirmation of the identity of the Plasmodium species by molecular methods. DNA was extracted from the 2 slides 8)as detailed previously , whose condition was diagnosed by microscopy as P. knowlesi. Both were subsistence farmers who had engaged in livelihood activities at night  in forested areas within a 50-km radius from their homes; neither had traveled out of Palawan within the past year. Before seeking medical treatment at the Palawan provincial malaria laboratory, they experienced chills, minor headaches, and daily low-grade fever, consistent with the reported quotidian fever pattern of this infection  on days 1 and 2, and 2 tablets on day 3; 3 tablets of primaquine (15 mg/tablet) on day 4). The farmers reportedly stayed overnight before onset of their illness in forested foothills that contained many breeding sites ideal for A. flavirostris mosquitoes. Long-tailed macaques (Macaca fascicularis), the natural hosts for P. knowlesi, were observed to be roaming freely in the area. An additional 9 samples , consisting of 5 blood films and 4 blood spots on filter paper, were obtained from patients at Bataraza and Roxas municipalities  and P. malariae infection was diagnosed by the local microscopists. These samples were subsequently examined by nested PCR assays at UNIMAS after DNA extraction. Three were identified as P. knowlesi, 4 as P. malariae, and the remaining 2 as mixed species infections  who lived in the villages of Tagbarungis and Bacungan near Puerto Princesa City, Palawan . The patfections . The finPrincesa . This suP. knowlesi infections from Thailand (P. knowlesi forms a previously unrecognized pool of infections that may be maintained in forested areas through its presence in a simian reservoir, despite control efforts in the human population. Current data suggest that human knowlesi malaria is strictly a zoonotic disease. To confirm this theory, further knowledge of the dynamics of human infection is needed.This report extends the geographic range of human


