bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of the Anteromedial and Posterolateral Bundles of the Anterior Cruciate Ligament on External and Internal Tibiofemoral Rotation
Authors: Lorbach Olaf , Pape Dietrich , Maas Stefan , Zerbe Tina , Busch Luder , Kohn Dieter , Seil Romain
Published: March 2010

Background

The influence of the anteromedial and posterolateral bundles of the anterior cruciate ligament on tibiofemoral rotation might be of great value to detect anterior cruciate ligament injuries and investigate the postoperative restoration of rotational stability.

Hypothesis

The anterior cruciate ligament and especially the posterolateral bundle will have a significant influence on isolated tibiofemoral rotation.

Study Design

Controlled laboratory study.

Methods

Tibiofemoral rotation was measured in 20 human cadaveric knees using a noninvasive external measurement device (Rotameter) and a knee navigation system. The measurements of the knees with the intact anterior cruciate ligament were compared with the measurements after isolated resection of the posterolateral bundle and after a complete resection of the anterior cruciate ligament at an applied torque of 5,10, and 15 N·m. Statistical analysis was made using analysis of variance and the post hoc Scheffé test. The Pearson coefficient was used to compare both measurement techniques.

Results

In comparison with knees with an intact anterior cruciate ligament, the knees after isolated resection of the posterolateral bundle showed significant increase of tibiofemoral rotation at almost all applied torques (P < .05). Total resection of the anterior cruciate ligament also produced significant increases compared with the intact anterior cruciate ligament at torques of 5, 10, and 15 N·m as measured by the Rotameter (P < .05). Total resection of the anterior cruciate ligament yielded increases in rotation compared with posterolateral bundle resection alone, but these differences were not significant. The results of the knee navigation system confirmed the measured results of the Rotameter. Comparison of the 2 measurement methods revealed a high correlation at all applied torques, with Pearson correlation coefficients ranging from .85 to .95.

Conclusion

The anterior cruciate ligament and especially the posterolateral bundle of the anterior cruciate ligament have a significant effect on isolated tibiofemoral rotation. Therefore, the developed noninvasive device might be of great importance to investigate the status and the postoperative reconstruction of the anterior cruciate ligament in the clinical setting.

Clinical Relevance

Noninvasive measurement of tibiofemoral rotation might be useful to detect anterior cruciate ligament tears and to evaluate the restoration of rotational stability after anterior cruciate ligament surgery.
Transformative Learning in the Context of Suicide Bereavement
Authors: Sands Diana , Tennant Mark
Published: March 2010

This article examines the experience of suicide bereavement through the lens of transformative learning. Its purpose is twofold: first, to analyse the dynamics of the grieving process and the transformative experience of the bereaved; second, to use this analysis to draw implications for theory, practice, and research on transformative learning. It is a study of the way in which those bereaved by suicide construct meaning about the self-volition of the death and their ongoing relationships with the deceased, themselves, and significant others. In common with transformative learning, this quest for meaning proceeds through discourse, dialogue, and the re-storying past events and relationships. While the study illustrates the general thrust of transformative learning theory, it also highlights some of its limitations as it is commonly expressed and conducted. These limitations are discussed in relation to the tension between cognition and affect, the role of relationships, and underlying conceptions of the self.
Salicylic Acid-grafted Chitosan Oligosaccharide Nanoparticle for Paclitaxel Delivery
Authors: Wei Xiao-Hong , Niu Yang-Ping , Xu Yang-Yan , Du Yong-Zhong , Hu Fu-Qiang , Hong Yuan
Published: March 2010

A hydrotropic agent, salicylic acid (SA), was grafted to chitosan oligosaccharide (CSO) backbone to develop a CSO/SA conjugate. The CSO/SA self-assembled to form nanoparticles (NPs) in aqueous medium. The sizes of the NPs were smaller as more SA was grafted and when lower molecular weight CSO was used. The ζ-potentials of all CSO/SA NPs were above 40 mV. The critical aggregation concentrations of NPs decreased from 454.79 to 164.0 μg/mL by increasing the grafted SA content or the CSO Mw. Paclitaxel (PTX)-loaded NPs were prepared by a dialysis method; the particle sizes and ζ-potentials were smaller than the blank NPs. A series of PTX-loaded CSO28,000/SA50% NPs were prepared; as the size decreased or the drug content increased, the in vitro release rate increased. The in vitro cytotoxicity of blank CSO/SA NPs was determined using the MCF-7 cell line. The CSO/SA provides a new means of making a stable delivery for PTX.
Future Plans of Urban Youth: Influences, Perceived Barriers, and Coping Strategies
Authors: Howard Kimberly A. S. , Budge Stephanie L. , Gutierrez Belinda , Owen Amy D. , Lemke Nicholas , Jones Janice E. , Higgins Kory
Published: March 2010

This study examines the academic and career goals set by urban youth as well as their perceived career barriers and the strategies they anticipate using to face these barriers. Nine adolescents in the 11th and 12th grades from two large, urban public schools in the Midwest were interviewed for this study. Students’ responses were analyzed using the consensual qualitative research method developed by Hill and colleagues. Seven domains were identified in participant responses, addressing participant ideas about both ideal and alternate career choices, the influences on their career choices, potential obstacles in their future, and methods for managing obstacles. Categories and subcategories are described and discussed and implications for practice and future research are offered.
King George III and porphyria: a clinical re-examination of the historical evidence
Authors: Peters Timothy J , Wilkinson D.
Published: March 2010

