bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell proliferation along vascular islands during microvascular network growth
Authors: Kelly-Goss Molly R , Winterer Erica R , Stapor Peter C , Yang Ming , Sweat Richard S , Stallcup William B , Schmid-Schönbein Geert W , Murfee Walter L
Published: November 2012

Background

Observations in our laboratory provide evidence of vascular islands, defined as disconnected endothelial cell segments, in the adult microcirculation. The objective of this study was to determine if vascular islands are involved in angiogenesis during microvascular network growth.

Results

Mesenteric tissues, which allow visualization of entire microvascular networks at a single cell level, were harvested from unstimulated adult male Wistar rats and Wistar rats 3 and 10 days post angiogenesis stimulation by mast cell degranulation with compound 48/80. Tissues were immunolabeled for PECAM and BRDU. Identification of vessel lumens via injection of FITC-dextran confirmed that endothelial cell segments were disconnected from nearby patent networks. Stimulated networks displayed increases in vascular area, length density, and capillary sprouting. On day 3, the percentage of islands with at least one BRDU-positive cell increased compared to the unstimulated level and was equal to the percentage of capillary sprouts with at least one BRDU-positive cell. At day 10, the number of vascular islands per vascular area dramatically decreased compared to unstimulated and day 3 levels.

Conclusions

These results show that vascular islands have the ability to proliferate and suggest that they are able to incorporate into the microcirculation during the initial stages of microvascular network growth.
Astragalus saponins downregulate vascular endothelial growth factor under cobalt chloride-stimulated hypoxia in colon cancer cells
Authors: Law Pui-Ching , Auyeung Kathy K , Chan Lok-Yi , Ko Joshua K
Published: November 2012

Background

Our ongoing research has revealed that total saponins extracted from the medicinal herb Radix Astragali (AST) exhibits significant growth-inhibitory and proapoptotic effects in human cancer cells. In the present study, the potential of AST in controlling angiogenesis was further investigated with elaboration of the underlying molecular mechanism in human colon cancer cell and tumor xenograft.

Results

AST decreased the protein level of VEGF and bFGF in HCT 116 colon cancer cells in a time- and dose-dependent manner. Among the Akt/mTOR signal transduction molecules being examined, AST caused PTEN upregulation, reduction in Akt phosphorylation and subsequent activation of mTOR. AST also suppressed the induction of HIF-1α and VEGF under CoCl2-mimicked hypoxia. These effects were intensified by combined treatment of AST with the mTOR inhibitor rapamycin. Despite this, our data also indicate that AST could attenuate cobalt chloride-evoked COX-2 activation, while such effect on COX-2 and its downstream target VEGF was intensified when indomethacin was concurrently treated. The anti-carcinogenic action of AST was further illustrated in HCT 116 xenografted athymic nude mice. AST significantly suppressed tumor growth and reduced serum VEGF level in vivo. In the tumor tissues excised from AST-treated animals, protein level of p-Akt, p-mTOR, VEGF, VEGFR1 and VEGFR2 was down-regulated. Immunohistochemistry has also revealed that AST effectively reduced the level of COX-2 in tumor sections when compared with that in untreated control.

Conclusion

Taken together, these findings suggest that AST exerts anti-carcinogenic activity in colon cancer cells through modulation of mTOR signaling and downregulation of COX-2, which together reduce VEGF level in tumor cells that could potentially suppress angiogenesis.
Cost-effectiveness analysis of different rescue therapies in patients with lamivudine-resistant chronic hepatitis B in China
Authors: Wu Bin , Shen Jinfang , Cheng Huafeng
Published: November 2012

Background

Several rescue therapies have been used in patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB); however, the economic outcome of these therapies is unclear. The object of the current analysis was to evaluate the lifetime cost-effectiveness of rescue therapies among patients with LAM-resistant CHB.

Methods

A Markov model was developed to simulate the clinical course of patients with LAM-resistant CHB. From the perspective of Chinese health care, a lifetime cost-utility analysis was performedfor 4 rescue strategies: adefovir (ADV), entecavir (ETV) or tenofovir (TDF) monotherapy and combination therapy using LAM and ADV. A hypothetical cohort of 45-year-old patients with genotypic or clinical LAM-resistant CHB entered the model, and the beginning health state was LAM-resistant CHB without other complications. The transition probabilities, efficacy and resistance data for each rescue therapy as well as the costs and utility data were estimated from the literature. The discount rate (3%) utilized for costs and benefits. Sensitivity analyses were used to explore the impact of uncertainty on the results.

Results

In LAM-resistant HBeAg-positive and HBeAg-negative CHB cohorts, TDF monotherapy and combination therapy were on the efficiency frontier for both positive and negative populations. Compared with no treatment, the use of combination therapy cost an additional $6,531.7 to gain 1 additional quality-adjusted life year (QALY) for HBeAg-positive patients and $4,571.7 to gain 1 additional QALY for HBeAg-negative patients. TDF monotherapy for HBeAg-positive patients, shows greater increase in QALYs but higher incremental cost-effectiveness ratio (ICER) in comparison with combination therapy. In probabilistic sensitivity analyses, combination therapy was the preferred option for health care systems with limited health resources, such as Chinese health care system.

Conclusion

In Chinese patients with LAM-resistant CHB, combination therapy is a more cost-effective option than the competing rescue therapies.
Lead level in seminal plasma may affect semen quality for men without occupational exposure to lead
Authors: Wu Hsien-Ming , Lin-Tan Dan-Tzu , Wang Mei-Li , Huang Hong-Yuan , Lee Chyi-Long , Wang Hsin-Shih , Soong Yung-Kuei , Lin Ja-Liang
Published: November 2012

Background

Infertility affects approximately 10–15% of reproductive-age couples. Poor semen quality contributes to about 25% of infertile cases. Resulting from the direct effect on testicular function or hormonal alterations, heavy metals exposure has been related to impaired semen quality. The objective of this study was to assess the level of lead in the seminal plasma in men without occupational exposure to lead, and to determine the relationship between semen quality and lead concentration in the semen.

Methods

This is a prospective and nonrandomized clinical study conducted in University infertility clinic and academic research laboratory. Three hundred and forty-one male partners of infertile couples undergoing infertility evaluation and management were recruited to the study. Semen samples collected for the analyses of semen quality were also used for the measurement of lead concentrations. Semen samples were evaluated according to the WHO standards.

Results

All subjects were married and from infertile couples without occupational exposure to lead. There is a significant inverse correlation between the lead concentration in seminal plasma and sperm count. A higher semen lead concentration was correlated with lower sperm count, but not with semen volume, sperm motility or sperm morphology as assessed by simple linear regression.

Conclusions

We found that semen lead concentration was significantly higher among the patients with lower sperm count. To our knowledge, this is the first study to demonstrate that a high level of lead accumulation in semen may reduce the sperm count contributing to infertility of men without occupational exposure to lead.
Prognostic value of KRAS genotype in metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx) according to extension of metastatic disease
Authors: Bruera Gemma , Cannita Katia , Di Giacomo Daniela , Lamy Aude , Troncone Giancarlo , Dal Mas Antonella , Coletti Gino , Frébourg Thierry , Sabourin Jean Christophe , Tosi Mario , Ficorella Corrado , Ricevuto Enrico
Published: November 2012

Background

Bevacizumab (BEV) plus triplet chemotherapy can increase efficacy of first-line treatment of metastatic colorectal cancer (MCRC), particularly integrated with secondary liver surgery in liver-limited (L-L) patients. The prognostic value of the KRAS genotype in L-L and other or multiple metastatic (O/MM) MCRC patients treated with the FIr-B/FOx regimen was retrospectively evaluated.

