bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pilot Pharmacokinetic Study of Human Immunodeficiency Virus-Infected Patients Receiving Tenofovir Disoproxil Fumarate (TDF): Investigation of Systemic and Intracellular Interactions between TDF and Abacavir, Lamivudine, or Lopinavir-Ritonavir
Authors: Pruvost Alain , Negredo Eugènia , Théodoro Frédéric , Puig Jordi , Levi Mikaël , Ayen Rafaela , Grassi Jacques , Clotet Bonaventura 
Published: March 2009

ABSTRACTPrevious work has demonstrated the existence of systemic interaction between tenofovir (TFV) disoproxil fumarate (TDF) and didanosine as well as between TDF and lopinavir-ritonavir (LPV/r). Here we investigated TDF interactions with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and abacavir (ABC), comparing both the concentrations of nucleoside/nucleotide reverse transcriptase inhibitors in plasma and the intracellular concentrations of their triphosphate metabolites (NRTI-TP) for human immunodeficiency virus-infected patients receiving these NRTIs with TDF and after 4 weeks of TDF interruption. We also looked at interactions between TDF-ABC and LPV/r, comparing patients receiving or not receiving LPV/r. Blood samples were taken at baseline and at 1, 2, and 4 h after dosing. Liquid chromatography-tandem mass spectrometry was used to measure NRTIs and NRTI-TPs. Statistical analyses were performed on pharmacokinetic parameters: the area under the concentration-time curve from 0 to 4 h (AUC0-4), the maximum concentration of the drug (Cmax), and the residual concentration of the drug at the end of the dosing interval (Ctrough) for plasma and the AUC0-4andCtroughfor intracellular data. Among the groups of patient discontinuing TDF, the very long intracellular half-life of elimination (150 h) of TFV-DP (the diphosphorylated metabolite of TFV, corresponding to a triphosphorylated species) was confirmed. Comparison between groups as well as the longitudinal study showed no significant systemic or intracellular interaction between TDF and ABC or 3TC. Significant differences were observed between patients receiving LVP/r and those receiving nevirapine. For ABC, plasma exposure was decreased (40%) under LVP/r, while, in contrast, plasma exposure to TFV was increased by 50% and the intracellular TFV-DP AUC0-4was increased by 59%. A trend for a gender effect was observed for TFV-DP at the intracellular level, with higher andCtroughvalues for women.
Immunoglobulin E (IgE) Responses to Paramyosin Predict Resistance to Reinfection withSchistosoma japonicumand Are Attenuated by IgG4
Authors: Jiz Mario , Friedman Jennifer F. , Leenstra Tjalling , Jarilla Blanca , Pablo Archie , Langdon Gretchen , Pond-Tor Sunthorn , Wu Hai-Wei , Manalo Daria , Olveda Remigio , Acosta Luz , Kurtis Jonathan D. 
Published: March 2009

ABSTRACTSchistosomiasis remains a public health concern in developing countries, and rapid reinfection fostered by continued exposure to contaminated water sources necessitates a vaccine to augment current mass treatment-based control strategies. We report isotype-specific (immunoglobulin A [IgA], IgE, IgG1, IgG4, and IgG) antibody responses to soluble worm antigen preparation and the recombinant vaccine candidates rSj97, rSj67, and rSj22 from aSchistosoma japonicum-infected cohort in Leyte, the Philippines, where schistosomiasis is endemic. Sera were collected from infected individuals 1 month posttreatment with praziquantel, and antibody responses were measured using a bead-based multiplex platform. Reinfection was monitored by stool sampling every 3 months, and data up to 1 year were included in the analysis (n= 553). In repeated-measures models, individuals with detectible IgE responses to rSj97 had a 26% lower intensity of reinfection at 12 months posttreatment compared to nonresponders after adjusting for age, gender, village, exposure, pretreatment infection intensity, and clustering by household (P= 0.018). In contrast, IgG4 responses to rSj97 as well as rSj67 and rSj22 were associated with markedly increased reinfection intensity. When stratified by IgG4 and IgE responder status, individuals with IgE but not IgG4 responses to rSj97 (n= 16) had a 77% lower intensity of reinfection at 12 months compared to individuals with IgG4 responses but not IgE responses (n= 274), even after adjusting for potential confounders (P= 0.016). Together with our previously described protective cytokine responses, these data further support paramyosin as a leading vaccine candidate for human schistosomiasis japonica and underscore the importance of careful adjuvant selection to avoid the generation of blocking IgG4 antibody responses.
Langerhans Cell Deficiency ImpairsIxodes scapularisSuppression of Th1 Responses in Mice
Authors: Vesely Diana L. , Fish Durland , Shlomchik Mark J. , Kaplan Daniel H. , Bockenstedt Linda K. 
Published: March 2009

