bluuebunny/crossref_metadata_2025 huggingface dataset:
Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy
Authors: Quintás-Cardama Alfonso , Kantarjian Hagop , Jones Dan , Shan Jianqin , Borthakur Gautam , Thomas Deborah , Kornblau Steven , O'Brien Susan , Cortes Jorge
Published: April 2009

Patients not in complete cytogenetic response (CCyR) continuously face the competing possibilities of eventually achieving a cytogenetic response versus progressing. We analyzed the probability of achieving a CCyR, major molecular response, and progression in 258 patients with chronic myeloid leukemia in early chronic phase at 3, 6, and 12 months from imatinib start. The initial imatinib dose was 800 mg/day in 208 (81%) and 400 mg/day in 50 (19%) patients. For patients not in CCyR, the probability of achieving CCyR (P = .002) or major molecular response (P = .004) significantly decreased, whereas the risk of progression increased (P = .16) at each time point. Patients with a BCR-ABL1/ABL1 ratio greater than 1% to 10% after 3 months of imatinib had a 92% probability of achieving CCyR with continued therapy, similar to the 98% for those with 1% or less, but their risk of progression (11%) was almost 3-fold that of patients with a BCR-ABL1/ABL1 transcript ratio of 1% or less (4%) and similar to that of patients with transcript levels more than 10% (13%). These results suggest that patients not in CCyR after 12 months on imatinib have a higher risk of progression. This risk is discernible as early as 3 months into imatinib therapy by molecular analysis and may provide the rationale to institute therapies that render higher rates of early response.
Invariant natural killer T cell–natural killer cell interactions dictate transplantation outcome after α-galactosylceramide administration
Authors: Kuns Rachel D. , Morris Edward S. , MacDonald Kelli P. A. , Markey Kate A. , Morris Helen M. , Raffelt Neil C. , Banovic Tatjana , Don Alistair L. J. , Rowe Vanessa , Burman Angela C. , Clouston Andrew D. , Farah Camile , Besra Gurdyal S. , Illarionov Petr A. , Smyth Mark J. , Porcelli Steven A. , Hill Geoffrey R.
Published: April 2009

Invariant natural killer T cells (iNKT cells) have pivotal roles in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects. iNKT cells are activated through their T-cell receptors by glycolipid moieties (typically the α-galactosylceramide [α-GalCer] derivative KRN7000) presented within CD1d. We investigated the ability of modified α-GalCer molecules to differentially modulate alloreactivity and GVL. KRN7000 and the N-acyl variant, C20:2, were administered in multiple well-established murine models of allogeneic stem cell transplantation. The highly potent and specific activation of all type I NKT cells with C20:2 failed to exacerbate and in most settings inhibited GVHD late after transplantation, whereas effects on GVL were variable. In contrast, the administration of KRN7000 induced hyperacute GVHD and early mortality in all models tested. Administration of KRN7000, but not C20:2, was found to result in downstream interleukin (IL)-12 and dendritic cell (DC)–dependent natural killer (NK)– and conventional T-cell activation. Specific depletion of host DCs, IL-12, or donor NK cells prevented this pathogenic response and the induction of hyperacute GVHD. These data demonstrate the ability of profound iNKT activation to modulate both the innate and adaptive immune response via the DC–NK-cell interaction and raise concern for the use of α-GalCer therapeutically to modulate GVHD and GVL effects.
Rational combined targeting of phosphodiesterase 4B and SYK in DLBCL
Authors: Kim Sang-Woo , Rai Deepak , McKeller Morgan R. , Aguiar Ricardo C. T.
Published: April 2009

Identification of rational therapeutic targets is an important strategy to improve the cure rate of diffuse large B-cell lymphoma (DLBCL). We previously showed that inhibition of the phosphodiesterase 4B (PDE4B) unleashes cyclic-AMP (cAMP) inhibitory effects toward the PI3K/AKT pathway and induces apoptosis. These data raised important considerations as to which upstream regulators mediate cAMP inhibition of PI3K/AKT, and how identifying this signaling route could be translated into clinical initiatives. We found that in normal and malignant B cells, cAMP potently inhibit the phosphorylation and activity of the tyrosine kinase SYK. Using genetic models of gain- and loss-of-function, we demonstrated the essential role for PDE4B in controlling these effects in DLBCL. Furthermore, we used a constitutively active SYK mutant to confirm its central role in transducing cAMP effects to PI3K/AKT. Importantly, given SYK credentials as a therapeutic target in B-cell tumors, we explored the role of PDE4B in these responses. In multiple DLBCL models, we found that genetically, hence specifically, inhibiting PDE4B expression significantly improved the efficacy of SYK inhibitors. Our data defined a hitherto unknown role for cAMP in negatively regulating SYK and indicate that combined inhibition of PDE4B and SYK should be actively pursued.
Estimating accuracy of RNA-Seq and microarrays with proteomics
Authors: Fu Xing , Fu Ning , Guo Song , Yan Zheng , Xu Ying , Hu Hao , Menzel Corinna , Chen Wei , Li Yixue , Zeng Rong , Khaitovich Philipp
Published: April 2009

Background

Microarrays revolutionized biological research by enabling gene expression comparisons on a transcriptome-wide scale. Microarrays, however, do not estimate absolute expression level accurately. At present, high throughput sequencing is emerging as an alternative methodology for transcriptome studies. Although free of many limitations imposed by microarray design, its potential to estimate absolute transcript levels is unknown.