The diagnosis that George III suffered from acute porphyria has gained widespread acceptance, but re-examination of the evidence suggests it is unlikely that he had porphyria.The porphyria diagnosis was advanced by Ida Macalpine and Richard Hunter, whose clinical symptomatology and historical methodology were flawed. They highlighted selected symptoms, while ignoring, dismissing or suppressing counter-evidence. Their claims about peripheral neuropathy, cataracts, vocal hoarseness and abdominal pains are re-evaluated; and it is also demonstrated that evidence of discoloured urine is exceedingly weak. Macalpine and Hunter believed that mental illnesses were primarily caused by physical diseases, and their diagnosis of George III formed part of a wider agenda to promote controversial views about past, contemporary and future methods in psychiatry.
Science and morals in the affective psychopathology of Philippe Pinel
Authors: Charland Louis C
Published: March 2010

Building on what he believed was a new ‘medico-philosophical’ method, Philippe Pinel made a bold theoretical attempt to find a place for the passions and other affective posits in psychopathology. However, his courageous attempt to steer affectivity onto the high seas of medical science ran aground on two great reefs that still threaten the scientific status of affectivity today. Epistemologically, there is the elusive nature of the signs and symptoms of affectivity. Ethically, there is the stubborn manner in which fact and value are intermingled in affectivity. Both obstacles posed insuperable difficulties for Pinel, who never really managed to extricate his affective psychopathology from the confines of the Lockean intellectual paradigm.
The work of John Hughlings Jackson: Part 1 by JM López Piñero
Authors: Berrios GE
Published: March 2010

After returning to Spain from a research period in London on a Wellcome Trust scholarship, José Maria López Piñero1 published in 1973 a short book entitled John Hughlings Jackson (1835—1911), Evolucionismo y Neurología (Madrid, Editorial Moneda). Written from the perspective of the classical German medical historiography that the author had imbibed from Werner Leibbrand and Annemarie Wettley, this work truly added to Jacksonian scholarship. Neither hagiographic nor nitpicking, it offered a sober assessment of the contribution of the great Yorkshireman and it was soon to become a minor classic among connoisseurs. Although important additions to Jacksonian scholarship have appeared since 1973,2 López Piñero’s book has retained its relevance. It will be published in History of Psychiatry in two parts.3
Protective effect of Thuja occidentalis against DMBA-induced breast cancer with reference to oxidative stress
Authors: Ojeswi BK , Khoobchandani M. , Hazra DK , Srivastava MM
Published: March 2010

In vivo experiment has been conducted to observe the preventive role of Thuja occidentalis Linn (leaves) against 7, 12 dimethylbenz(a)anthracene (DMBA)-induced mammary cancer. Ethyl acetate (EtOAc) and methanolic (MeOH) extracts in two doses (5 and 10 mg/kg body weight) of the plant were tested for DMBA-induced Indian Cancer Research Centre (ICRC) mice mammary carcinoma in terms of tumor weight, volume, life span, histological variation and oxidative stress against the reference drug doxorubicin using standard animal protocol. EtOAc extract (10 mg/kg body weight) of the plant exhibits reduction of tumor weight (39%), tumor volume (50%), reduced glutathione (GSH) (83%) and malignant cells compared to cancerous control group while the increase in body weight and life span in comparison with cancerous control and doxorubicin-treated group. EtOAc extract being most potent extract has been subjected to detailed chromatographic separation. The most potent chromatographic fraction exhibits the presence of flavonoidal unit. Structural elucidation of bioactive principle is in progress. It is inferred that the plant T. occidentalis (leaves) possess significant potential for phytopreventive bioefficacy against DMBA-induced mammary carcinogenesis.
Full recovery from a potentially lethal dose of orphenadrine ingestion using conservative treatment: A case report
Authors: Mao Yan-Chiao , Hung Dong-Zong , Yang Chen-Chang , Wang Jiaan-Der
Published: March 2010

Intoxication by orphenadrine is uncommon. The clinical features consist of both central and peripheral anticholinergic effects. Ingestion of 2 to 3 g orphenadrine in an adult has been associated with fatality. A 46-year-old female was brought to our emergency department 1.5 hours after ingesting 40 tablets of 100 mg orphenadrine. She became stuporous 3 hours post-ingestion and developed generalized convulsions 1 hour later. Fifty-five hours post-ingestion, she had recovered and was found to have anterior shoulder dislocation. In addition, severe rhabdomyolysis and persistent nausea were observed. All of the above-noted toxic effects resolved with conservative treatment. Although orphenadrine intoxication can cause convulsions and hemodynamic instability, there is no available antidote and treatment remains supportive.
A General Strain Theory of Prison Violence and Misconduct: An Integrated Model of Inmate Behavior
Authors: Blevins Kristie R. , Johnson Listwan Shelley , Cullen Francis T. , Lero Jonson Cheryl
Published: March 2010