ABSTRACTIxodes scapularisticks transmit a number of human pathogens, including the Lyme disease spirocheteBorrelia burgdorferi. I. scapularissuppresses host immunity in the skin to promote feeding and systemically skew T-helper (Th)-cell differentiation toward Th2 cells in secondary lymphoid organs. Although components of tick saliva are known to influence Th-cell polarization, the mechanism whereby tick feeding in the skin modulates regional and systemic Th-cell responses is unknown. In this study, the role of the epidermal Langerhans cell (LC) subset of skin dendritic cells in tick-mediated Th1/Th2-cell immunomodulation was assessed. Mice deficient in LCs (Langerin-DTA mice) exhibited enhanced lymph node (LN) concanavalin A (ConA)-induced Th1 responses after tick infestation in comparison to results for uninfested Langerin-DTA or wild-type (WT) mice, whereas effects on Th2-cell production of interleukin 4 were more variable. Nonetheless, the altered T-cell response did not impact tick feeding or refeeding. Gamma interferon production by ConA-stimulated LN cells of both WT and LC-deficient mice was enhanced by as much as fourfold afterB. burgdorferi-infected-tick feeding, indicating that immunomodulatory effects of tick saliva were not able to attenuate the Th1 immune responses induced by this pathogen. Taken together, these findings show a requirement for LCs in the tick-mediated attenuation of Th1 responses in regional lymph nodes but not in the spleens of mice and show that the presence of a pathogen can overcome the Th1-inhibitory effects of tick feeding on the host.
Anthrax Edema Toxin Induces Maturation of Dendritic Cells and Enhances Chemotaxis towards Macrophage Inflammatory Protein 3β
Authors: Maldonado-Arocho Francisco J. , Bradley Kenneth A. 
Published: March 2009

ABSTRACTBacillus anthracissecretes two bipartite toxins, edema toxin (ET) and lethal toxin (LT), which impair immune responses and contribute directly to the pathology associated with the disease anthrax. Edema factor, the catalytic subunit of ET, is an adenylate cyclase that impairs host defenses by raising cellular cyclic AMP (cAMP) levels. Synthetic cAMP analogues and compounds that raise intracellular cAMP levels lead to phenotypic and functional changes in dendritic cells (DCs). Here, we demonstrate that ET induces a maturation state in human monocyte-derived DCs (MDDCs) similar to that induced by lipopolysaccharide (LPS). ET treatment results in downregulation of DC-SIGN, a marker of immature DCs, and upregulation of DC maturation markers CD83 and CD86. Maturation of DCs by ET is accompanied by an increased ability to migrate toward the lymph node-homing chemokine macrophage inflammatory protein 3β, like LPS-matured DCs. Interestingly, cotreating with LT differentially affects the ET-induced maturation of MDDCs while not inhibiting ET-induced migration. These findings reveal a mechanism by which ET impairs normal innate immune function and may explain the reported adjuvant effect of ET.
Rehabilitation after anterior cruciate ligament injury influences joint loading during walking but not hopping
Authors: Risberg M A , Moksnes H , Storevold A , Holm I , Snyder-Mackler L 
Published: March 2009