Blissus occiduus Barber (Hemiptera: Blissidae), is an important pest of buffalograss, Buchloë dactyloides  Engelmann and potentially other turfgrass, crop, and non-crop hosts. Choice studies documented the number of B. occiduus present on selected turfgrasses, crops and weeds, and provided important insights into the host preferences of this chinch bug. Grasses with the most chinch bugs present included the warm-season turfgrasses B. dactyloides, zoysiagrass, Zoysia japonica Steudel, bermudagrass, Cynodon dactylon (L.) Pers., and St. Augustinegrass, Stenotaphrum secundatum  Kuntze. The other grasses tested, green foxtail, Setaria viridis (L.) Beauv, Kentucky bluegrass, Poa pratensis L., perennial ryegrass, Lolium perenne L., rye, Secale cereale L., sorghum, Sorghum bicolor (L.) Moench, tall fescue, Festuca arundinacea Schreb. and wheat Tritium aestivum L. had significantly fewer chinch bugs. Buffalograss and zoysiagrass had the highest numbers of chinch bugs among the warm-season grasses and the buffalograss cultivars ‘86–120’ and ‘PX-3-5-1’ had more chinch bugs than the zoysiagrass cultivars ‘Meyers’ and ‘El Toro’ after the two hour evaluation time.The chinch bug,  Buchloë dactyloides  Engelmann, is a warm-season turfgrass that is drought tolerant and has low maintenance requirements, offering an alternative to more traditional high input turfgrasses typically used in turf settings. In the early 1990's, the chinch bug, Blissus occiduus Barber emerged as a serious pest of buffalograss grown for turf , green foxtail, Setaria viridis (L.) Beauv., Kentucky bluegrass, Poa pratensis L., large crabgrass, Digitaria sanguinalis (L.) Scop., perennial ryegrass, Lolium perenne L., rye, Secale cereale L., sorghum, Sorghum bicolor (L.) and yellow foxtail, Setaria glauca. The ability of this chinch bug to feed and reproduce on a wide variety of the grasses present in both agronomic and horticultural settings emphasizes the need for further information regarding the host preference of B. occiduus in habitats containing several suitable hosts.Buffalograss, for turf . During Nebraska , increasn Canada . Reporte mays L. , sugarcanarum L.  wheat, Ttivum L. , barley,mus spp.  and buffmus spp. . In addiBlissus leucopterus leucopterus Say, can be a serious pest of corn, sorghum, millet, rye, many bunch-grasses species, and both cool and warm season turfgrasses  identified as potential hosts of B. occiduus are commonly found in or adjacent to horticultural and agronomic cropping systems, it is important to determine if any are preferred by B. occiduus. Knowledge of the preferred hosts of B. occiduus will assist in monitoring B. occiduus populations by allowing earlier detection of chinch bug infestations before they build to damaging levels. Further, increased knowledge of B. occiduus biology and chinch bug-host interactions will aid in the development and/or more efficient use of improved management approaches including biological control, plant resistance, habitat modification, proper maintenance practices and chemical controls. The objective of this study was to investigate the alternant host preferences of B. occiduus in the presence of its preferred host buffalograss.Although  species . FurtherB. occiduus host preference for selected turfgrass, crop and weed species. The following eleven grasses were evaluated in each of the studies: bermudagrass, cultivar unknown; buffalograss, NE 86-120; Kentucky bluegrass, ‘Eclipse’; perennial ryegrass, (nonendophyte-enhanced), “Saturn II”; St. Augustinegrass, “Raleigh”; tall fescue, Festuca arundinacea Schreb., “Falcon II.”; zoysiagrass, ‘El Toro’; rye, cultivar unknown; sorghum, “Garst 5715 ” and wheat, “Hondo” and the agronomic weed species green foxtail. These grasses were selected based on their susceptibility to B. occiduus as reported by Two choice studies were conducted using growth chamber conditions to determine Following methods outlined by B. occiduus and shows only moderate resistance (tolerance) to chinch bug feeding  were released in the center of each arena. The number of chinch bugs on each grass was visually determined at 1, 2, 4, 8, 24, 48, and 72 h after chinch bug introduction. Based on the results of these studies a third choice study was conducted using four highly preferred buffalograss and zoysiagrass cultivars (Eickhoff unpublished data). The grasses evaluated in this study included the buffalograsses NE86-120 and ‘PX-3-5-1’, and the zoysiagrass cultivars ‘Myers’ and ‘El Toro’. Turfgrasses used in this study were acquired from the same sources and established in the greenhouse as previously described. Chinch bugs were again collected from buffalograss research plots.Fifty 4Individual plants were placed in vials of water and sealed with paraffin wax heated to 63 ± 2° C. Vials with grasses were randomly inserted into 1.7 cm diameter holes drilled in circular test arenas (16 cm diameter by 8 cm deep).th and 5th instar chinch bugs (sex unknown) were released in the center of each arena. The number of chinch bugs used in this study was reduced from the previous studies since smaller test arenas and fewer grasses were used. The number of chinch bugs on each grass was visually determined at 1, 2, 4, 8, 24, 48, and 72 h after chinch bug introduction.Twenty-five 4All experiments were conducted in a growth chamber that was maintained at 28 ± 2° C under 24 h lighting. The experimental design was a randomized complete block design with ten replications for choice studies 1 and 2, and fifteen replications for choice study 3.Mixed model analyses  between choice studies 1 and 2 were detected, therefore the data were pooled. A significant interaction  between grass species and evaluation time was detected. This interaction likely reflects changes in chinch bug numbers on the different grasses over time as well as significant differences between grasses at the individual evaluation times. When chinch bugs were first introduced, for the first 10–15 minutes the insects appeared to move randomly to a grass host. If the first grass visited was not a preferred host, the chinch bugs gradually moved to more preferred hosts over the next 72 h  were, in general, more preferred than any of the cool-season turfgrasses and other grasses evaluated. During the course of this study, more than 50% of the chinch bugs selected either buffalograss or zoysiagrass in the first 8 hours, and by 24 h this number rose to over 70%. Collectively, the warm season turfgrasses made up over 75% of the grasses chosen in the first 4 h. This rose to over 80% during the remaining evaluation times. Combined, the remaining grasses never exceeded 25%. This number decreased over the remaining evaluations to less than 10% at 48 h. Further research is needed to determine which grasses B. occiduus would select in the absence of buffalograss and zoysiagrass.Buffalograss had significantly more chinch bugs present than any other grass, at all evaluation times except for zoysiagrass at 48 and 72 h after introduction . ZoysiagP < 0.0008) and seven evaluation times   . The greB. occiduus for warm-season turfgrasses over all other turfgrass, crop and weed species tested as well as document the host preferences of B. occiduus among these grass hosts. Further, B. occiduus has a high preference for buffalograss and zoysiagrass when compared to other warm-season turfgrasses.These studies suggest the preference of B. occiduus may initially select a host based on morphological characteristics and/or plant architecture. B. l. leucopterus over all other grasses tested because of differences in grass blade width. In this study, the warm season turfgrasses  were initially selected over all of the other evaluated grasses . These stoloniferous turfgrasses may provide more cover for host-seeking B. occiduus than the non-stoloniferous species. Interestingly, two of these warm season grasses (St. Augustinegrass and bermudagrass) were neither highly preferred feeding or reproductive hosts  maybe an effective strategy for avoiding B. occiduus infestations. However, B. occiduus' potential to cause damage and reproduce on a wide variety of grass hosts must be considered, and the potential infestation of these alternative grasses should not be discounted especially where large areas of preferred hosts have become severely damaged by heavy infestations of B. occiduus.