Results

In this study, we evaluate relative accuracy of microarrays and transcriptome sequencing (RNA-Seq) using third methodology: proteomics. We find that RNA-Seq provides a better estimate of absolute expression levels.

Conclusion

Our result shows that in terms of overall technical performance, RNA-Seq is the technique of choice for studies that require accurate estimation of absolute transcript levels.
Evolution of alternative and constitutive regions of mammalian 5'UTRs
Authors: Resch Alissa M , Ogurtsov Aleksey Y , Rogozin Igor B , Shabalina Svetlana A , Koonin Eugene V
Published: April 2009

Background

Alternative splicing (AS) in protein-coding sequences has emerged as an important mechanism of regulation and diversification of animal gene function. By contrast, the extent and roles of alternative events including AS and alternative transcription initiation (ATI) within the 5'-untranslated regions (5'UTRs) of mammalian genes are not well characterized.

Results

We evaluated the abundance, conservation and evolution of putative regulatory control elements, namely, upstream start codons (uAUGs) and open reading frames (uORFs), in the 5'UTRs of human and mouse genes impacted by alternative events. For genes with alternative 5'UTRs, the fraction of alternative sequences (those present in a subset of the transcripts) is much greater than that in the corresponding coding sequence, conceivably, because 5'UTRs are not bound by constraints on protein structure that limit AS in coding regions. Alternative regions of mammalian 5'UTRs evolve faster and are subject to a weaker purifying selection than constitutive portions. This relatively weak selection results in over-abundance of uAUGs and uORFs in the alternative regions of 5'UTRs compared to constitutive regions. Nevertheless, even in alternative regions, uORFs evolve under a stronger selection than the rest of the sequences, indicating that some of the uORFs are conserved regulatory elements; some of the non-conserved uORFs could be involved in species-specific regulation.

Conclusion

The findings on the evolution and selection in alternative and constitutive regions presented here are consistent with the hypothesis that alternative events, namely, AS and ATI, in 5'UTRs of mammalian genes are likely to contribute to the regulation of translation.
Moyamoya disease: A clinical spectrum, literature review and case series from a tertiary care hospital in Pakistan
Authors: Shoukat Sana , Itrat Ahmed , Taqui Ather M , Zaidi Moazzam , Kamal Ayeesha K
Published: April 2009

Background

Moyamoya is a rare cerebrovascular disease of unknown etiology. The data on moyamoya disease from Pakistan is sparse. We report a case series of 13 patients who presented with moyamoya disease to a tertiary care hospital in Pakistan with a national referral base.

Methods

We conducted a retrospective review of thirteen patients who presented to The Aga Khan University and diagnosed with "Moyamoya Disease" during the period 1988 – 2006. These patients were identified from existing hospital database via ICD-9 codes. A predesigned questionnaire containing information about clinical presentation, management and neuroimaging was administered to all identified patients.

Results

There were seven males and six females. Mean age at presentation was 16.5 years and a female predominance was found in the pediatric age group (n = 10, 71.4%). Stroke (n = 11, 84.2%) was the most common presentation with motor deficit being the universal cortical symptom. Fever was a common symptom in the lower age groups (n = 4, 51.7%). Cerebral Angiography and Magnetic Resonance Angiography showed bilateral involvement of the vessels in eleven patients while unilateral in two. Subarachnoid and interventricular haemorrhage appeared in 2(15.4%) adults. Twelve (92.3%) patients were discharged as independent with minor deficits regardless of therapeutic modality. Only three (23.0%) patients underwent surgery whereas the remaining were managed conservatively.

Conclusion

Physicians when dealing with childhood strokes and characteristic deficits in adult population should consider Moyamoya disease.
Numerical investigations on the strain-adaptive bone remodelling in the periprosthetic femur: Influence of the boundary conditions
Authors: Behrens Bernd-Arno , Nolte Ingo , Wefstaedt Patrick , Stukenborg-Colsman Christina , Bouguecha Anas
Published: April 2009

Background

There are several numerical investigations on bone remodelling after total hip arthroplasty (THA) on the basis of the finite element analysis (FEA). For such computations certain boundary conditions have to be defined. The authors chose a maximum of three static load situations, usually taken from the gait cycle because this is the most frequent dynamic activity of a patient after THA.

Materials and methods

The numerical study presented here investigates whether it is useful to consider only one static load situation of the gait cycle in the FE calculation of the bone remodelling. For this purpose, 5 different loading cases were examined in order to determine their influence on the change in the physiological load distribution within the femur and on the resulting strain-adaptive bone remodelling. First, four different static loading cases at 25%, 45%, 65% and 85% of the gait cycle, respectively, and then the whole gait cycle in a loading regime were examined in order to regard all the different loadings of the cycle in the simulation.

Results

The computed evolution of the apparent bone density (ABD) and the calculated mass losses in the periprosthetic femur show that the simulation results are highly dependent on the chosen boundary conditions.