Explanations of prison violence and other forms of misconduct have been dominated by three competing models: (a) the deprivation model, (b) the importation model, and (c) the coping model. We propose that these three seemingly competing models can be integrated within Agnew’s general strain theory (GST). GST enriches the deprivation model by revealing three distinctive categories of strain. GST encompasses the importation model in hypothesizing that criminal cultural values and affiliations will structure the response to the strains of imprisonment. And GST incorporates the coping model in its emphasis on how social support, social capital, and human capital can blunt the effects of potentially criminogenic strains. Finally, GST is sufficiently broad to include factors (e.g., emotions, self-control) in the explanation of prison maladjustment not covered by the three main models of prison inmate behavior. In short, GST offers a general integrated framework for reconceptualizing our understanding of prison violence and misconduct.
Verifying Theories of Language Acquisition Using Computer Models of Language Evolution
Authors: Vogt Paul , Lieven Elena
Published: March 2010

This article presents a dense database study of child language acquisition from a usage-based perspective and a new analysis of data from an earlier study on simulating language evolution. The new analysis is carried out to show how computer modeling studies can be designed to generate predictions (results) that can be compared quantitatively with empirical data obtained from the dense database studies. Although the comparison shows that the computer model in question is still far from realistic, the study illustrates how to carry out agent-based simulations of language evolution that allow quantitative verification of predictions with empirical data to validate theories on child language acquisition.
Pannexin-I/P2X 7 Purinergic Receptor Channels Mediate the Release of Cardioprotectants Induced by Ischemic Pre- and Postconditioning
Authors: Vessey Donald A. , Li Luyi , Kelley Michael
Published: March 2010

Ischemic pre- and postconditioning protect ex vivo rat hearts from ischemia/reperfusion injury by promoting the release of cardioprotective agents by an unknown mechanism. Because P2X 7 purinergic receptors are known to combine with pannexin-1 to form channels that allow adenosine triphosphate (ATP) release from cells, we hypothesized that these channels have a role in the release of multiple cardioprotectants during ischemic preconditioning (IPC). Addition of either a pannexin-1 hemichannel blocker (5 μmol/L carbenoxolone [CBX] or 0.4 μmol/L mefloquine [MF]) or a selective antagonist of the rat P2X7 purinergic receptor (2 μmol/L brilliant blue G [BBG]) blocked IPC. These antagonists also blocked ischemic postconditioning. Preconditioning by exogenous addition of either sphingosine-1-phosphate or adenosine was not blocked by either CBX or BBG, indicating that they only affected the release of endogenous mediators, not any subsequent steps. To determine if only ATP release was mediated by pannexin-1/P2X7 channels, we added an extra cycle of IPC to release sufficient quantities of additional cardioprotectants to eliminate the dependence on adenosine derivatives. This did not override the inhibition of IPC by CBX or MF, suggesting that the channel mediates the release of multiple cardioprotectants. Inhibitors of other P2X receptors, P2Y receptors, or connexins did not affect IPC. We conclude that a pannexin-1/P2X7 channel is responsible for the release of cardioprotectants induced by ischemic pre- and postconditioning.
Effects of Additional Administration of Low-Dose Indapamide on Patients With Hypertension Treated With Angiotensin II Receptor Blocker
Authors: Yamada Hirotsugu , Mishiro Yuichiro , Kusunose Kenya , Sata Masataka
Published: March 2010

Background: Low-dose thiazide or thiazide-like diuretics have proven useful for the management of blood pressure in patients older than 65 years (elderly group). However, there are few reports about the antihypertensive effects of antihypertensive diuretic agents in patients younger than 65 years (middle-aged group). So, we evaluated the efficacy of low-dose indapamide on blood pressure. Methods: Indapamide(1 mg) was given daily for 3 months and was then given every other day for 3 months to patients whose hypertension was poorly controlled with angiotensin II receptor blocker (ARB)-based treatment. Results: After daily administration of indapamide, blood pressure was significantly decreased in both the middle-aged and elderly groups. Blood pressure was not significantly changed by every-other-day administration compared with that observed after daily administration in either group. The rate of attainment of the target blood pressure was 90.3% and 85.7% in the middle-aged and elderly groups, respectively. The serum uric acid levels were reduced after every-other-day administration compared to daily administration but tended to be higher than the levels at the baseline in both groups. Conclusions: The addition of low-dose indapamide is a useful strategy for the management of hypertension, as it reduced blood pressure without marked side effects.
At the Intersection of Interpersonal Violence, Masculinity, and Alcohol Use: The Experiences of Heterosexual Male Perpetrators of Intimate Partner Violence
Authors: Peralta Robert L. , Tuttle Lori A. , Steele Jennifer L.
Published: March 2010

This article examines the relationship between violence, masculinity, and alcohol use among heterosexual, economically disadvantaged, and primarily Black men officially identified as batterers. Violence occurred against intimates and strangers. Alcohol use coupled with violence against intimates and violence against others (e.g., strangers) appeared to be used for masculinity construction. The use of alcohol before and during assaultive behavior combined with the use of violence symbolized dominance and control. This occurred in situations where markers of masculinity were largely absent (e.g., steady employment) in instances of both intimate partner violence and stranger violence.
Boosting endogenous neuroprotection in multiple sclerosis: the ASsociation of Inosine and Interferon β in relapsing- remitting Multiple Sclerosis (ASIIMS) trial
Authors: Gonsette Richard E , Sindic Christian , D'hooghe Marie B , De Deyn Peter-Paul , Medaer Robert , Michotte Alex , Seeldrayers Pierrette , Guillaume Daniel ,   ASIIMS study group
Published: March 2010

Anti-inflammatory drugs are effective on relapses, but neuroprotective agents to prevent disability are still unavailable. Uric acid has neuroprotective effects in experimental models including encephalomyelitis and appears to be involved in multiple sclerosis. Oral administration of inosine, a precursor of uric acid, increases serum uric acid levels and is well tolerated. Our objective was to test the possibility that a combination therapy associating an anti-inflammatory drug (interferon β) and an endogenous neuroprotective molecule (uric acid) would be more effective than interferon β alone on the accumulation of disability. Patients with relapsing—remitting multiple sclerosis on interferon β for at least 6 months were randomized to interferon β + inosine or interferon β + placebo for 2 years. The dose of inosine was adjusted to maintain serum uric acid levels in the range of asymptomatic hyperuricaemia (≤10 mg/dl). The primary end points were percentage of patients with progression of disability and time to sustained progression (Kaplan—Meier analysis). The combination of interferon β and inosine was safe and well tolerated but did not provide any additional benefit on accumulation of disability compared with interferon β alone. We conclude that endogenous neuroprotective mechanisms recently identified in multiple sclerosis are complex and uric acid does not reflect the entire story.
Rapid benefits of a new formulation of subcutaneous interferon beta-1a in relapsing—remitting multiple sclerosis
Authors: De Stefano Nicola , Curtin François , Stubinski Bettina , Blevins Gregg , Drulovic Jelena , Issard Delphine , Shotekov Penko , Gasperini Claudio , IMPROVE study investigators
Published: March 2010

This study evaluated the efficacy of a new formulation of subcutaneous (sc) interferon (IFN)-β1a in relapsing—remitting multiple sclerosis (RRMS). Patients ( n = 180) were randomized (2 : 1) to IFN-β1a or placebo for 16 weeks; all patients then received IFN-β1a for 24 weeks. Monthly brain MRI was performed. At week 16, the mean number of combined unique active (CUA) lesions was lower with IFN-β1a than with placebo ( p < 0.001; 69% fewer lesions). The mean cumulative number of CUA lesions was already lower with IFN-β1a by week 4 (post hoc analysis; p = 0.015). The new formulation of sc IFN-β1a has rapid beneficial effects on MRI outcomes in RRMS.
Can the Millennium Development Goals database be used to measure the effects of globalisation on women’s health in Sub-Saharan Africa? A critical analysis
Authors: Wamala Sarah , Breman Anna , Richardson Matt X. , Loewenson Rene
Published: March 2010

Background: Africa has had poor returns from integration with world markets in globalisation, has experienced worsening poverty and malnutrition and has high burdens of HIV and communicable disease, with particular burdens on women. It is therefore essential to describe the impact of globalisation on women’s health. Indicators such as the Millennium Development Goals (MDGs) are presented as having a major role in measuring this impact, but an assessment of the adequacy of aggregate national indicators used in monitoring the MDGs for this purpose is lacking. Methods: The Millennium Development Goals’ panel database 2000 to 2006 was used to investigate the association between globalisation and women’s health in Sub-Saharan Africa based on various determinants of heath. Out of the 148 countries classified as developing countries, 48 were in Sub-Saharan Africa. Results: Results suggest that developing countries are becoming more integrated with world markets through some lowering of trade barriers. At the same time, women’s occupational roles are changing, which could affect their health status. However, it is difficult to measure the impact of globalisation on women’s health from the MDG database. First, data on trade liberalization is aggregated at the regional level and does not hold any information on individual countries. Second, too few indicators in the MDG database are disaggregated by sex, making it difficult to separate the effects on women from those on men. Conclusions: The MDG database is not adequate to assess the effects of globalisation on women’s health in Sub-Saharan Africa. We recommend that researchers aim to address this research question to find other data sources or turn to case studies. We hope that results from this study will stimulate research on globalisation and health using reliable sources.
Calculation of the performance parameters of tungsten filament lamps using the exponent rules
Authors: Agrawal DC
Published: March 2010

The experimentally known values of the 14 exponents associated with the exponent-rules for vacuum and gas-filled tungsten filament lamps are utilized to obtain the temperature dependence of performance parameters such as power demand, lumen output, life and efficacy. It is also shown that the data on emissivity of tungsten reported by Jones and Langmuir are consistent with theory in contrast to those obtained by Roser and Wensel. Further, the analysis predicts a higher power loss factor and a longer life for gas-filled tungsten filament lamps than for vacuum lamps.
The revelations of investigative journalism in France
Authors: Marchetti Dominique
Published: March 2010

Since the 1970s and 1980s, national newspapers in France, both general and political, have regularly praised ‘investigative journalism’ and its role in unveiling ‘scandals’. To gain an understanding of how this new model of professional excellence arose, even though it concerns only a small number of journalists, we need to show the extent to which it is first of all largely symptomatic of a series of changes that have occurred outside the field of journalism, especially in the political and legal worlds, and in the relationships these spaces maintain with one another. In particular it is important to show that the media space has become highly strategic, notwithstanding its relative lack of autonomy. What is covered by the media is largely the outcome of power relations within different social spaces that are then translated in accordance with media processes. Thus ‘investigative journalism’ is often based less on journalists’ own investigations than on state-sponsored studies: reports, inquests, etc. The present article endeavours to show how and why these ‘scandals’ have been exposed only where such external changes have also found an echo in the field of general and political media nationally, in particular among a group of politicized journalists who constitute a new specialist field within the profession. The rise of ‘investigative journalism’ and its successful profile in the discourse of the profession both result from and reveal transformations affecting the whole space of journalism.
Hezbollah’s Media
Authors: Lamloum Olfa
Published: March 2010

Since 1985, the Lebanese Hezbollah has developed a centralized communications apparatus which was a major instrument in building its leadership in the Shiite community. My contribution intends to explore the main media of this party as both cognitive and political resources for mobilization and as spaces for the involvement of its activists, sympathizers and cadres. In doing so, it revisits the social history of this political formation and examines its modes of organization and related tensions.
Influence of metabolic syndrome on risk stratification in hypertensive patients: differences between 2003 and 2007 ESH-ESC guidelines
Authors: Martell Nieves , Alvarez-Alvarez Beatriz , Fernandez-Cruz Arturo
Published: March 2010

Objective: To investigate the influence of metabolic syndrome (MS) on risk stratification and ulterior classification in hypertensive patients at entry into a hypertension unit by comparing the criteria of ESH-ESC 2003 and 2007 guidelines.

Methods: 720 consecutive patients attending a hospital-located hypertension unit were included in the study. They were classified with or without MS according to the ATP-III 2005 report. Patients underwent repeated office BP measurements and routine blood/urine examinations. In addition ultrasensitive CRP (uCRP), echocardiogram, fasting insulin, urinary albumin excretion were determined and HOMA index was calculated.

Results: The prevalence of MS was 58.8 %. Abdominal obesity and fasting glucose were the most prevalent components of MS, and HDL-cholesterol the least prevalent. MS group had higher levels of LDL-cholesterol and higher prevalence of left ventricular hypertrophy and microalbuminuria. Patients with MS also presented a significant elevation in uCRP, fasting insulin and HOMA. BP was controlled in 55.6%. When we applied the 2003 guideline, 48.9% patients showed a high or very high added cardiovascular risk. With the applications of the 2007 guide the prevalence of this two categories reach 73.9%.

Conclusions: A significant difference in the risk pattern distribution is found when MS is considered in risk stratification in our hypertensive population. The accompanying increase in the levels of other cardiovascular risk factors and in the prevalence of target organ damage justifies the global intervention on cardiovascular risk recommended by 2007 ESH-ESC guidelines.
β-blockers and risk of all-cause mortality in non-cardiac surgery
Authors: Angeli Fabio , Verdecchia Paolo , Karthikeyan Ganesan , Mazzotta Giovanni , Repaci Salvatore , del Pinto Maurizio , Gentile Giorgio , Cavallini Claudio , Reboldi Gianpaolo
Published: March 2010

Myocardial ischemia is a frequent complication in patients undergoing non-cardiac surgery and β-blockers may exert a protective effect. The main benefit of β-blockers in perioperative cardiovascular morbidity and mortality is believed to be linked to specific effects on myocardial oxygen supply and demand. β-blockers may exert anti-inflammatory and anti-arrhythmic effects. Randomized clinical trials which evaluated the effects of β-blockers on all-cause mortality in patients undergoing non-cardiac surgery have yielded conflicting results. In 9 trials, 10,544 patients with non-cardiac surgery were randomized to β-blockers (n = 5274) or placebo (n = 5270) and there were a total of 304 deaths. Patients randomized to β-blockers group showed a 19% increased risk of all-cause mortality (odds ratio [OR] 1.19, 95% confidence interval (CI) 0.95-1.50; p = 0.135). However, trials included in the meta-analysis differed in several aspects, and a significant degree of heterogeneity (I 2 = 46.5%) was noted. A recent analysis showed that the surgical risk category had a substantial influence on the overall estimate of the effect of β-blockers. Compared with patients in the intermediate-high-surgical-risk category, those in the high-risk category showed a 73% reduction in the risk of total mortality with β-blockers compared with placebo (OR 0.27, 95% CI 0.10-0.71, p = 0.016). These data suggest that perioperative β-blockers confer a benefit which is mostly limited to patients undergoing high-risk surgery.
Palmitoylation of oncogenic NRAS is essential for leukemogenesis
Authors: Cuiffo Benjamin , Ren Ruibao
Published: March 2010

Activating mutations of NRAS are common in acute myeloid leukemia, chronic myelomonocytic leukemia, and myelodysplastic syndrome. Like all RAS proteins, NRAS must undergo a series of post-translational modifications for differential targeting to distinct membrane subdomains. Although farnesylation is the obligatory first step in post-translational modifications of RAS, to date, successes of therapies targeting farnesyl protein transferase are modest. Other RAS modifications, such as palmitoylation, are required for optimal plasma membrane association of RAS proteins. However, the relative importance of these latter modifications of RAS in leukemogenesis is not clear. We have previously shown that expression of oncogenic NRAS using a bone marrow transduction and transplantation model efficiently induces a chronic myelomonocytic leukemia- or acute myeloid leukemia-like disease in mice. Here we examined the role of palmitoylation in NRAS leukemogenesis using this model. We found that palmitoylation is essential for leukemogenesis by oncogenic NRAS. We also found that farnesylation is essential for NRAS leukemogenesis, yet through a different mechanism from that of palmitoylation deficiency. This study demonstrates, for the first time, that palmitoylation is an essential process for NRAS leukemogenesis and suggests that the development of therapies targeting RAS palmitoylation may be effective in treating oncogenic NRAS-associated malignancies.
Human embryonic stem cells: a source of mast cells for the study of allergic and inflammatory diseases
Authors: Kovarova Martina , Latour Anne M. , Chason Kelly D. , Tilley Stephen L. , Koller Beverly H.
Published: March 2010

Human mast cells are tissue resident cells with a principal role in allergic disorders. Cross-linking of the high-affinity receptor for immunoglobulin E (FcϵRI) results in release of inflammatory mediators initiating the clinical symptoms of allergy and anaphylaxis. Much of our knowledge regarding the mechanisms of mast cell activation comes from studies of mouse bone marrow–derived mast cells. However, clear differences have been identified between human and mouse mast cells. Studies of human mast cells are hampered by the limited sources available for their isolation, the resistance of these cells to genetic manipulation, and differences between cultures established from different persons. To address this limitation, we developed a simple coculture-free method for obtaining mast cells from human embryonic stem cells (hES). These hES-derived mast cells respond to antigen by releasing mast cell mediators. Moreover, the cells can be generated in numbers sufficient for studies of the pathways involved in their effector functions. Genetically modified mast cells, such as GFP-expressing cells, can be obtained by introduction and selection for modification in hES cells before differentiation. This direct coculture-free differentiation of hES cells represents a new and unique model to analyze the function and development of human mast cells.
Bortezomib modulates surface CD20 in B-cell malignancies and affects rituximab-mediated complement-dependent cytotoxicity
Authors: Bil Jacek , Winiarska Magdalena , Nowis Dominika , Bojarczuk Kamil , Dąbrowska-Iwanicka Anna , Basak Grzegorz W. , Sułek Kazimierz , Jakobisiak Marek , Golab Jakub
Published: March 2010

Unresponsiveness to rituximab treatment develops in many patients prompting elucidation of underlying molecular pathways. It was recently observed that rituximab-resistant lymphoma cells exhibit up-regulation of components of the ubiquitin-proteasome system (UPS). Therefore, we investigated in more detail the role of this system in the regulation of CD20 levels and the influence of proteasome inhibitors on rituximab-mediated complement-dependent cytotoxicity (R-CDC). We observed that incubation of Raji cells with rituximab leads to increased levels of ubiquitinated CD20. However, inhibition of the UPS was not associated with up-regulation of surface CD20 levels, although it significantly increased its ubiquitination. Short-term (24 hours) incubation of Raji cells with 10 or 20nM bortezomib did not change surface CD20 levels, but sensitized CD20+ lymphoma cells to R-CDC. Prolonged (48 hours) incubation with 20nM bortezomib, or incubation with 50nM bortezomib for 24 hours led to a significant decrease in surface CD20 levels as well as R-CDC. These effects were partly reversed by bafilomycin A1, an inhibitor of lysosomal/autophagosomal pathway of protein degradation. These studies indicate that CD20 levels are regulated by 2 proteolytic systems and that the use of proteasome inhibitors may be associated with unexpected negative influence on R-CDC.
Platelet interleukin-1α drives cerebrovascular inflammation
Authors: Thornton Peter , McColl Barry W. , Greenhalgh Andrew , Denes Adam , Allan Stuart M. , Rothwell Nancy J.
Published: March 2010

White blood cell infiltration across an activated brain endothelium contributes to neurologic disease, including cerebral ischemia and multiple sclerosis. Identifying mechanisms of cerebrovascular activation is therefore critical to our understanding of brain disease. Platelet accumulation in microvessels of ischemic mouse brain was associated with endothelial activation in vivo. Mouse platelets expressed interleukin-1α (IL-1α), but not IL-1β, induced endothelial cell adhesion molecule expression (ICAM-1 and VCAM-1), and enhanced the release of CXC chemokine CXCL1 when incubated with primary cultures of brain endothelial cells from wild-type or IL-1α/β–deficient mice. A neutralizing antibody to IL-1α (but not IL-1β) or application of IL-1 receptor antagonist inhibited platelet-induced endothelial activation by more than 90%. Platelets from IL-1α/β–deficient mice did not induce expression of adhesion molecules in cerebrovascular endothelial cells and did not promote CXCL1 release in vitro. Conditioned medium from activated platelets induced an IL-1α–dependent activation of mouse brain endothelial cells and supported the transendothelial migration of neutrophils in vitro. Thus, we have identified platelets as a key source of IL-1α and propose that platelet activation of brain endothelium via IL-1α is a critical step for the entry of white blood cells, major contributors to inflammation-mediated injury in the brain.
Promiscuity of enhancer, coding and non-coding transcription functions in ultraconserved elements
Authors: Licastro Danilo , Gennarino Vincenzo A , Petrera Francesca , Sanges Remo , Banfi Sandro , Stupka Elia
Published: March 2010

Background

Ultraconserved elements (UCEs) are highly constrained elements of mammalian genomes, whose functional role has not been completely elucidated yet. Previous studies have shown that some of them act as enhancers in mouse, while some others are expressed in both normal and cancer-derived human tissues. Only one UCE element so far was shown to present these two functions concomitantly, as had been observed in other isolated instances of single, non ultraconserved enhancer elements.