We analysed the relation between coffee consumption and hepatocellular carcinoma in two case-control studies conducted between 1984 and 1998 in Italy and Greece, including 834 cases and 1912 controls. Compared to non coffee drinkers, the multivariate odds ratio was 0.7 for drinkers of three or more cups per day.British Journal of Cancer (2002) 87, 956–959. doi:10.1038/sj.bjc.6600582www.bjcancer.comCancer Research UK© 2002  The possible relation between coffee drinking and the risk of several cancers, particularly of cancers of the urinary bladder, pancreas and colorectum, has been widely investigated. These have shown a direct relation with bladder, an inverse one with colorectum, but no consistent association with other major sites, including liver cancer .Coffee drinking has been inversely related to the risk of liver cirrhosis in several studies  per day during the year before the onset of the index disease, and duration of the habit; the Greek study included three items for coffee consumption . For each item, the number of cups per week and the total duration of the habit (in years) were elicited. Total daily coffee consumption was computed summing up these three items.ORs and the corresponding 95% confidence intervals (CI) were derived from unconditional multiple logistic regression . All theTable 1P for trend <0.001). The inverse relation was consistent in the Italian and Greek datasets. After allowance for alcohol drinking, tobacco smoking and other potential confounding factors, these figures became 1.0 and 0.7, and the trend in risk with number of cups per day was significant. No association emerged with duration of coffee drinking, the OR being 0.8 for 40 years or more, compared to non coffee drinkers. When the reference category was set to subjects drinking ⩽1 cup per day, the multivariate ORs were 0.9 (95% CI: 0.7–1.1) for 2 and 0.7 (95% CI: 0.5–0.9) for ⩾3 cups per day.Table 2Table 3This combined re-analysis suggests that coffee is inversely related to the risk of liver cancer. Coffee consumption has been inversely related to γ-glutamyltransferase (GGT) activity in studies from Italy, Finland, France, Japan and the United States . Thus, iIn several case-control studies, coffee consumption showed an inverse association with the incidence or diagnosis of liver cirrhosis, with significant trends in risk with dose and duration (Weaknesses and strengths of the studies have been discussed elsewhere . BrieflyIn conclusion, the present study confirms in a large dataset the hypothesis of an inverse association between coffee drinking and liver cancer. However, the interpretation of this association and the consequent inference on causality remains open.


Previous studies have shown that tumour-suppressor genes play an important role in the progression of solid tumours. Recently, the p21WAF1/CIP1 tumour-suppressor protein has been reported to work as a critical downstream effector of p53 and a potent inhibitor of cyclin-dependent kinases. Thus, the p21WAF1/CIP1 gene is thought to play a central role in tumour suppression. In this study we investigated p21 protein expression in gastric carcinomas. A total of 172 primary gastric carcinoma specimens were immunohistochemically stained for p21 protein expression. Correlations between p21 expression and clinicopathological features were examined. Loss of p21 expression was observed in 104 of 172 tumour tissues (60.4%), and the frequency of p21 loss increased as the stage progressed. Expression of p21 in the primary tumour was frequently lost in patients with either lymph node, liver or peritoneal metastases as compared with patients without metastases. In patients with p21-negative tumours, the risk of recurrence following curative surgery was significantly higher, and the prognosis was significantly poorer than in patients with p21-positive tumours. Loss of p21 expression in primary gastric carcinoma correlates with disease progression. The status of p21 gene expression may have prognostic value in this disease.


Cytogenetic investigation was performed on direct preparations of 15 endometrial cancers showing different histotypes. Clonal abnormalities were found in 11 out of 13 analysable cases. The modal chromosome number was near diploid in all cases. The abnormal karyotypes contained relatively simple numerical or structural aberrations in the majority of tumours. In contrast, two neoplasms with serous papillary and mixed mullerian morphological features shared multiple complex changes as well as cytogenetic evidence of intratumoral heterogeneity. The most frequent chromosome abnormality in our series of endometrial neoplasms was 6q deletion, which was detected in serous papillary, endometrioid and mixed mullerian tumours. The loss of the 6q region, which is also frequently involved in ovarian carcinoma, suggests a relationship between endometrial and ovarian cancers based on a common histogenesis.


Numerical results as well as graphic display of NEAR OR and NEAR RR with their 95% CIs are easily obtained by downloading the freely available application offered at the following Web site: