bluuebunny/crossref_metadata_2025 huggingface dataset:
Affine tensors in mechanics of freely falling particles and rigid bodies
Authors: de Saxcé Géry , Vallée Claude
Published: October 2011

In a previous paper, we proposed an approach for the dynamics of 3D bodies and shells based on the use of affine tensors. This new theoretical frame is very large and the applications are not limited to the mechanics of continua. In the present paper, we show how it can be also applied to the description of the mechanics of freely falling particles and rigid bodies. The mass, the linear and angular momenta are structured as a single object called a torsor. Excluding all metric notions, we define the torsors as skew-symmetric bilinear mappings operating on the linear space of the affine functions. Torsors are a particular family of affine tensors. On this ground, we define an intrinsic differential operator called the affine covariant derivative. Next, we claim that the torsor characterizing the behaviour of a freely falling particle is affine covariant derivative free, that allows recovering both laws of linear and angular momentum. Finally, it is shown how the motion of rigid bodies can be described within this frame.
Reconsidering Culture and Homicide
Authors: Lee Matthew R.
Published: October 2011

This article fleshes out a perspective on culture and lethal violence using examples from two contexts where they are believed to be strongly linked: among rural southern Whites and urban Blacks. Concepts from the cultural paradigm which focuses on understanding how people use cultural resources instead of discerning the content of cultures are employed. Through the lenses of this alternative cultural paradigm, violence in these two settings is partly attributable to an abundance of strategies of action condoning the use of violence. Strategies of action pertinent to defensive or honor-based violence emerge where the law is unavailable and may be amplified by moderate or high levels of poverty. However, when socioeconomic disadvantage is so severe that there is widespread institutional breakdown, strategies of action promoting more predatory and instrumental forms of violence may also evolve. This is because mainstream institutions are a primary source of socialization where cultural tool kits containing strategies of action are expanded and diversified. When they are weak, socialization through street peer groups or illegal markets may be more pronounced, facilitating the contextual transference of violent scripts for action to situations other than those involving honor or character contests. Actors immersed in violent communities are not subsequently mired down in circumstances beyond their control. Through participation in violent activities, they can actively create and reinforce their own violent social environment.
Cost-benefit analysis and non-utilitarian ethics
Authors: Lowry Rosemary , Peterson Martin
Published: October 2011

Cost-benefit analysis is commonly understood to be intimately connected with utilitarianism and incompatible with other moral theories, particularly those that focus on deontological concepts such as rights. We reject this claim and argue that cost-benefit analysis can take moral rights as well as other non-utilitarian moral considerations into account in a systematic manner. We discuss three ways of doing this, and claim that two of them (output filters and input filters) can account for a wide range of rights-based moral theories, including the absolute notions of moral rights proposed by Hayek, Mayo, Nozick, and Shue. We also discuss whether the use of output filters and input filters can be generalized to cover other non-utilitarian theories, such as Kantian duty ethics and virtue ethics.
Verbal fluency in Alzheimer's disease and Aphasia
Authors: Arroyo-Anlló E.M. , Lorber M. , Rigaleau F. , Gil R.
Published: October 2011

This study examined the impact of two neurological diseases on access to semantic knowledge and the status of semantic representations. Patients with Alzheimer's disease (AD) and Aphasia (APH) were compared with control groups using the supermarket fluency task. We measured several aspects: number of category names produced, number of categories sampled to produce the words, the number of words per category sampled, number of exemplars and kinds of errors recorded. Both AD and APH groups produced significantly fewer words on the fluency task than control groups. As compared with the APH and control groups, in the AD group verbal fluency was characterized by a tendency to generate more category names with fewer exemplars within a category. The findings are consistent with the view that a bottom-up disruption in semantic knowledge occurs in AD and a general semantic disruption occurs in Aphasia.
Reverse Transcriptase Genotypes in Pediatric Patients Failing Initial Antiretroviral Therapy in Gaborone, Botswana
Authors: Tolle Michael , Howard Leigh , Kirk Brianna , Gomila Andres , Schwarzwald Heidi , Anabwani Gabriel
Published: October 2011

Background

Limited data are available on patterns of resistance mutations in pediatric patients in southern Africa, where HIV-1 subtype C (HIV-1C) predominates.

Methods

Retrospective chart review of pediatric patients. Nucleoside reverse transcriptase inhibitor (NRTI)- and nonnucleoside reverse transcriptase inhibitor (NNRTI)-associated resistance mutations quantified from population-based sequencing genotypic resistance assay results taken at time of first-line antiretroviral therapy (ART) failure (first-line ART = stavudine [d4T] or zidovudine [ZDV] + lamivudine [3TC] + nevirapine [NVP] or efavirenz [EFV]).

Results

Total number of patients with resistance assays analyzed is 45. Nucleoside reverse transcriptase inhibitor-associated mutation frequencies noted were M184V (n = 41; 91.1%); thymidine analogue mutations (TAMs; n = 20; 44.4%); >1 TAM (n = 9; 20%); TAM-2 pathway (n = 10; 22.2%); TAM-1 pathway (n = 7; 15.6%); TAM-1 and TAM-2 pathways (n = 3; 6.7%); K65R (n = 2; 4.4%); Q151M (n = 1; 2.2%); and L74V (n = 0; 0%). Nonnucleoside reverse transcriptase inhibitor-associated mutation frequencies noted were associated with notable resistance to either/both NVP and EFV (n = 40; 88.9%); K103N (n = 15; 33.3%); ≥1 mutations associated with etravirine (ETR) failure (K101E, Y181C, and G190A; n =20; 44.4%); and ≥2 notable NNRTI mutations (n = 12; 26.7%).

Conclusions

In this cohort, low-genetic barrier mutations were common, as were TAMs, including more than 1 TAM. Mutations compromising nonthymidine analogue backbones were rare, suggesting that it is likely that children who fail first-line NRTI backbones containing d4T or ZDV/3TC would still respond to abacavir (ABC), didanosine (ddI), and, for adolescents, tenofovir (TDF). Our data support the empiric continuation of 3TC in second-line regimens.
Pros, cons and potential risks of on-site decontamination methods used on neonatal units for articles indirectly associated with infant feeding, including breast pump collection kits and neonatal dummies
Authors: Gilks Joanne , Price Elizabeth , Hateley Paul , Gould Dinah , Weaver Gillian
Published: October 2011

We discuss the pros, cons and potential risks of on-site decontamination methods used on neonatal units for articles indirectly associated with infant feeding, such as breast pump collection kits and neonatal dummies (pacifiers, comforters or soothers). Some practical recommendations are made and areas requiring further review are indicated. For neonatal units, decontamination methods involving use of chlorine-releasing disinfectants or domestic steam-producing equipment should be reassessed. They would not be considered acceptable on intensive care units for adult patients.
Mechanical Ventilation in the Pediatric Cardiac Intensive Care Unit
Authors: Rimensberger Peter C. , Heulitt Mark J. , Meliones Jon , Pons Marti , Bronicki Ronald A.
Published: October 2011

Ventilating a child or newborn in the postoperative course after repair of congenital heart disease requires a solid basic understanding of respiratory system mechanics (pressure–volume relationship of the respiratory system and the concept of its time constants) and cardiopulmonary physiology. Furthermore, careful attention has to be paid to avoid damaging the lungs by potentially injurious mechanical ventilation. Optimizing ventilator settings during controlled and assisted ventilation, allowing as early as possible for spontaneous ventilation by still assisting mechanically the patient’s respiratory efforts are important features for lung protection, for minimizing potential hemodynamic side effects of positive pressure ventilation, and for early weaning from mechanical ventilation. In the search for being less invasive, the use of noninvasive ventilation in the cardiac intensive care setting is rapidly increasing despite still lacking evidence of its theoretical superiority and requires good knowledge of specific techniques and equipment available for this approach in this setting. This review will address many of these aspects and highlight the essentials to be known when ventilating a child in the Cardiac Intensive Care Unit (CICU).
Left Main Coronary Artery Atresia and Associated Cardiac Defects: Report on Concomitant Surgical Treatment
Authors: Jatene Marcelo , Juaneda Ignacio , Miranda Rogerio dos Anjos , Gato Rafaella , Marcial Miguel Lorenzo Barbero
Published: October 2011

A 9-year-old boy with congenital atresia of the left main coronary artery underwent myocardial revascularization. Coarctation of the aorta and ventricular septal defect were diagnosed at the age of 1 year. At age 7 years, the child presented with syncope while exercising. Preoperative evaluation included cardiac catheterization which revealed the unexpected finding of congenital atresia of the left main coronary artery with origin of the circumflex artery from the right coronary artery. Surgical correction included myocardial revascularization by means of left internal mammary artery graft to the anterior descending coronary artery, coarctation resection, and ventricular septal defect repair. The patient recovered uneventfully. We report the details of this extremely rare case with successful concomitant surgical management of the congenital coronary artery anomaly and the associated structural heart disease.
Second-Stage Palliation After Bilateral Pulmonary Artery Bands for HLHS and its Variants—Which is Better, Modified Norwood or Norwood Plus Bidirectional Glenn?
Authors: Sakamoto Takahiko , Harada Yorikazu , Kosaka Yoshimichi , Umezu Kentaro , Yasukochi Satoshi , Takigiku Kiyohiro , Matsui Hikoro , Inoue Nao
Published: October 2011

Background. The purpose of this study was to evaluate the surgical outcomes and pulmonary artery (PA) development associated with a new strategy wherein the modified Norwood (N) procedure is performed at 1-2 months after bilateral pulmonary artery banding (PAB). Methods. Between January 2008 and February 2010, 16 patients underwent Norwood-type operation after previous bilateral PAB. For analysis, patients were divided into two groups. Group I (n = 11) underwent modified Norwood procedure with either right modified Blalock Taussig (RMBT) shunt (n = 4) or right ventricle to pulmonary artery (RV-PA) conduit (n = 7). Group II (n = 5) underwent Norwood procedure plus bidirectional Glenn anastomosis. Diagnoses were hypoplastic left heart syndrome in 6 and its variants in 10. Results. There was no surgical death and no late death. Pulmonary artery interventions were performed at the time of the Norwood procedure in 27% in Group I and in 100% in Group II (p < 0.05). Additional PA interventions were performed during the period of follow-up in 4 cases in Group I (36.4%), and in 4 cases in Group II (80.0%). Additional Blalock Taussig shunts were performed in 7 patients, resulting in significant increase in PA index. In all, four patients have reached total cavopulmonary connection, and one has undergone biventricular repair. Eight patients in Group I and one patient in II Group reached bidirectional Glenn anastomosis. In Gp II, two patients showed LPA narrowing or obstruction with PA index of 80 ± 12 mm2/m2. Conclusions. Regarding the second-stage palliation after bilateral PAB, modified Norwood procedure with either RMBT or RV-PA conduit has some advantages compared with Norwood plus BDG with respect to subsequent pulmonary artery development. Additional BT shunt may contribute to PA development, even in the patients with Norwood procedure with RV-PA conduit.
Feasibility of VSD Closure and Debanding Without Pulmonary Artery Patch Repair in VSD Patients After PA Banding
Authors: Baharestani Bahadour , Omrani Gholamreza , Afjaei Reza Sadat , Ghivetag Nader , Adambeigh Ahmed , Sharifi Mehrzad
Published: October 2011

From 2004 to 2008, 64 infants with large ventricular septal defects were managed using a two-stage surgical approach. In the first stage, banding of the main pulmonary trunk was performed. The defect was then repaired months later. Debanding of pulmonary artery was accomplished without the need for pulmonary artery reconstruction.
Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance
Authors: Kreisel Daniel , Sugimoto Seiichiro , Zhu Jihong , Nava Ruben , Li Wenjun , Okazaki Mikio , Yamamoto Sumiharu , Ibrahim Mohsen , Huang Howard J. , Toth Kelsey A. , Ritter Jon H. , Krupnick Alexander S. , Miller Mark J. , Gelman Andrew E.
Published: October 2011

The mechanisms by which innate immune signals regulate alloimmune responses remain poorly understood. In the present study, we show by intravital 2-photon microscopy direct interactions between graft-infiltrating neutrophils and donor CD11c+ dendritic cells (DCs) within orthotopic lung allografts immediately after reperfusion. Neutrophils isolated from the airways of lung transplantation recipients stimulate donor DCs in a contact-dependent fashion to augment their production of IL-12 and expand alloantigen-specific IFN-γ+ T cells. DC IL-12 expression is largely regulated by degranulation and induced by TNF-α associated with the neutrophil plasma membrane. Extended cold ischemic graft storage enhances G-CSF–mediated granulopoiesis and neutrophil graft infiltration, resulting in exacerbation of ischemia-reperfusion injury after lung transplantation. Ischemia reperfusion injury prevents immunosuppression-mediated acceptance of mouse lung allografts unless G-CSF–mediated granulopoiesis is inhibited. Our findings identify granulopoiesis-mediated augmentation of alloimmunity as a novel link between innate and adaptive immune responses after organ transplantation.
Evaluation of epithelial mesenchymal transition in patients with chronic obstructive pulmonary disease
Authors: Sohal Sukhwinder S , Reid David , Soltani Amir , Ward Chris , Weston Steven , Muller H Konrad , Wood-Baker Richard , Walters E Haydn
Published: October 2011

Background

The reticular basement membrane (Rbm) in smokers and especially smokers with COPD is fragmented with "clefts" containing cells staining for the collagenase matrix-metalloproteinase-9 (MMP-9) and fibroblast protein, S100A4. These cells are also present in the basal epithelium. Such changes are likely hallmarks of epithelial mesenchymal transition (EMT). We aimed to confirm the epithelial origin of these Rbm cells, and to exclude potential confounding by infiltrating inflammatory cells.

Methods

Endobronchial biopsy sections from 17 COPD current smokers, with documented Rbm splitting and cellularity were stained for neutrophil elastase (neutrophil marker), CD68 (macrophage/mature fibroblasts), CD4+/CD8+ T lymphocytes, CD19 (B-cells), CD11c (dendritic cells/inflammatory cells), and S100 (Langerhans cells). The number of cells in the Rbm and epithelium staining for these "inflammatory" cell markers were then compared to numbers staining for S100A4, "a documented EMT epitope". Slides were double stained for S100A4 and cytokeratin(s).

Results

In the basal epithelium significantly more cells stained for S100A4 compared to infiltrating macrophages, fibroblasts or immune cells: median, 26 (21.3 - 37.3) versus 0 (0 - 9.6) per mm, p < 0.003. Markedly more S100A4 staining cells were also observed in the Rbm compared to infiltrating macrophages, neutrophils, fibroblasts or immune cells or any sub-type: 58 (37.3 - 92.6) versus 0 (0 - 4.8) cells/mm Rbm, p < 0.003. Cells in the basal epithelium 26 (21.3 - 37.3) per mm) and Rbm (5.9 (2.3 - 13.8) per mm) frequently double stained for both cytokeratin and S100A4.

Conclusions

These data provide additional support for active EMT in COPD airways.
The evolution of the tape measure protein: units, duplications and losses
Authors: Belcaid Mahdi , Bergeron Anne , Poisson Guylaine
Published: October 2011

Background

A large family of viruses that infect bacteria, calledphages, is characterized by long tails used to inject DNA into their victims' cells. Thetape measure proteingot its name because the length of the corresponding gene is proportional to the length of the phage's tail: a fact shown by actually copying or splicing out parts of DNA in exemplar species. A natural question is whether there existunitsfor these tape measures, and if different tape measures have different units and lengths. Such units would allow us to retrace the evolution of tape measure proteins using their duplication/loss history. The vast number of sequenced phages genomes allows us to attack this problem with a comparative genomics approach.

Results

Here we describe a subset of phages whose tape measure proteins contain variable numbers of an 11 amino acids sequence repeat, aligned with sequence similarity, structural properties, and simple arithmetics. This subset provides a unique opportunity for the combinatorial study of phage evolution, without the added uncertainties of multiple alignments, which are trivial in this case, or of protein functions, that are well established. We give a heuristic that reconstructs the duplication history of these sequences, using divergent strains to discriminate between mutations that occurred before and after speciation, or lineage divergence. The heuristic is based on an efficient algorithm that gives an exhaustive enumeration of all possible parsimonious reconstructions of the duplication/speciation history of a single nucleotide. Finally, we present a method that allows, when possible, to discriminate between duplication and loss events.

Conclusions

Establishing the evolutionary history of viruses is difficult, in part due to extensive recombinations and gene transfers, and high mutation rates that often erase detectable similarity between homologous genes. In this paper, we introduce new tools to address this problem.
Application of latent semantic analysis for open-ended responses in a large, epidemiologic study
Authors: Leleu Travis D , Jacobson Isabel G , LeardMann Cynthia A , Smith Besa , Foltz Peter W , Amoroso Paul J , Derr Marcia A , Ryan Margaret AK , Smith Tyler C ,   the Millennium Cohort Study Team
Published: October 2011

Background

The Millennium Cohort Study is a longitudinal cohort study designed in the late 1990s to evaluate how military service may affect long-term health. The purpose of this investigation was to examine characteristics of Millennium Cohort Study participants who responded to the open-ended question, and to identify and investigate the most commonly reported areas of concern.

Methods

Participants who responded during the 2001-2003 and 2004-2006 questionnaire cycles were included in this study (n = 108,129). To perform these analyses, Latent Semantic Analysis (LSA) was applied to a broad open-ended question asking the participant if there were any additional health concerns. Multivariable logistic regression was performed to examine the adjusted odds of responding to the open-text field, and cluster analysis was executed to understand the major areas of concern for participants providing open-ended responses.

Results

Participants who provided information in the open-ended text field (n = 27,916), had significantly lower self-reported general health compared with those who did not provide information in the open-ended text field. The bulk of responses concerned a finite number of topics, most notably illness/injury, exposure, and exercise.

Conclusion

These findings suggest generalized topic areas, as well as identify subgroups who are more likely to provide additional information in their response that may add insight into future epidemiologic and military research.
Gene expression profile of circulating tumor cells in breast cancer by RT-qPCR
Authors: Strati Areti , Markou Athina , Parisi Cleo , Politaki Eleni , Mavroudis Dimitris , Georgoulias Vasilis , Lianidou Evi
Published: October 2011

Background

Circulating tumor cells (CTCs) have been associated with prognosis especially in breast cancer and have been proposed as a liquid biopsy for repeated follow up examinations. Molecular characterization of CTCs is difficult to address since they are very rare and the amount of available sample is very limited.

Methods

We quantified by RT-qPCR CK-19, MAGE-A3, HER-2, TWIST1, hTERT α+β+, and mammaglobin gene transcripts in immunomagnetically positively selected CTCs from 92 breast cancer patients, and 28 healthy individuals. We also compared our results with the CellSearch system in 33 of these patients with early breast cancer.

Results

RT-qPCR is highly sensitive and specific and can detect the expression of each individual gene at the one cell level. None of the genes tested was detected in the group of healthy donors. In 66 operable breast cancer patients, CK-19 was detected in 42.4%, HER-2 in 13.6%, MAGE-A3 in 21.2%, hMAM in 13.6%, TWIST-1 in 42.4%, and hTERT α+β+ in 10.2%. In 26 patients with verified metastasis, CK-19 was detected in 53.8%, HER-2 in 19.2%, MAGE-A3 in 15.4%, hMAM in 30.8%, TWIST-1 in 38.5% and hTERT α+β+in 19.2%. Our preliminary data on the comparison between RT-qPCR and CellSearch in 33 early breast cancer patients showed that RT-qPCR gives more positive results in respect to CellSearch.

Conclusions

Molecular characterization of CTCs has revealed a remarkable heterogeneity of gene expression between breast cancer patients. In a small percentage of patients, CTCs were positive for all six genes tested, while in some patients only one of these genes was expressed. The clinical significance of these findings in early breast cancer remains to be elucidated when the clinical outcome for these patients is known.
Implementation and first-year screening results of an ocular telehealth system for diabetic retinopathy in China
Authors: Peng Jinjuan , Zou Haidong , Wang Weiwei , Fu Jiong , Shen Bingjie , Bai Xuelin , Xu Xun , Zhang Xi
Published: October 2011

Background

To describe implementation and first-year screening results of the first Chinese telehealth system for diabetic retinopathy (DR) - the Beixinjing Community Diabetic Retinopathy Telehealth system (BCDRT).

Methods

BCDRT implementation was based on the acquisition of adequate digital retinographs, secure digital transmission, storage and retrieval of participants' data and reader-generated medical reports. Local diabetic residents meeting inclusion criteria were enrolled into the BCDRT system beginning in 2009. Participants recommended for further in-person examination with ophthalmologists were followed, and the consistencies in diagnoses between BCDRT and ophthalmologists for DR or macular edema were calculated.

Results

A total of 471 diabetic residents participated in BCDRT screening in 2009. The proportions of total DR, proliferative DR, and diabetic macular edema were 24.42% (115 patients), 2.12% (10 patients) and 6.47% (24 patients), respectively: 56 patients consulted ophthalmologists for further in-person retinal examination with funduscopy after pupil dilation. High rates of consistency between BCDRT screening and ophthalmologists were observed for macular edema (Kappa = 0.81), moderate or severe non-proliferative DR grade (Kappa = 0.92), and other DR grades (Kappa = 1). A total of 456 (96.82%) patients were willing to participate in the next BCDRT screening.

Conclusions

BCDRT was a reliable and valid system for DR screening, and offers the potential to increase DR annual screening rates in local residents.
Lipopolysaccharide modulates astrocytic S100B secretion: a study in cerebrospinal fluid and astrocyte cultures from rats
Authors: Guerra Maria Cristina , Tortorelli Lucas S , Galland Fabiana , Da Ré Carollina , Negri Elisa , Engelke Douglas S , Rodrigues Letícia , Leite Marina C , Gonçalves Carlos-Alberto
Published: October 2011

Background

Inflammatory responses in brain are primarily mediated by microglia, but growing evidence suggests a crucial importance of astrocytes. S100B, a calcium-binding protein secreted by astrocytes, has properties of a neurotrophic or an inflammatory cytokine. However, it is not known whether primary signals occurring during induction of an inflammatory response (e.g. lipopolysaccharide, LPS) directly modulate S100B.

Methods

In this work, we evaluated whether S100B levels in cerebrospinal fluid (CSF) and serum of Wistar rats are affected by LPS administered by intraperitoneal (IP) or intracerebroventricular (ICV) injection, as well as whether primary astrocyte cultures respond directly to lipopolysaccharide.

Results

Our data suggest that S100B secretion in brain tissue is stimulated rapidly and persistently (for at least 24 h) by ICV LPS administration. This increase in CSF S100B was transient when LPS was IP administered. In contrast to these S100B results, we observed an increase in in TNFα levels in serum, but not in CSF, after IP administration of LPS. In isolated astrocytes and in acute hippocampal slices, we observed a direct stimulation of S100B secretion by LPS at a concentration of 10 μg/mL. An involvement of TLR4 was confirmed by use of specific inhibitors. However, lower levels of LPS in astrocyte cultures were able to induce a decrease in S100B secretion after 24 h, without significant change in intracellular content of S100B. In addition, after 24 h exposure to LPS, we observed a decrease in astrocytic glutathione and an increase in astrocytic glial fibrillary acidic protein.

Conclusions

Together, these data contribute to the understanding of the effects of LPS on astrocytes, particularly on S100B secretion, and help us to interpret cerebrospinal fluid and serum changes for this protein in neuroinflammatory diseases. Moreover, non-brain S100B-expressing tissues may be differentially regulated, since LPS administration did not lead to increased serum levels of S100B.
Comparative performance evaluation of hepatitis C virus genotyping based on the 5' untranslated region versus partial sequencing of the NS5B region of brazilian patients with chronic hepatitis C
Authors: Nakatani Sueli M , Santos Carlos A , Riediger Irina N , Krieger Marco A , Duarte Cesar AB , do Carmo Debur Maria , Carrilho Flair J , Ono Suzane K
Published: October 2011

Background

Genotyping of hepatitis C virus (HCV) has become an essential tool for prognosis and prediction of treatment duration. The aim of this study was to compare two HCV genotyping methods: reverse hybridization line probe assay (LiPA v.1) and partial sequencing of the NS5B region.

Methods

Plasma of 171 patients with chronic hepatitis C were screened using both a commercial method (LiPA HCV Versant, Siemens, Tarrytown, NY, USA) and different primers targeting the NS5B region for PCR amplification and sequencing analysis.

Results

Comparison of the HCV genotyping methods showed no difference in the classification at the genotype level. However, a total of 82/171 samples (47.9%) including misclassification, non-subtypable, discrepant and inconclusive results were not classified by LiPA at the subtype level but could be discriminated by NS5B sequencing. Of these samples, 34 samples of genotype 1a and 6 samples of genotype 1b were classified at the subtype level using sequencing of NS5B.

Conclusions

Sequence analysis of NS5B for genotyping HCV provides precise genotype and subtype identification and an accurate epidemiological representation of circulating viral strains.
Bayesian probit regression model for the diagnosis of pulmonary fibrosis: proof-of-principle
Authors: Meltzer Eric B , Barry William T , D'Amico Thomas A , Davis Robert D , Lin Shu S , Onaitis Mark W , Morrison Lake D , Sporn Thomas A , Steele Mark P , Noble Paul W
Published: October 2011

Background

The accurate diagnosis of idiopathic pulmonary fibrosis (IPF) is a major clinical challenge. We developed a model to diagnose IPF by applying Bayesian probit regression (BPR) modelling to gene expression profiles of whole lung tissue.

Methods

Whole lung tissue was obtained from patients with idiopathic pulmonary fibrosis (IPF) undergoing surgical lung biopsy or lung transplantation. Controls were obtained from normal organ donors. We performed cluster analyses to explore differences in our dataset. No significant difference was found between samples obtained from different lobes of the same patient. A significant difference was found between samples obtained at biopsy versus explant. Following preliminary analysis of the complete dataset, we selected three subsets for the development of diagnostic gene signatures: the first signature was developed from all IPF samples (as compared to controls); the second signature was developed from the subset of IPF samples obtained at biopsy; the third signature was developed from IPF explants. To assess the validity of each signature, we used an independent cohort of IPF and normal samples. Each signature was used to predict phenotype (IPF versus normal) in samples from the validation cohort. We compared the models' predictions to the true phenotype of each validation sample, and then calculated sensitivity, specificity and accuracy.

Results

Surprisingly, we found that all three signatures were reasonably valid predictors of diagnosis, with small differences in test sensitivity, specificity and overall accuracy.

Conclusions

This study represents the first use of BPR on whole lung tissue; previously, BPR was primarily used to develop predictive models for cancer. This also represents the first report of an independently validated IPF gene expression signature. In summary, BPR is a promising tool for the development of gene expression signatures from non-neoplastic lung tissue. In the future, BPR might be used to develop definitive diagnostic gene signatures for IPF, prognostic gene signatures for IPF or gene signatures for other non-neoplastic lung disorders such as bronchiolitis obliterans.
Enhanced Toll-like receptor (TLR) responses of TNFR-associated factor 3 (TRAF3)-deficient B lymphocytes
Authors: Xie Ping , Poovassery Jayakumar , Stunz Laura L , Smith Sonja M , Schultz Mark L , Carlin Lindsey E , Bishop Gail A
Published: October 2011

The key role of TRAF6 in TLR signaling pathways is well known. More recent evidence has implicated TRAF3 as another TRAF family member important to certain TLR responses of myeloid cells. Previous studies demonstrate that TRAF3 functions are highly context-dependent, displaying receptor and cell-type specificity. We thus examined the TLR responses of TRAF3−/−mouse B lymphocytes to test the hypothesis that TRAF3 plays distinct roles in such responses, depending on cell type. TRAF3−/− DC are known to have a defect in type 1 IFN production and here, showed diminished production of TNF and IL-10 and unaltered IL-6. In marked contrast, TRAF3−/− B cells made elevated amounts of TNF and IL-6 protein, as well as IL-10 and IP-10 mRNA, in response to TLR ligands. Also, in contrast to TRAF3−/− DC, the type 1 IFN pathway was elevated in TRAF3−/− B cells. Increased early responses of TRAF3−/− B cells to TLR signals were independent of cell survival or proliferation but associated with elevated canonical NF-κB activation. Additionally, TRAF3−/− B cells displayed enhanced TLR-mediated expression of AID and Ig isotype switching. Thus, TRAF3 plays varied and cell type-specific, biological roles in TLR responses.
Minireview: Stress-Related Psychiatric Disorders with Low Cortisol Levels: A Metabolic Hypothesis
Authors: Yehuda Rachel , Seckl Jonathan
Published: October 2011

Several stress-associated neuropsychiatric disorders, notably posttraumatic stress disorder and chronic pain and fatigue syndromes, paradoxically exhibit somewhat low plasma levels of the stress hormone cortisol. The effects appear greatest in those initially traumatized in early life, implying a degree of developmental programming, perhaps of both lower cortisol and vulnerability to psychopathology. In these conditions, lowered cortisol is not due to any adrenal or pituitary insufficiency. Instead, two processes appear involved. First, there is increased target cell sensitivity to glucocorticoid action, notably negative feedback upon the hypothalamic-pituitary-adrenal (stress) axis. Altered density of the glucocorticoid receptor is inferred, squaring with much preclinical data showing early life challenges can permanently program glucocorticoid receptors in a tissue-specific manner. These effects involve epigenetic mechanisms. Second, early life trauma/starvation induces long-lasting lowering of glucocorticoid catabolism, specifically by 5α-reductase type 1 (predominantly a liver enzyme) and 11β-hydroxysteroid dehydrogenase type 2 (in kidney), an effect also seen in model systems. These changes reflect a plausible early-life adaptation to increase the persistence of active cortisol in liver (to maximize fuel output) and kidney (to increase salt retention) without elevation of circulating levels, thus avoiding their deleterious effects on brain and muscle. Modestly lowered circulating cortisol and increased vulnerability to stress-associated disorders may be the outcome. This notion implies a vulnerable early-life phenotype may be discernable and indicates potential therapy by modest glucocorticoid replacement. Indeed, early clinical trials with cortisol have shown a modicum of promise.
Quantitative Calibration Models for the Determination of Azithromycin and Decladinosylazithromycin in Azithromycin Injection Powder by Using Diffuse Reflectance near Infrared Spectroscopy
Authors: Dong Ji-Xiong , Zhou Wen-Bo , Feng Yan-Chun , Song Dan-Qing , Hu Chang-Qin
Published: October 2011

A quantitative analysis method based on near infrared (NIR) spectroscopy was developed for determining the azithromycin content and its degradation product impurity (decladinosylazithromycin) in azithromycin for injection. Two quantitative models were obtained by evaluating 18 laboratory samples and 44 commercial samples formulated as hydrochlorate, phosphate, lactate and citrate salts. The samples had an azithromcyin content ranging from 74.2% to 91.0% (w/w) and decladinosylazithromycin ranging from 0.1% to 7.7% (w/w). The root mean square error of cross-validation for the azithromycin model and decladinosylazithromycin model were 1.54% and 0.49%, respectively. The estimated limit of detection and limit of quantification for the decladinosylazithromycin calibration were about 1.2% and 4.1% (w/w), respectively. In addition, the quantitative models were validated in terms of specificity, linearity, accuracy, repeatability and intermediate precision, according to the International Conference on Harmonisation guidelines, by evaluating the characteristics of the NIR spectra. The results showed that the models were satisfactory. Our results demonstrated that a universal quantitative model based on NIR diffuse reflectance spectroscopy could be used as a quick and reliable method for quality control of low-dose impurities in pharmaceutical drugs.
The Importance of Balanced Data Sets for Partial Least Squares Discriminant Analysis: Classification Problems Using Hyperspectral Imaging Data
Authors: Lindström Susanne W. , Geladi Paul , Jonsson Oskar , Pettersson Fredrik
Published: October 2011

This study investigates the effect of imbalanced spectral data in the training set, when developing partial least squares discriminant analysis (PLS-DA) classification models for use in future predictions. The experimental study was performed using a real hyperspectral short-wavelength infrared image data set collected from bakery products (buns) containing contaminants (flies) but similar applications for other insects, paper and plastic were also tested. The contaminants represent a very small proportion of the images relative to the bun. The PLS-DA model aims at accurately detecting and classifying the contaminants and this requires a modification of the calibration data set. The paper deals with problems caused by unbalanced calibration data sets and how to remedy them. In the example it was demonstrated that, by balancing the calibration data from 58,476 bun pixels + 279 fly pixels to 279 bun + 279 fly pixels, the number of true predictions could be improved with a smaller number of PLS components used in the model. The improvement for flies increased from 65% true predictions with ten PLS components to > 99% true prediction with five to six PLS components. The true prediction for bun went from 100% to 99.5% with six PLS components which is an acceptable reduction. Theoretical explanations are included.
Soil Carbon Determination in a Mediterranean Vertisol by Visible and near Infrared Reflectance Spectroscopy
Authors: Fontán José M. , López-Bellido Luis , García-Olmo Juan , López-Bellido Rafael J.
Published: October 2011

The monitoring of the C content of agricultural lands requires long-term experiments, the analysis of a large number of samples, various sampling depths and adequate analytical tools to perform the experiments. Near infrared (NIR) reflectance spectroscopy is a fast, reliable and low-cost analytical tool for the determination of soil C content. The objective of this study was to present NIR spectroscopy technology as a reliable method to monitor C concentration (total C, inorganic C and organic C) of soil samples from a long-term experiment established in 1986 in Cordoba (Spain). The soil is a rain-fed vertisol, characteristic of Mediterranean agricultural systems. The soil samples studied from four different years (1997, 2000, 2003 and 2006) included all of the variabilities existing in the long-term experiment: tillage system (conventional tillage vs no tillage), crop rotations [wheat ( Triticum aestivum L)-chickpea ( Cicer arietinum L), wheat-faba bean ( Vicia faba L), wheat-sunflower ( Helianthus annus L), wheat-fallow and wheat-wheat], N fertiliser rate (0 kg N ha−1, 50 kg N ha−1, 100 kg N ha−1 and 150 kg N ha−1), as well as different soil depths (0–15 cm, 15–30 cm, 30–60 cm and 60–90 cm). Calibration models were obtained with 492 samples from the aforementioned vertisol using visible and NIR spectroscopy (vis-NIR) and, when tested using a validation sample set, returned the values: total C ( r2 = 0.92, SEP = 1 g kg−1, RER = 26, RPD = 4.8); inorganic C ( r2 = 0.95, SEP = 1.5 g kg−1, RER = 26.6, RPD = 4.6) and organic C ( r2 = 0.76, SEP = 0.8 g kg−1 RER = 12.3, RPD = 2). The vis-NIR models developed reliably predicted the total, inorganic and organic C content at plot scale (homogeneous sample set). The advantage deriving from very specific vis-NIR calibrations for prediction of soil C is that one can rapidly and economically predict C in the study area, enabling monitoring to compare soil C evolution depending on time and variables such as tillage, crop rotation and fertilisation. To develop vis-NIR models at local and regional scales would require a more heterogeneous sample set and adequate calibration/validation strategies.
Increased MMP-2 in healthy postmenopausal women
Authors: Muzzio María Luz , Miksztowicz Veronica , Repetto Esteban Martín , Brites Fernando , Berg Gabriela , Schreier Laura
Published: October 2011

Background

Matrix metalloproteases 2 (MMP-2) and 9 (MMP-9) are involved in the atherosclerosis process. The objective of the study was to evaluate MMP-2 and MMP-9 activities and other circulating inflammatory factors in healthy postmenopausal women (PMW) as a model of subclinical atherosclerosis.

Methods

Twenty-three PMW and 13 premenopausal women (PreMW) were selected following established criteria. The main measurements in plasma samples were: lipid–lipoprotein profile, high-sensitivity C-reactive protein (hs-CRP) (immunoturbidimetry), soluble vascular cellular adhesion molecules (sVCAM-1) enzyme-linked immunosorbent assay and MMP activity by zymography.

Results

The relative areas of MMP-2 were increased in PMW: 1.1 (0.1) versus 0.6 (0.05), P < 0.02. MMP-9 was only detected in three PMW and one PreMW. MMP-2 correlated with HDL-cholesterol ( r = −0.51), triglycerides ( r = 0.67), apolipoprotein B ( r = 0.47), hs-CRP ( r = 0.42), homeostasis model assessment ( r = 0.53) and waist circumference ( r = 0.40), at least P < 0.02. sVCAM-1 showed no difference between groups: 28.7 (5.5) versus 35.5 (20) ng/mL, but correlated with MMP-2 and hs-CRP ( r = 0.46 and r = 0.48 respectively, P < 0.05).

Conclusions

In postmenopause, the increase in MMP-2 reflects the systemic specific inflammatory process that accompanies atherogenesis.
Leucovorin, Fluorouracil, and Irinotecan (FOLFIRI) plus Bevacizumab for Metastatic Colorectal Cancer
Authors: Massoud R. Vivian , Solimando Dominic A. , Waddell J. Aubrey
Published: October 2011

The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases.
Romiplostim: Idiopathic Thrombocytopenic Purpura (Children/Adolescents)
Authors: Generali Joyce A. , Cada Dennis J.
Published: October 2011

This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a quarterly publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to jgeneral@kumc.edu .
Boceprevir and Telaprevir
Authors: Cada Dennis J. , Levien Terri L. , Baker Danial E.
Published: October 2011

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. Subscribers to The Formulary Monograph Service also receive access to a pharmacy bulletin board, The Formulary Information Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy are discussed on The F.I.X.

Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service or The F.I.X., call The Formulary at 800-322-4349. The October 2011 monograph topics are on ticagrelor, peginesatide, linaclotide, vemurafenib, and tafluprost. The DUE/MUE is on ticagrelor.
Cell-Autonomous and Non-Cell-Autonomous Neuroprotective Functions of RORα in Neurons and Astrocytes during Hypoxia
Authors: Jolly Sarah , Journiac Nathalie , Naudet Frédéric , Gautheron Vanessa , Mariani Jean , Vernet-der Garabedian Béatrice
Published: October 2011

There is increasing evidence to suggest that the neuronal response to hypoxia is regulated through their interactions with astrocytes. However, the hypoxia-induced molecular mechanisms within astrocytes which influence neuronal death have yet to be characterized. In this study, we investigated the roles of the nuclear receptor RORα (retinoid-related orphan receptor-α) respectively in neurons and astrocytes during hypoxia using cultures and cocultures of neurons and astrocytes obtained from RORα-deficient mice. We found that loss of RORα function in neuronal cultures increases neuronal death after hypoxia, suggesting a cell-autonomous neuroprotective effect of RORα. Moreover, wild-type neurons cocultured with RORα-deficient astrocytes are characterized by a higher death rate after hypoxia than neurons cocultured with wild-type astrocytes, suggesting that RORα also has a non-cell-autonomous action. By using cocultures of neurons and astrocytes of different genotypes, we showed that this neuroprotective effect of RORα in astrocytes is additive to its effect in neurons, and is mediated in part by cell-to-cell interactions between neurons and astrocytes. We also found that RORα is upregulated by hypoxia in both neurons and astrocytes. Furthermore, our data showed that RORα does not alter oxidative mechanisms during hypoxia but regulates hypoxic inducible factor 1α (HIF-1α) expression, a major regulator of hypoxia sensing, in a cell-specific manner. Indeed, the neuroprotective function of RORα in astrocytes correlates with a downregulation of HIF-1α selectively in these cells. Altogether, our results show that RORα is a key molecular player in hypoxia, protecting neurons through its dual action in neurons and astrocytes.
Heightened Nicotinic Regulation of Auditory Cortex during Adolescence
Authors: Kawai Hideki D. , Kang Ho-An , Metherate Raju
Published: October 2011

Adolescent smoking is associated with auditory-cognitive deficits and structural alterations to auditory thalamocortical systems, suggesting that higher auditory function is vulnerable to nicotine exposure during adolescence. Although nicotinic acetylcholine receptors (nAChRs) regulate thalamocortical processing in adults, it is not known whether they regulate processing at earlier ages since their expression pattern changes throughout postnatal development. Here we investigate nicotinic regulation of tone-evoked current source density (CSD) profiles in mouse primary auditory cortex from just after hearing onset until adulthood. At the youngest ages, systemic nicotine did not affect CSD profiles. However, beginning in early adolescence nicotine enhanced characteristic frequency (CF)-evoked responses in layers 2–4 by enhancing thalamocortical, early intracortical, and late intracortical response components. Nicotinic responsiveness developed rapidly and peaked over the course of adolescence, then declined thereafter. Generally, responsiveness in females developed more quickly, peaked earlier, and declined more abruptly and fully than in males. In contrast to the enhancement of CF-evoked responses, nicotine suppressed shorter-latency intracortical responses to spectrally distant (non-CF) stimuli while enhancing longer-latency responses. Intracortical infusion of nAChR antagonists showed that enhancement of CF-evoked intracortical processing involves α4β2*, but not α7, nAChRs, whereas both receptor subtypes regulate non-CF-evoked late intracortical responses. Notably, antagonist effects in females implied regulation by endogenous acetylcholine. Thus, nicotinic regulation of cortical processing varies with age and sex, with peak effects during adolescence that may contribute to the vulnerability of adolescents to smoking.