Methods

Tumoral and metastatic samples were screened for KRAS codon 12 and 13 and BRAF mutations by SNaPshot and/or direct sequencing. Fit MCRC patients <75 years were consecutively treated with FIr-B/FOx regimen: weekly 12-h timed flat-infusion/5-fluorouracil (TFI 5-FU) 900 mg/m2, days 1, 2, 8, 9, 15, 16, 22 and 23; irinotecan (CPT-11) 160 mg/m2 plus BEV 5 mg/kg, days 1, 15; oxaliplatin (OXP) 80 mg/m2, days 8, 22; every 4 weeks. MCRC patients were classified as L-L and O/MM. Activity and efficacy were evaluated and compared using log-rank test.

Results

In all, 59 patients were evaluated: 31 KRAS wild-type (53%), 28 KRAS mutant (47%). At 21.5 months median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months. PFS and OS were not significantly different. PFS and OS were significantly different in L-L compared to O/MM evaluable patients. In KRAS wild-type patients, clinical outcome of 12 L-L compared to 18 O/MM was significantly different: PFS 21 versus 12 months and OS 47 versus 28 months, respectively. In KRAS mutant patients, the clinical outcome of 13 L-L compared to 14 O/MM was not significantly different: PFS 11 months equivalently and OS 39 versus 19 months, respectively.

Conclusions

The KRAS genotype wild-type and mutant does not significantly affect different clinical outcomes for MCRC patients treated with the first-line FIr-B/FOx intensive regimen. KRAS wild-type patients with L-L disease may achieve a significantly prolonged clinical outcome due to integration with secondary liver surgery, with respect to KRAS mutant patients.
Polymers containing phosphorus groups and polyethers: from synthesis to application
Authors: Iliescu Smaranda , Zubizarreta Leire , Plesu Nicoleta , Macarie Lavinia , Popa Adriana , Ilia Gheorghe
Published: November 2012

Background

Phosphorus-containing high performance polymers have aroused wide interest, mainly due to good mechanical properties and their excellent fire resistance. The flexibility of synthetic polyphosphoesters allows the development of polymers in order to obtain solid polymer electrolytes for rechargeable lithium batteries based on solid films with superior fire resistance.

Results

Novel linear Phosphonate-PEG polymers were synthesized by solution polycondensation of 4-chlorophenyldichlorophosphonate as a linking agent and poly(ethylene glycol)s with different molecular weights in the presence of triethylamine or 1-methylimidazole as acid scavenger. The yields were between 54% and 88% and inherent viscosity between 0.18-0.48 dl/g. Molar masses, Mn were about 26300 g/mol for polyphosphonates with PEG 2000 and 4600 g/mol for polyphosphonates with PEG 200. The LOI values for these polymers and membranes are in the range of 26–29. The membranes based on polyphosphonate with PEG 200 and 2000 showed conductivity between 6 × 10-8 S.cm-1 and 6 × 10-7 S.cm-1 at room temperature and total ionic transference number between 0.87- 0.96. The evolution of conductivity vs. temperature is linear.

Conclusions

1-methylimidazole was found to be better HCl scavenger than triethylamine, and allowed higher yields and more eco-friendly synthesis of the Phosphonate-PEG polymers for SPE. These polymers and membranes based on these polymers showed good LOI values and indicate an improvement of the safety of lithium batteries. The membranes present conductivities around 6 × 10-7 S.cm-1at room temperature and total ionic transference number is higher for membranes based on polymers with high EG unit content. Best results yield 88%, inherent viscosities 0.48 dl/g and Mn 26000 were obtained with 1-methylimidazole and PEG 2000. These membranes based on these polymers showed good LOI values (in the range 26-29%) and indicate an improvement of the safety of lithium batteries.
Crystal structures of wild-type and mutated cyclophilin B that causes hyperelastosis cutis in the American quarter horse
Authors: Boudko Sergei P , Ishikawa Yoshihiro , Lerch Thomas F , Nix Jay , Chapman Michael S , Bächinger Hans Peter
Published: November 2012

Background

Hyperelastosis cutis is an inherited autosomal recessive connective tissue disorder. Affected horses are characterized by hyperextensible skin, scarring, and severe lesions along the back. The disorder is caused by a mutation in cyclophilin B.