Conclusion

These numerical investigations prove that a static load situation is insufficient for representing the whole gait cycle. This causes severe deviations in the FE calculation of the bone remodelling. However, accompanying clinical examinations are necessary to calibrate the bone adaptation law and thus to validate the FE calculations.
A supervised land cover classification of a western Kenya lowland endemic for human malaria: associations of land cover with larval Anopheles habitats
Authors: Mutuku FM , Bayoh MN , Hightower AW , Vulule JM , Gimnig JE , Mueke JM , Amimo FA , Walker ED
Published: April 2009

Background

A supervised land cover classification was developed from very high resolution IKONOS satellite data and extensive ground truth sampling of a ca. 10 sq km malaria-endemic lowland in western Kenya. The classification was then applied to an investigation of distribution of larval Anopheles habitats. The hypothesis was that the distribution and abundance of aquatic habitats of larvae of various species of mosquitoes in the genus Anopheles is associated with identifiable landscape features.

Results and discussion

The classification resulted in 7 distinguishable land cover types, each with a distinguishable vegetation pattern, was highly accurate (89%, Kappa statistic = 0.86), and had a low rate of omission and commission errors. A total of 1,198 habitats and 19,776 Anopheles larvae of 9 species were quantified in samples from a rainy season, and 184 habitats and 582 larvae from a dry season. Anopheles gambiae s.l. was the dominant species complex (51% of total) and A. arabiensis the dominant species. Agricultural land covers (mature maize fields, newly cultivated fields, and pastured grasslands) were positively associated with presence of larval habitats, and were located relatively close to stream channels; whilst nonagricultural land covers (short shrubs, medium shrubs, tall shrubs, and bare soil around residences) were negatively associated with presence of larval habitats and were more distant from stream channels. Number of larval habitats declined exponentially with distance from streams. IKONOS imagery was not useful in direct detection of larval habitats because they were small and turbid (resembling bare soil), but was useful in localization of them through statistical associations with specific land covers.

Conclusion

A supervised classification of land cover types in rural, lowland, western Kenya revealed a largely human-modified and fragmented landscape consisting of agricultural and domestic land uses. Within it, larval habitats of Anopheles vectors of human malaria were associated with certain land cover types, of largely agricultural origin, and close to streams. Knowledge of these associations can inform malaria control to gather information on potential larval habitats more efficiently than by field survey and can do so over large areas.
Infrared thermography as an access pathway for individuals with severe motor impairments
Authors: Memarian Negar , Venetsanopoulos Anastasios N , Chau Tom
Published: April 2009

Background

People with severe motor impairments often require an alternative access pathway, such as a binary switch, to communicate and to interact with their environment. A wide range of access pathways have been developed from simple mechanical switches to sophisticated physiological ones. In this manuscript we report the inaugural investigation of infrared thermography as a non-invasive and non-contact access pathway by which individuals with disabilities can interact and perhaps eventually communicate.

Methods

Our method exploits the local temperature changes associated with mouth opening/closing to enable a highly sensitive and specific binary switch. Ten participants (two with severe disabilities) provided examples of mouth opening and closing. Thermographic videos of each participant were recorded with an infrared thermal camera and processed using a computerized algorithm. The algorithm detected a mouth open-close pattern using a combination of adaptive thermal intensity filtering, motion tracking and morphological analysis.

Results

High detection sensitivity and low error rate were achieved for the majority of the participants (mean sensitivity of all participants: 88.5% ± 11.3; mean specificity of all participants: 99.4% ± 0.7). The algorithm performance was robust against participant motion and changes in the background scene.

Conclusion

Our findings suggest that further research on the infrared thermographic access pathway is warranted. Flexible camera location, convenience of use and robustness to ambient lighting levels, changes in background scene and extraneous body movements make this a potential new access modality that can be used night or day in unconstrained environments.
High Concentrations of Morphine Sensitize and Activate Mouse Dorsal Root Ganglia via TRPV1 and TRPA1 Receptors
Authors: Forster Alexander B , Reeh Peter W , Messlinger Karl , Fischer Michael JM
Published: April 2009

Background

Morphine and its derivatives are key drugs in pain control. Despite its well-known analgesic properties morphine at high concentrations may be proalgesic. Particularly, short-lasting painful sensations have been reported upon dermal application of morphine. To study a possible involvement of TRP receptors in the pro-nociceptive effects of morphine (0.3 – 10 mM), two models of nociception were employed using C57BL/6 mice and genetically related TRPV1 and TRPA1 knockout animals, which were crossed and generated double knockouts. Hindpaw skin flaps were used to investigate the release of calcitonin gene-related peptide indicative of nociceptive activation.

Results

Morphine induced release of calcitonin gene-related peptide and sensitized the release evoked by heat or the TRPA1 agonist acrolein. Morphine activated HEK293t cells transfected with TRPV1 or TRPA1. Activation of C57BL/6 mouse dorsal root ganglion neurons in culture was investigated with calcium imaging. Morphine induced a dose-dependent rise in intracellular calcium in neurons from wild-type animals. In neurons from TRPV1 and TRPA1 knockout animals activation by morphine was markedly reduced, in the TRPV1/A1 double knockout animals this morphine effect was abrogated. Naloxone induced an increase in calcium levels similar to morphine. The responses to both morphine and naloxone were sensitized by bradykinin.

Conclusion

Nociceptor activation and sensitization by morphine is conveyed by TRPV1 and TRPA1.
Evaluation of animal models of neurobehavioral disorders
Authors: van der Staay F Josef , Arndt Saskia S , Nordquist Rebecca E
Published: April 2009

Animal models play a central role in all areas of biomedical research. Theprocessof animal model building, development and evaluation has rarely been addressed systematically, despite the long history of using animal models in the investigation of neuropsychiatric disorders and behavioral dysfunctions. An iterative, multi-stage trajectory for developing animal models and assessing their quality is proposed. The process starts with defining the purpose(s) of the model, preferentially based on hypotheses about brain-behavior relationships. Then, the model is developed and tested. The evaluation of the model takes scientific and ethical criteria into consideration.

Model development requires a multidisciplinary approach. Preclinical and clinical experts should establish a set of scientific criteria, which a model must meet. The scientific evaluation consists of assessing the replicability/reliability, predictive, construct and external validity/generalizability, and relevance of the model. We emphasize the role of (systematic and extended) replications in the course of the validation process. One may apply a multiple-tiered 'replication battery' to estimate the reliability/replicability, validity, and generalizability of result.

Compromised welfare is inherent in many deficiency models in animals. Unfortunately, 'animal welfare' is a vaguely defined concept, making it difficult to establish exact evaluation criteria. Weighing the animal's welfare and considerations as to whether action is indicated to reduce the discomfort must accompany the scientific evaluation at any stage of the model building and evaluation process. Animal model building should be discontinued if the model does not meet the preset scientific criteria, or when animal welfare is severely compromised. The application of the evaluation procedure is exemplified using the rat with neonatal hippocampal lesion as a proposed model of schizophrenia.

In a manner congruent to that for improving animal models, guided by the procedure expounded upon in this paper, the developmental and evaluation procedure itself may be improved by careful definition of the purpose(s) of a model and by defining better evaluation criteria, based on the proposed use of the model.
Multiple synchronous primary malignancies induced by benzene exposure: a case report
Authors: Wang Pingli , Zhang Gensheng , Shen Huahao
Published: April 2009

Background

Chronic exposure to high concentrations of benzene is usually associated with the development of haematological diseases. However, solid tumors induced by benzene exposure are less frequent.

Case presentation

We present an unusual case of triple synchronous primary malignancies most likely induced by occupational benzene exposure in a male patient. This spray painter was diagnosed as chronic aplastic anemia in his 21 years old after exposing to high concentration of benzene for three years. Then he was treated with glucocorticoid for four years. 40 years later, this patient developed three synchronous primary neoplasms with three different histologies including a basaloid squamous cell carcinoma of the esophagus, primary hepatocellular carcinoma, and well-differentiated squamous cell carcinoma of the gum.

Conclusion

This case reminds us that the occurrence of solid tumors should be monitored in workers with occupational history linked with a high concentration exposure to benzene, though it's rarely happened.
Mortality in human sepsis is associated with downregulation of Toll-like receptor 2 and CD14 expression on blood monocytes
Authors: Schaaf Bernhard , Luitjens Karen , Goldmann Torsten , van Bremen Tobias , Sayk Friedhelm , Dodt Christoph , Dalhoff Klaus , Droemann Daniel
Published: April 2009

Pattern recognition receptors are a key component of the first line host defense against infection, recognizing specific microbial products. We hypothesize that monocyte hyporesponsiveness in human sepsis is associated with a downregulation of the pattern recognition receptors Toll-like receptor (TLR)-2 and TLR4.

Protein expression of CD14, TLR2 and TLR4 on blood monocytes was examined using flow cytometry from 29 patients with sepsis and 14 healthy controls. In addition LPS stimulated TNF-α and IL-10 production was studied in a 24 hour whole blood assay.

We found an increased expression of CD14, TLR2 and TLR4 in patients with sepsis compared to controls (p < 0.01). In patients with sepsis, death was associated with significant lower CD14 and TLR2 expression at admission (CD14: 25.7 +- 19.1 vs 39.1 +- 17.3 mean fluorescence intensity [MFI], p = 0.02; TLR2: 21.8 +- 9.4 vs. 30.9 +- 9.6, p = 0.01). At 72 hours the TLR2 expression on monocytes was associated with the IL-10 inducibility after LPS stimulation (r = 0.52, p = 0.02) and the CD14 expression with the IL-6, IL-10 and TNF inducibility.

We conclude that septic patients are characterized by an increased expression of CD14, TLR2 and TLR4 on monocytes compared to controls. Death is associated with downregulation of TLR2 and CD14 expression on monocytes correlating with reduced cytokine inducibility. We suggest that CD14 and TLR2 are a key factor in monocyte hyporesponsibility during severe sepsis.
Analysis of colorectal cancers for human cytomegalovirus presence
Authors: Bender Cecilia , Zipeto Donato , Bidoia Carlo , Costantini Silvia , Zamò Alberto , Menestrina Fabio , Bertazzoni Umberto
Published: April 2009

Background

A possible association between human cytomegalovirus (HCMV) infection and colorectal cancer progression has been inferred by the identification in tumour tissues of HCMV antigens and specific viral DNA or RNA sequences. To further investigate the relationship between HCMV and colorectal cancers we developed qualitative and quantitative PCR assay to detect HCMV DNA in 56 formalin-fixed paraffin-embedded (FFPE) tissue samples from patients belonging to 4 different histological phenotypes: adenoma; poorly, moderately and well differentiated adenocarcinomas.

Results

Of the 56 FFPE tested tissue samples, 6 (11%) were positive for HCMV nested PCR amplification, and more precisely 1 (5%) of 20 cases of adenoma and 5 (21%) of 24 cases of moderately differentiated adenocarcinoma. No PCR positivity was obtained in samples from well and poorly differentiated adenocarcinomas.

Conclusion

Our observations suggest that there is no evidence of a direct association between HCMV and colorectal cancer. Moreover, the results obtained are not supportive of a causal role of HCMV in the processes of carcinogenesis and/or progression of colorectal cancer. However, the fact that the virus may present a "hit and run" like-mechanism and HCMV can thus only be detectable at a particular stage of a processing adenocarcinoma, suggests that a significant number of colorectal cancers might have been the subject of HCMV infection that could contribute to trigger the oncogenic differentiation. Our analysis does not exclude the possibility of HCMV infection subsequent viral clearance.
Post-translational aging of proteins in osteoarthritic cartilage and synovial fluid as measured by isomerized aspartate
Authors: Catterall Jonathan B , Barr Daniel , Bolognesi Michael , Zura Robert D , Kraus Virginia B
Published: April 2009

Introduction

Aging proteins undergo non-enzymatic post-translational modification, including isomerization and racemization. We hypothesized that cartilage with many long-lived components could accumulate non-enzymatically modified amino acids in the form of isomerized aspartate and that its liberation due to osteoarthritis (OA)-related cartilage degradation could reflect OA severity.

Methods

Articular cartilage and synovial fluid were obtained from 14 randomly selected total knee arthroplasty cases (56 to 79 years old) and non-arthritis cartilage from 8 trauma cases (51 to 83 years old). Paired lesional cartilage and non-lesioned OA cartilage were graded histologically using a modified Mankin system. Paired cartilage and synovial fluids were assayed for isomerized aspartate, phosphate-buffered saline/EDTA (ethylenediaminetetraacetic acid) extractable glycosaminoglycans, and total protein. Macroscopically normal non-lesioned OA cartilage was separated into superficial and deep regions when cartilage thickness was at least 3 mm (n = 6).

Results

Normalized to cartilage wet weight, normal cartilage and deep non-lesioned OA cartilage contained significantly (P < 0.05) more isomerized aspartate than superficial non-lesioned OA cartilage and lesioned cartilage. Synovial fluid isomerized aspartate correlated positively (R2 = 0.53, P = 0.02) and glycosaminoglycans correlated negatively (R2 = 0.42, P = 0.04) with histological OA lesion severity. Neither synovial fluid isomerized aspartate nor glycosaminoglycans nor total protein correlated with histological scores of non-lesioned areas.

Conclusions

We show for the first time that human cartilage and synovial fluid contain measurable quantities of an isomerized amino acid and that synovial fluid concentrations of isomerized aspartate reflected severity of histological OA. Further assessment is warranted to identify the cartilage proteins containing this modification and to assess the functional consequences and biomarker applications of this analyte in OA.
What patients think about ICU follow-up services: a qualitative study
Authors: Prinjha Suman , Field Kate , Rowan Kathy
Published: April 2009

Introduction

UK policy recommendations advocate the use of intensive care unit (ICU) follow-up services to help detect and treat patients' physical and emotional problems after hospital discharge and as a means of service evaluation. This study explores patients' perceptions and experiences of these services.

Methods

Thirty-four former ICU patients were recruited throughout the UK, using maximum variation sampling to achieve as broad a range of experiences of the ICU as possible. Participants were interviewed at home by a qualitative researcher unconnected to their hospital care. Interviews were recorded and transcribed for analysis. We report a qualitative thematic analysis of patients' experiences of ICU follow up.

Results

Former patients said they valued ICU follow-up services, which had made an important contribution to their physical, emotional and psychological recovery in terms of continuity of care, receiving information, gaining expert reassurance and giving feedback to ICU staff. Continuity of care included having tests and being monitored, referrals to other specialists and ICU follow-up appointments soon after hospital discharge. Information about physical, emotional and psychological recovery was particularly important to patients, as was information that helped them make sense of their ICU experience. Those without access to ICU follow-up care often felt abandoned or disappointed because they had no opportunity to be monitored, referred or get more information.

Conclusions

Former patients value having ICU follow-up services but many found that their healthcare needs were unmet because hospitals were unable to provide the aftercare they required. Most participants were aware of the financial constraints on the health system. Although they valued ICU follow-up care, they did not want it to continue indefinitely, with many of them declining appointment invitations when they themselves felt they no longer needed them.
Expression of SKAP-HOM in DCs is required for an optimal immune response in vivo
Authors: Reinhold Annegret , Reimann Sibylle , Reinhold Dirk , Schraven Burkhart , Togni Mauro
Published: April 2009

The genetic deletion of SKAP-HOM, an ubiquitously expressed cytosolic adapter protein, affected DC:T cell interactions reducing immune response.