Objective:The purpose of this study was to identify changes in clinical outcome and lower extremity biomechanics during walking and hopping in ACL-injured subjects before and after a 20-session neuromuscular and strength training programme.Study design:Pre and post experimental design.Setting:Outpatient clinic, primary care.Patients:32 subjects with unilateral ACL injury, mean 60 (SD 35) days after injury, with a mean age of 26.2 (5.4) years.Intervention:The rehabilitation programme consisted of neuromuscular and strength exercises.Main outcome measurements:Outcome measurements assessed before and after a 20-session rehabilitation programme were: self-assessment questionnaires (KOS-ADL, IKDC2000, Global function), four single-leg hop tests, and isokinetic muscle strength tests. Lower extremity kinematics and kinetics were captured during the stance phase of gait and landing after a single leg hop, synchronised with three force plates.Results:These ACL-injured individuals significantly improved their clinical outcome after rehabilitation. Gait analysis disclosed a significantly improved knee extension moment after rehabilitation, but no change in hip or knee excursions. During landing after hop no change in knee excursion or knee moment was recorded.Conclusion:After rehabilitation the ACL-injured subjects showed a significantly improved clinical outcome, but lower extremity biomechanics were still significantly impaired during both walking and hopping. The rehabilitation programme influenced knee joint loading during walking, but not during hopping. Longer rehabilitation should be considered before ACL-injured individuals return to jumping activities.
Dilip Roy at Itsun Heavy Industries India Pvt. Ltd. (IHIIPL)
Authors: Parikh Margie 
Published: March 2009

Dilip Roy is a country head at Itsun Heavy Industry (India) Pvt. Ltd. (IHIIPL) in Delhi, India. It is a wholly owned subsidiary of Itsun China, a leading private sector construction equipment company. Dilip graduated as a mechanical engineer with reputed National Science Talent Search Scholarship, started his career as a Graduate Trainee Engineer and became a Vice President in another company before he joined IHIIPL as a country head. Hu, the representative of Itsun China in India was exploring the Indian market and he ended up offering a job to Dilip after a series of interactions concerning the Indian Construction Equipment Industry. This was the first opportunity for Dilip to head an entire company. He knew the industry thoroughly and felt excited that finally his ambition was at the verge of fulfillment. When Dilip joined, IHIPL had yet to be incorporated though some business activities had started. Dilip's time at IHIIPL is dotted with problem after problem. The key problems encountered were confusion about reporting relationships, unresponsive head office with its unilateral decisions, and unprofessional and incompetent colleagues. Dilip had taken steps to address most of the company's problems: developing local solutions, drawing on personal resources, and hiring new staff. The business was growing fast on the back of increasing demand. Subsequently, Dilip realized that he was not considered trustworthy by the head office and was not involved in major decisions. His initial perception about his job and IHIIPL changed. Even though he was later given the certificate of honor with an invitation to attend the award ceremony in China, he left the company. This case is useful for examining the issues of cross-cultural management and leadership.
DMP
Authors: Devietti Joseph , Lucia Brandon , Ceze Luis , Oskin Mark 
Published: March 2009

Current shared memory multicore and multiprocessor systems are nondeterministic. Each time these systems execute a multithreaded application, even if supplied with the same input, they can produce a different output. This frustrates debugging and limits the ability to properly test multithreaded code, becoming a major stumbling block to the much-needed widespread adoption of parallel programming.
In this paper we make the case for fully deterministic shared memory multiprocessing (DMP). The behavior of an arbitrary multithreaded program on a DMP system is only a function of its inputs. The core idea is to make inter-thread communication fully deterministic. Previous approaches to coping with nondeterminism in multithreaded programs have focused on replay, a technique useful only for debugging. In contrast, while DMP systems are directly useful for debugging by offering repeatability by default, we argue that parallel programs should execute deterministically in the field as well. This has the potential to make testing more assuring and increase the reliability of deployed multithreaded software. We propose a range of approaches to enforcing determinism and discuss their implementation trade-offs. We show that determinism can be provided with little performance cost using our architecture proposals on future hardware, and that software-only approaches can be utilized on existing systems.
Mixed-mode multicore reliability
Authors: Wells Philip M. , Chakraborty Koushik , Sohi Gurindar S. 
Published: March 2009