Results

We used a custom microarray to assess the levels of UCE transcription during mouse development and integrated these data with published microarray and next-generation sequencing datasets as well as with newly produced PCR validation experiments. We show that a large fraction of non-exonic UCEs is transcribed across all developmental stages examined from only one DNA strand. Although the nature of these transcripts remains a mistery, our meta-analysis of RNA-Seq datasets indicates that they are unlikely to be short RNAs and that some of them might encode nuclear transcripts. In the majority of cases this function overlaps with the already established enhancer function of these elements during mouse development. Utilizing several next-generation sequencing datasets, we were further able to show that the level of expression observed in non-exonic UCEs is significantly higher than in random regions of the genome and that this is also seen in other regions which act as enhancers.

Conclusion

Our data shows that the concurrent presence of enhancer and transcript function in non-exonic UCE elements is more widespread than previously shown. Moreover through our own experiments as well as the use of next-generation sequencing datasets, we were able to show that the RNAs encoded by non-exonic UCEs are likely to be long RNAs transcribed from only one DNA strand.
Subarachnoidal Neurocysticercosis non-responsive to cysticidal drugs: a case series
Authors: Cárdenas Graciela , Carrillo-Mezo Roger , Jung Helgi , Sciutto Edda , Hernandez Jose Luis Soto , Fleury Agnès
Published: March 2010

Background

Neurocysticercosis (NC) is one of the most frequent parasitic diseases of the central nervous system. Cysticidal drugs, albendazole and praziquantel, are generally effective when parasites localize in the parenchyma. In contrast, parasites lodged in the subarachnoid basal cisterns are less responsive to treatment.

Case Presentation

The clinical and radiological pictures of six Mexican patients non-respondent to cysticidal treatment are presented.

Conclusions

The possible factors involved in the cysticidal non-response are discussed and hints are provided of potentially useful changes to therapeutic protocols.
Origin of measles virus: divergence from rinderpest virus between the 11th and 12th centuries
Authors: Furuse Yuki , Suzuki Akira , Oshitani Hitoshi
Published: March 2010

Measles, caused by measles virus (MeV), is a common infection in children. MeV is a member of the genusMorbillivirusand is most closely related to rinderpest virus (RPV), which is a pathogen of cattle. MeV is thought to have evolved in an environment where cattle and humans lived in close proximity. Understanding the evolutionary history of MeV could answer questions related to divergence times of MeV and RPV.

We investigated divergence times using relaxed clock Bayesian phylogenetics. Our estimates reveal that MeV had an evolutionary rate of 6.0 - 6.5 × 10-4substitutions/site/year. It was concluded that the divergence time of the most recent common ancestor of current MeV was the early 20thcentury. And, divergence between MeV and RPV occurred around the 11thto 12thcenturies. The result was unexpected because emergence of MeV was previously considered to have occurred in the prehistoric age.

MeV may have originated from virus of non-human species and caused emerging infectious diseases around the 11thto 12thcenturies. In such cases, investigating measles would give important information about the course of emerging infectious diseases.
Increased hematogones in an infant with bicytopenia and leucocytosis:a case report
Authors: Agarwal Kiran , Aggarwal Meenu , Aggarwal Vikas Kumar , Pujani Meenu , Nain Manupriya
Published: March 2010

Hematogones are the normal bone marrow constituents of bone marrow in children and their number decreases with age. As hematogones can resemble malignant lymphoblasts by their morphologic features and by expression of an immature B-cell phenotype, an accurate distinction of hematogone-rich lymphoid regeneration from leukemic lymphoblasts is critical for patient care. The increased number of hematogones had been reported in the bone marrow of children recovering from chemotherapy, aplastic conditions, other forms of bone marrow injury, infections like Cytomegalovirus, HIV and immune thrombocytopenia disorders. We describe here a case of one and half month old male infant with bicytopenia and leucocytosis associated with increased hematogones in the bone marrow due to an unknown probable viral infection.
Gram-negative bacteremia induces greater magnitude of inflammatory response than Gram-positive bacteremia
Authors: Abe Ryuzo , Oda Shigeto , Sadahiro Tomohito , Nakamura Masataka , Hirayama Yo , Tateishi Yoshihisa , Shinozaki Koichiro , Hirasawa Hiroyuki
Published: March 2010

Introduction

Bacteremia is recognized as a critical condition that influences the outcome of sepsis. Although large-scale surveillance studies of bacterial species causing bacteremia have been published, the pathophysiological differences in bacteremias with different causative bacterial species remain unclear. The objective of the present study is to investigate the differences in pathophysiology and the clinical course of bacteremia caused by different bacterial species.

Methods

We reviewed the medical records of all consecutive patients admitted to the general intensive care unit (ICU) of a university teaching hospital during the eight-year period since introduction of a rapid assay for interleukin (IL)-6 blood level to routine ICU practice in May 2000. White blood cell count, C-reactive protein (CRP), IL-6 blood level, and clinical course were compared among different pathogenic bacterial species.

Results

The 259 eligible patients, as well as 515 eligible culture-positive blood samples collected from them, were included in this study. CRP, IL-6 blood level, and mortality were significantly higher in the septic shock group (n = 57) than in the sepsis group (n = 127) (P < 0.001). The 515 eligible culture-positive blood samples harbored a total of 593 isolates of microorganisms (Gram-positive, 407; Gram-negative, 176; fungi, 10). The incidence of Gram-negative bacteremia was significantly higher in the septic shock group than in the sepsis group (P < 0.001) and in the severe sepsis group (n = 75, P < 0.01). CRP and IL-6 blood level were significantly higher in Gram-negative bacteremia (n = 176) than in Gram-positive bacteremia (n = 407) (P < 0.001, <0.0005, respectively).