The cytosolic adaptor molecule SKAP-HOM, similar to the T cell-specific homologue SKAP55, interacts directly with ADAP, and both molecules are involved in inside-out signaling. Previous studies have shown that in the absence of SKAP-HOM, antigen receptor-triggered integrin-mediated adhesion is impaired severely in B cells but not in T cells. In addition, loss of SKAP-HOM results in a less severe clinical course of EAE. DCs are the most potent APCs and express SKAP-HOM. However, the role of SKAP-HOM in DCs remains unknown. Here, we assessed whether the reduced severity of EAE observed in SKAP-HOM-deficient mice is at least partially a result of an impaired cooperation between APCs and T cells. We demonstrate that migration of LC in vivo and the spontaneous motility of BMDCs in vitro are increased in the absence of SKAP-HOM. In contrast, triggering of the integrin results in a drastic decrease of DC motility and in enhanced actin polymerization in SKAP-HOM-deficient DCs. Furthermore, the antigen-dependent conjugate formed between wild-type T cells and SKAP-HOM−/− DCs is delayed in comparison with wild-type DCs. Strikingly, fewer antigen-specific T cells are induced by immunization with SKAP-HOM−/− BMDCs as compared with wild-type BMDCs in vivo. Thus, these findings suggest that SKAP-HOM expression in DCs is required for the induction of an optimal immune response.
Sepsis-induced human lymphocyte apoptosis and cytokine production in “humanized” mice
Authors: Unsinger Jacqueline , McDonough Jacquelyn S , Shultz Leonard D , Ferguson Thomas A , Hotchkiss Richard S
Published: April 2009

Sepsis in mice possessing a functional human immune system causes extensive apoptotic death of human immune effector cells and increases in both pro- and anti-inflammatory human cytokines.

Sepsis is the leading cause of death in critically ill patients in the United States with over 210,000 deaths annually. One stumbling block to an effective therapy of sepsis has been the lack of a clinically relevant animal model. There are important distinctions in the mouse versus human immune system regarding the host response to invading pathogens. These differences may explain the disappointing results in many sepsis clinical trials despite the clear efficacy of these agents in mouse models of sepsis. The purpose of the present study was to develop a “humanized” mouse model of sepsis and to determine if the model recapitulated the major findings of lymphocyte apoptosis and cytokine response that exist in patients with sepsis. Two-day-old NOD-scid IL2rγnull mice received an adoptive transfer of hCD34+ hematopoietic cord blood stem cells. These mice acquired a functional human innate and adaptive immune system, as evidenced by the development of all lineages of human immune cells as well as by mounting a DTH response. Eight weeks post-transfer, mice were made septic using the highly clinical relevant CLP model of sepsis, and sepsis induced marked elevations in human pro- and anti-inflammatory cytokines as well as a dramatic increase in human T and B cell apoptosis. Collectively, these results show that the humanized mouse model recapitulates many of the classic findings in patients with sepsis. Therefore, it represents an advanced, clinically relevant model for mechanistic studies of sepsis and testing of novel therapies.
The Types and Functions of Samizdat Publications in Czechoslovakia, 1948–1989
Authors: Machovec Martin
Published: April 2009

The term samizdat, now widespread, denotes the unofficial dissemination of any variety of text (book, magazine, leaflet, etc.) within “totalitarian” political systems, especially those after World War II. Such publishing, though often not explicitly forbidden by law, was always punishable through the misuse of a variety of laws under various pretexts. It occurred first in the Soviet Union as early as the 1920s, before the term was used, and then, labeled as such, from the 1950s onward. While samizdat publication occurred in Czechoslovakia after 1948, the word itself was used there only from the 1970s on. This article seeks to clarify the term and the phenomenon of samizdat with regard to the Czech literary scene to trace its historical limits and the justification for it. I will first describe the functions of Czech samizdat during the four decades of the totalitarian regime (1948–89), that is, examine it as a nonstatic, developing phenomenon, and then I will offer criteria by which to classify it. Such texts are classifiable by motivations for publishing and distributing samizdat; the originator; traditionally recognized types of printed material; date of production and of issuance, if different; textual content; occurrence in the chronology of political and cultural events under the totalitarian regime; and type of technology used in production. The applicability of such criteria is tested against the varied samizdat activities of the Czech poet and philosopher Egon Bondy.
Notch signaling controls liver development by regulating biliary differentiation
Authors: Zong Yiwei , Panikkar Archana , Xu Jie , Antoniou Aline , Raynaud Peggy , Lemaigre Frederic , Stanger Ben Z.
Published: April 2009

In the mammalian liver, bile is transported to the intestine through an intricate network of bile ducts. Notch signaling is required for normal duct formation, but its mode of action has been unclear. Here, we show in mice that bile ducts arise through a novel mechanism of tubulogenesis involving sequential radial differentiation. Notch signaling is activated in a subset of liver progenitor cells fated to become ductal cells, and pathway activation is necessary for biliary fate. Notch signals are also required for bile duct morphogenesis, and activation of Notch signaling in the hepatic lobule promotes ectopic biliary differentiation and tubule formation in a dose-dependent manner. Remarkably, activation of Notch signaling in postnatal hepatocytes causes them to adopt a biliary fate through a process of reprogramming that recapitulates normal bile duct development. These results reconcile previous conflicting reports about the role of Notch during liver development and suggest that Notch acts by coordinating biliary differentiation and morphogenesis.
Notch signaling promotes airway mucous metaplasia and inhibits alveolar development
Authors: Guseh J. Sawalla , Bores Sam A. , Stanger Ben Z. , Zhou Qiao , Anderson William J. , Melton Douglas A. , Rajagopal Jayaraj
Published: April 2009

The airways are conduits that transport atmospheric oxygen to the distal alveolus. Normally, airway mucous cells are rare. However, diseases of the airway are often characterized by mucous metaplasia, in which there are dramatic increases in mucous cell numbers. As the Notch pathway is known to regulate cell fate in many contexts, we misexpressed the active intracellular domain of the mouse Notch1 receptor in lung epithelium. Notch misexpression resulted in an increase in mucous cells and a decrease in ciliated cells in the airway. Similarly, mouse embryonic tracheal explants and adult human airway epithelium treated with Notch agonists displayed increased mucous cell numbers and decreased ciliated cell numbers. Notch antagonists had the opposite effect. Notably, Notch antagonists blocked IL13-induced mucous metaplasia. IL13 has a well-established role as an inflammatory mediator of mucous metaplasia and functions through Stat6-mediated gene transcription. We found that Notch ligands, however, are able to cause mucous metaplasia in Stat6-null cultured trachea, thus identifying a novel pathway that stimulates mucous metaplasia. Notch signaling may therefore play an important role in airway disease and, by extension, Notch antagonists may have therapeutic value. Conversely, in the distal lung, Notch misexpression prevented the differentiation of alveolar cell types. Instead, the distal lung formed cysts composed of cells that were devoid of alveolar markers but that expressed some, but not all, markers of proximal airway epithelium. Occasional distal cystic cells appeared to differentiate into normal proximal airway cells, suggesting that ectopic Notch signaling arrests the normal differentiation of distal lung progenitors before they initiate an alveolar program.
Short- and long-range functions of Goosecoid in zebrafish axis formation are independent of Chordin, Noggin 1 and Follistatin-like 1b
Authors: Dixon Fox Monica , Bruce Ashley E. E.
Published: April 2009

The organizer is essential for dorsal-ventral (DV) patterning in vertebrates. Goosecoid (Gsc), a transcriptional repressor found in the organizer, elicits partial secondary axes when expressed ventrally in Xenopus, similar to an organizer transplant. Although gsc is expressed in all vertebrate organizers examined, knockout studies in mouse suggested that it is not required for DV patterning. Moreover, experiments in Xenopus and zebrafish suggest a role in head formation, although a function in axial mesoderm formation is less clear. To clarify the role of Gsc in vertebrate development, we used gain- and loss-of-function approaches in zebrafish. Ventral injection of low doses of gsc produced incomplete secondary axes, which we propose results from short-range repression of BMP signaling. Higher gsc doses resulted in complete secondary axes and long-range signaling, correlating with repression of BMP and Wnt signals. In striking contrast to Xenopus, the BMP inhibitor Chordin (Chd) is not required for Gsc function. Gsc produced complete secondary axes in chd null mutant embryos and gsc-morpholino knockdown in chd mutants enhanced the mutant phenotype, suggesting that Gsc has Chd-independent functions in DV patterning. Even more striking was that Gsc elicited complete secondary axes in the absence of three secreted BMP antagonists, Chd, Follistatin-like 1b and Noggin 1, suggesting that Gsc functions in parallel with secreted BMP inhibitors. Our findings suggest that Gsc has dose dependent effects on axis induction and provide new insights into molecularly distinct short- and long-range signaling activities of the organizer.
A cluster of three long-range enhancers directs regionalShhexpression in the epithelial linings
Authors: Sagai Tomoko , Amano Takanori , Tamura Masaru , Mizushina Yoichi , Sumiyama Kenta , Shiroishi Toshihiko
Published: April 2009

The sonic hedgehog (Shh) pathway plays indispensable roles in the morphogenesis of mouse epithelial linings of the oral cavity and respiratory and digestive tubes. However, no enhancers that regulate regional Shhexpression within the epithelial linings have been identified so far. In this study, comparison of genomic sequences across mammalian species and teleost fishes revealed three novel conserved non-coding sequences (CNCSs) that cluster in a region 600 to 900 kb upstream of the transcriptional start site of the mouse Shh gene. These CNCSs drive regional transgenic lacZ reporter expression in the epithelial lining of the oral cavity,pharynx, lung and gut. Together, these enhancers recapitulate the endogenous Shh expression domain within the major epithelial linings. Notably,genomic arrangement of the three CNCSs shows co-linearity that mirrors the order of the epithelial expression domains along the anteroposterior body axis. The results suggest that the three CNCSs are epithelial lining-specific long-range Shh enhancers, and that their actions partition the continuous epithelial linings into three domains: ectoderm-derived oral cavity, endoderm-derived pharynx, and respiratory and digestive tubes of the mouse. Targeted deletion of the pharyngeal epithelium specific CNCS results in loss of endogenous Shh expression in the pharynx and postnatal lethality owing to hypoplasia of the soft palate, epiglottis and arytenoid. Thus, this long-range enhancer is indispensable for morphogenesis of the pharyngeal apparatus.
sonic hedgehog is required in pulmonary endoderm for atrial septation
Authors: Hoffmann Andrew D. , Peterson Michael A. , Friedland-Little Joshua M. , Anderson Stuart A. , Moskowitz Ivan P.
Published: April 2009