Future processors are expected to observe increasing rates of hardware faults. Using Dual-Modular Redundancy (DMR), two cores of a multicore can be loosely coupled to redundantly execute a single software thread, providing very high coverage from many difference sources of faults. This reliability, however, comes at a high price in terms of per-thread IPC and overall system throughput.
We make the observation that a user may want to run both applications requiring high reliability, such as financial software, and more fault tolerant applications requiring high performance, such as media or web software, on the same machine at the same time. Yet a traditional DMR system must fully operate in redundant mode whenever any application requires high reliability.
This paper proposes a Mixed-Mode Multicore (MMM), which enables most applications, including the system software, to run with high reliability in DMR mode, while applications that need high performance can avoid the penalty of DMR. Though conceptually simple, two key challenges arise: 1) care must be taken to protect reliable applications from any faults occurring to applications running in high performance mode, and 2) the desire to execute additional independent software threads for a performance application complicates the scheduling of computation to cores. After solving these issues, an MMM is shown to improve overall system performance, compared to a traditional DMR system, by approximately 2X when one reliable and one performance application are concurrently executing.
Efficient online validation with delta execution
Authors: Tucek Joseph , Xiong Weiwei , Zhou Yuanyuan 
Published: March 2009

Software systems are constantly changing. Patches to fix bugs and patches to add features are all too common. Every change risks breaking a previously working system. Hence administrators loathe change, and are willing to delay even critical security patches until after fully validating their correctness. Compared to off-line validation, on-line validation has clear advantages since it tests against real life workloads. Yet unfortunately it imposes restrictive overheads as it requires running the old and new versions side-by-side. Moreover, due to spurious differences (e.g. event timing, random number generation, and thread interleavings), it is difficult to compare the two for validation.
To allow more effective on-line patch validation, we propose a new mechanism, called delta execution, that is based on the observation that most patches are small. Delta execution merges the two side-by-side executions for most of the time and splits only when necessary, such as when they access different data or execute different code. This allows us to perform on-line validation not only with lower overhead but also with greatly reduced spurious differences, allowing us to effectively validate changes.
We first validate the feasibility of our idea by studying the characteristics of 240 patches from 4 server programs; our examination shows that 77% of the changes should not be expected to cause large changes and are thereby feasible for Delta execution. We then implemented Delta execution using dynamic instrumentation. Using real world patches from 7 server applications and 3 other programs, we compared our implementation of Delta execution against a traditional side-by-side on-line validation. Delta execution outperformed traditional validation by up to 128%; further, for 3 of the changes, spurious differences caused the traditional validation to fail completely while Delta execution succeeded. This demonstrates that Delta execution can allow administrators to use on-line validation to confidently ensure the correctness of the changes they apply.
Dynamic prediction of collection yield for managed runtimes
Authors: Wegiel Michal , Krintz Chandra 
Published: March 2009

The growth in complexity of modern systems makes it increasingly difficult to extract high-performance. The software stacks for such systems typically consist of multiple layers and include managed runtime environments (MREs). In this paper, we investigate techniques to improve cooperation between these layers and the hardware to increase the efficacy of automatic memory management in MREs.
General-purpose MREs commonly implement parallel and/or concurrent garbage collection and employ compaction to eliminate heap fragmentation. Moreover, most systems trigger collection based on the amount of heap a program uses. Our analysis shows that in many cases this strategy leads to ineffective collections that are unable to reclaim sufficient space to justify the incurred cost. To avoid such collections, we exploit the observation that dead objects tend to cluster together and form large, never-referenced, regions in the address space that correlate well with virtual pages that have not recently been referenced by the application. We leverage this correlation to design a new, simple and light-weight, yield predictor that estimates the amount of reclaimable space in the heap using hardware page reference bits. Our predictor allows MREs to avoid low-yield collections and thereby improve resource management.
We integrate this predictor into three state-of-the-art parallel compactors, implemented in the HotSpot JVM, that represent distinct canonical heap layouts. Our empirical evaluation, based on standard Java benchmarks and open-source applications, indicates that inexpensive and accurate yield prediction can improve performance significantly.
How could MDMA (ecstasy) help anxiety disorders? A neurobiological rationale
Authors: Johansen PØ , Krebs TS 
Published: March 2009