Conclusions

The incidence of Gram-negative bacteremia was significantly higher in bacteremic ICU patients with septic shock than in those with sepsis or severe sepsis. Furthermore, CRP and IL-6 levels were significantly higher in Gram-negative bacteremia than in Gram-positive bacteremia. These findings suggest that differences in host responses and virulence mechanisms of different pathogenic microorganisms should be considered in treatment of bacteremic patients, and that new countermeasures beyond conventional antimicrobial medications are urgently needed.
Leukocyte function in the aging immune system
Authors: Desai Anjali , Grolleau-Julius Annabelle , Yung Raymond
Published: March 2010

Review of the current understanding of age-dependent changes in leukocyte function and their contribution to aging-related disease processes.

Aging is associated with a progressive dysregulation of immune responses. Whether these changes are solely responsible for the observed increased mortality and morbidity amongst the elderly is uncertain. Recent advances have highlighted the age-associated changes that occur beyond T and B lymphocytes. Additionally, multiple human and animal studies have identified a relationship between chronic low-grade inflammation and geriatric syndromes, such as frailty, suggesting that the phenomenon of “inflamm-aging” may provide a rationale for the increased vulnerability to chronic inflammatory diseases in older adults. In the present review, we broadly summarize our current understanding of age-dependent changes in leukocyte function and their contribution to aging-related disease processes.
MAPK-directed phosphatases preferentially regulate pro- and anti-inflammatory cytokines in experimental visceral leishmaniasis: involvement of distinct protein kinase C isoforms
Authors: Kar Susanta , Ukil Anindita , Sharma Gunjan , Das Pijush K
Published: March 2010

MAP kinase-directed phosphatases in the disease progression of leishmaniasis have a role in modulation of cytokine balance and iNOS expression.

The role of phosphatases in the impairment of MAPK signaling, which is directly responsible for Leishmania-induced macrophage dysfunction, is still poorly understood. Gene expression profiling revealed that Leishmania donovani infection markedly up-regulated the expression of three phosphatases: MKP1, MKP3, and PP2A. Inhibition of these phosphatases prior to infection points toward preferential induction of the Th2 response through deactivation of p38 by MKP1. On the other hand, MKP3 and PP2A might play significant roles in the inhibition of iNOS expression through deactivation of ERK1/2. Among various PKC isoforms, PKCζ was associated with induction of MKP3 and PP2A in infected macrophages, whereas PKCε was correlated with MKP1 induction. Inhibition of phosphatases in L. donovani-infected BALB/c mice shifted the cytokine balance in favor of the host by inducing TNF-α and iNOS expression. This was validated by cystatin, an immunomodulator and curing agent for experimental visceral leishmaniasis, which showed that inhibition of MKPs and PP2A activity may be necessary for a favorable T cell response and suppression of organ parasite burden. This study, for the first time, suggests the possibility of the involvement of MAPK-directed phosphatases in the establishment of L. donovani infection.
Apoptosis signal-regulating kinase 1 in peptidoglycan-induced COX-2 expression in macrophages
Authors: Hsu Ming-Jen , Chang Chia-Kai , Chen Mei-Chieh , Chen Bing-Chang , Ma Hon-Ping , Hong Chuang-Ye , Lin Chien-Huang
Published: March 2010

PGN activates TLR2-mediated PP2A-ASK1-JNK-AP-1-C/EBPβ cascade and subsequent COX-2 expression in macrophages.

In this study, we investigated the role of ASK1 in PGN-induced C/EBPβ activation and COX-2 expression in RAW 264.7 macrophages. The PGN-induced COX-2 expression was attenuated by the DNs of ASK1, JNK1, JNK2, a JNK inhibitor (SP600125), and an AP-1 inhibitor (curcumin). PGN caused ASK1 dephosphorylation time-dependently at Ser967, dissociation from the ASK1-14-3-3 complex, and subsequent ASK1 activation. In addition, PGN activated PP2A and suppression of PP2A by okadaic acid markedly inhibited PGN-induced ASK1 Ser967 dephosphorylation and COX-2 expression. PGN induced the activation of the JNK-AP-1 signaling cascade downstream of ASK1. PGN-increased C/EBPβ expression and DNA-binding activity were inhibited by the ASK1-JNK-AP-1 signaling blockade. COX-2 promoter luciferase activity induced by PGN was attenuated in cells transfected with the COX-2 reporter construct possessing the C/EBP-binding site mutation. In addition, the ASK1-JNK-AP-1-C/EBPβ cascade was activated in human peripheral mononuclear cells exposure to PGN. The TLR2 agonist Pam3CSK4 was also shown to induce ASK1 Ser967 dephosphorylation, JNK and c-jun phosphorylation, C/EBPβ activation, and COX-2 expression in RAW 264.7 macrophages. PGN-induced COX-2 promoter luciferase activity was prevented by selective inhibition of TLR2 and c-Jun in RAW 264.7 macrophages. Our data demonstrate that PGN might activate the TLR2-mediated PP2A-ASK1-JNK-AP-1-C/EBPβ cascade and subsequent COX-2 expression in RAW 264.7 macrophages.