The genesis of the septal structures of the mammalian heart is central to understanding the ontogeny of congenital heart disease and the evolution of cardiac organogenesis. We found that Hedgehog (Hh) signaling marked a subset of cardiac progenitors specific to the atrial septum and the pulmonary trunk in the mouse. Using genetic inducible fate mapping with Gli1CreERT2, we marked Hh-receiving progenitors in anterior and posterior second heart field splanchnic mesoderm between E8 and E10. In the inflow tract, Hh-receiving progenitors migrated from the posterior second heart field through the dorsal mesocardium to form the atrial septum,including both the primary atrial septum and dorsal mesenchymal protrusion(DMP). In the outflow tract, Hh-receiving progenitors migrated from the anterior second heart field to populate the pulmonary trunk. Abrogation of Hh signaling during atrial septal progenitor specification resulted in atrial and atrioventricular septal defects and hypoplasia of the developing DMP. Hedgehog signaling appeared necessary and sufficient for atrial septal progenitor fate:Hh-receiving cells rendered unresponsive to the Hh ligand migrated into the atrium in normal numbers but populated the atrial free wall rather than the atrial septum. Conversely, constitutive activation of Hh signaling caused inappropriate enlargement of the atrial septum. The close proximity of posterior second heart field cardiac progenitors to pulmonary endoderm suggested a pulmonary source for the Hh ligand. We found that Shh is required in the pulmonary endoderm for atrial septation. Therefore, Hh signaling from distinct pulmonary and pharyngeal endoderm is required for inflow and outflow septation, respectively. These data suggest a model in which respiratory endoderm patterns the morphogenesis of cardiac structural components required for efficient cardiopulmonary circulation.
Numerical simulation of sheet stamping process using flexible punch
Authors: Ramezani M , Ripin Z M , Ahmad R
Published: April 2009

Different from the conventional stamping process, rubber forming uses a rubber pad contained in a rigid box to act as a punch. The main attraction of the process is its simplicity, and it can be used for prototype development or for low-volume production. In this study, an axisymmetric rubber-pad forming operation is investigated via numerical simulations and experiments. Some key process parameters, such as rubber material, hardness of flexible punch, stamping velocity, rubber-pad thickness, and friction are studied in detail. Good correlation is achieved between the finite element predicted and experimentally measured thickness—thinning in the formed part. Stress and strain distributions in the specimen are investigated numerically during the process using ABAQUS/Standard.
On the eigencharacteristics of a centrifugally stiffened, visco-elastic beam
Authors: Gürgöze M , Zeren S
Published: April 2009

The present study is concerned with the out-of-plane vibrations of a rotating, internally damped (Kelvin—Voigt model) Bernoulli—Euler beam carrying a tip mass, which can be thought of as a simplified model of a helicopter rotor blade or a blade of an auto-cooling fan. The differential eigenvalue problem set up is solved by using the Frobenius method of solution in a power series. The developed characteristic equation is then solved numerically. The simulation results are tabulated for a variety of non-dimensional rotational speeds, tip mass, and internal damping parameters. These are compared with the results of conventional finite element (FE) modelling as well and excellent agreement is obtained. Furthermore, it is seen that the numerical calculations according to the proposed solution method need much less computer time as compared to the conventional FE method.
Investigations for a statistically controlled rapid casting solution of lead alloys using three-dimensional printing
Authors: Singh J P , Singh R
Published: April 2009

The purpose of the present investigation is to study the feasibility of decreasing the shell thickness for a statistically controlled rapid casting solution of lead alloy using three-dimensional printing technology. Starting from the identification of a component/benchmark, technological prototypes were produced with different shell thickness. Measurements on a coordinate measuring machine helped in calculating the dimensional tolerances of the castings produced. Some important mechanical properties were also compared to verify the suitability of the castings and further results are supported by microstructure analysis. The study suggested that the shell thickness having a value less than the recommended one is more suitable from a dimensional accuracy and an economic point of view. The provided data from the experimentation are extremely useful for the industrial application of the considered technology. The result indicates that at 1 mm shell thickness, the hardness of the casting improves from the recommended 12 mm. Further, production costs and production time have been reduced by 45.75 and 43 per cent, respectively, in comparison with the 12 mm recommended shell thickness.
Study of a sound field separation technique based on a single holographic surface and wave superposition method
Authors: Jia W Q , Chen J , Yang C , Wang Z Y
Published: April 2009

In order to overcome the limitation of traditional near-field acoustical holography (NAH), that the sound field on one side of the holographic surface must be free, a sound field separation technique based on single holographic surface and wave superposition method (WSM) is proposed. According to the WSM, the field on and near the measurement surface may be approximated by the field produced by virtual source points placed on a surface inside the structure. The source strengths are evaluated by applying boundary conditions on the measurement surface. Here, the ‘pseudo’ sound pressure of the reconstruction surface is first obtained based on the principle of sound field mirror image and WSM, then the sound pressure of the target sound source acting on the holographic surface is separated by the sound pressures of the holographic surface and the reconstruction surface, and the sound field separation is realized. The technique requires the inversion of the Green's function matrix, which may be ill-conditioned. The Tikhonov regularization method is used to invert it, and the value of the regularization parameter is determined by the L-curve criteria. Through the numerical simulation and experiment, the results show the validity and efficiency of this technique.