Abstract Exposure therapy is known to be an effective treatment for anxiety disorders. Nevertheless, exposure is not used as much as it should be, and instead patients are often given supportive medications such as serotonin reuptake inhibitors (SSRIs) and benzodiazepines, which may even interfere with the extinction learning that is the aim of treatment. Given that randomized controlled trials are now investigating a few doses of ±3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) in combination with psychotherapy for treatment-resistant anxiety disorders, we would like to suggest the following three mechanisms for this potentially important new approach: 1) MDMA increases oxytocin levels, which may strengthen the therapeutic alliance; 2) MDMA increases ventromedial prefrontal activity and decreases amygdala activity, which may improve emotional regulation and decrease avoidance and 3) MDMA increases norepinephrine release and circulating cortisol levels, which may facilitate emotional engagement and enhance extinction of learned fear associations. Thus, MDMA has a combination of pharmacological effects that, in a therapeutic setting, could provide a balance of activating emotions while feeling safe and in control, as described in case reports of MDMA-augmented psychotherapy. Further clinical and preclinical studies of the therapeutic value of MDMA are indicated.
Maternal and foetal outcomes in pregnant patients with active lupus nephritis
Authors: Wagner SJ , Craici I , Reed D , Norby S , Bailey K , Wiste HJ , Wood CM , Moder KG , Liang KP , Liang KV , Rose C , Rozkos T , Sitina M , Grande JP , Garovic VD 
Published: March 2009

The objective of this study was to determine the impact of lupus nephritis disease activity on maternal and foetal outcomes in pregnant patients with systemic lupus erythematosus (SLE). Medical records of all pregnant patients with SLE treated at our institution between 1976 and 2007 were reviewed. All patients met American College of Rheumatology classification criteria for SLE. Demographic data, history of lupus nephritis, nephritis disease activity and maternal and foetal outcomes of pregnancy were abstracted. Active lupus nephritis was defined as the presence of proteinuria >0.5 g/day and/or active urinary sediment with or without an elevation in serum creatinine (Cr). Quiescent lupus nephritis was confirmed in the presence of proteinuria <0.5 mg/day and inactive urinary sediment. We identified 58 patients with 90 pregnancies. Compared with pregnancies in SLE patients without renal involvement ( n = 47), pregnancies in patients with active lupus nephritis ( n = 23) were associated with a higher incidence of maternal complications (57% vs 11%, P < 0.001), whereas those with quiescent lupus nephritis ( n = 20) were not (35% vs 11%, P = 0.10). Women with active lupus nephritis were more likely to deliver preterm than women without lupus nephritis, median of 34 weeks vs 40 gestational weeks, respectively ( P = 0.002) and were more likely to suffer foetal loss (35% vs 9%, P = 0.031). Active, but not quiescent, lupus nephritis during pregnancy is associated with a higher incidence of maternal and foetal complications compared with pregnancies in SLE patients without renal involvement.
CEACAM1+ myeloid cells control angiogenesis in inflammation
Authors: Horst Andrea K. , Bickert Thomas , Brewig Nancy , Ludewig Peter , van Rooijen Nico , Schumacher Udo , Beauchemin Nicole , Ito Wulf D. , Fleischer Bernhard , Wagener Christoph , Ritter Uwe 
Published: March 2009

AbstractLocal inflammation during cutaneous leishmaniasis is accompanied by accumulation of CD11b+ cells at the site of the infection. A functional role for these monocytic cells in local angiogenesis in leishmaniasis has not been described so far. Here, we show that CD11b+ cells express high levels of the myeloid differentiation antigen carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). In experimental cutaneous leishmaniasis in C57BL/6 wild-type (B6.WT) and B6.Ceacam1−/− mice, we found that only B6.Ceacam1−/− mice develop edemas and exhibit impairment of both hemangiogenesis and lymphangiogenesis. Because CEACAM1 expression correlates with functional angiogenesis, we further analyzed the role of the CD11b+ population. In B6.Ceacam1−/− mice, we found systemic reduction of Ly-6Chigh/CD11bhigh monocyte precursors. To investigate whether CEACAM1+ myeloid cells are causally related to efficient angiogenesis, we used reverse bone marrow transplants (BMTs) to restore CEACAM1+ or CEACAM1− bone marrow in B6.Ceacam1−/− or B6.WT recipients, respectively. We found that angiogenesis was restored by CEACAM1+ BMT only. In addition, we observed reduced morphogenic potential of inflammatory cells in Matrigel implants in CEACAM1− backgrounds or after systemic depletion of CD11bhigh macrophages. Taken together, we show for the first time that CEACAM1+ myeloid cells are crucial for angiogenesis in inflammation.