Results

The crystal structures of both wild-type and mutated (Gly6->Arg) horse cyclophilin B are presented. The mutation neither affects the overall fold of the enzyme nor impairs the catalytic site structure. Instead, it locally rearranges the flexible N-terminal end of the polypeptide chain and also makes it more rigid.

Conclusions

Interactions of the mutated cyclophilin B with a set of endoplasmic reticulum-resident proteins must be affected.
Immunoregulatory properties of rapamycin-conditioned monocyte-derived dendritic cells and their role in transplantation
Authors: Macedo Camila , Turquist Hēth , Metes Diana , Thomson Angus W
Published: November 2012

In efforts to minimize the chronic administration of immunosuppression (IS) drugs in transplantation and autoimmune disease, various cell-based tolerogenic therapies, including the use of regulatory or tolerogenic dendritic cells (tolDC) have been developed. These DC-based therapies aim to harness the inherent immunoregulatory potential of these professional antigen-presenting cells. In this short review, we describe both the demonstrated tolerogenic properties, and current limitations of rapamycin-conditioned DC (RAPA-DC). RAPA-DC are generated through inhibition of the integrative kinase mammalian target of rapamycin (mTOR) by the immunosuppressive macrolide rapamycin during propagation of monocyte-derived DC. Consistent with the characteristics of tolDC, murine RAPA-DC display resistance to phenotypic maturation induced by pro-inflammatory stimuli; exhibit the ability to migrate to secondary lymphoid tissue (important for ‘cross-presentation’ of antigen to T cells), and enrich for naturally-occurring CD4+ regulatory T cells. In rodent models, delivery of recipient-derived RAPA-DC pulsed with donor antigen prior to organ transplantation can prolong allogeneic heart-graft survival indefinitely, especially when combined with a short course of IS. These encouraging data support ongoing efforts to develop RAPA-DC for clinical testing. When compared to murine RAPA-DC however, human RAPA-DC have proven only partially resistant to maturation triggered by pro-inflammatory cytokines, and display heterogeneity in their impact on effector T-cell expansion and function. In total, the evidence suggests the need for more in-depth studies to better understand the mechanisms by which mTOR controls human DC function. These studies may facilitate the development of RAPA-DC therapy alone or together with agents that preserve/enhance their tolerogenic properties as clinical immunoregulatory vectors.
Organic amendment of an ultisol: effects on soil properties, growth, and yield of maize in Southern Guinea savanna zone of Nigeria
Authors: Ogundare Kayode , Agele Samuel , Aiyelari Peter
Published: November 2012

Background

The Southern Guinea savanna zone of Nigeria is characterized by inherently low soil fertility status and rapid nutrient depletion especially soil organic matter. However, this zone is characterized by abundant agricultural land and is a potential for crop production. Field experiments were conducted in order to evaluate the effects of integrated use of agricultural waste materials and compound mineral fertilizer on soil and plant nutrient status, growth, and yield of maize in ultisol in the Southern Guinea savanna zone of Nigeria.

Results

Application of organic waste alone and in combination with mineral fertilizer enhanced root and shoot biomass, leaf area development, and yield and components of maize. Treatment effects were significant on growth characteristics of maize (stem girth, leaf area, plant height and days to 50% tasselling, root and shoot biomass). Sole application of NPK fertilizer (400 kg/ha) was not significant over the combined use of poultry manure and NPK on girth, leaf area, and plant height. Mean values of stem girth, leaf area, and plant height ranged between 2.05 and 3.8 cm, 0.26 and 0.54 m2, and 84.7 and 209.4 cm, respectively. Root and shoot dry weights were highest under sole NPK application compared with plots where either sole wastes or wastes in combination with reduced NPK were application of NPK fertilizer (400 kg/ha) was not significant over combined use of poultry manure and NPK on stem applied. Integrated use of agricultural wastes and NPK also enhanced root and shoot dry weights compared with sole application of wastes as well as seed weight per plant, 100-seed weight, and number of seeds per cob and grain yield. Among the agricultural wastes applied, poultry manure enhanced the growth and seed yield characteristics of maize. This treatment increased the seed weight per plant, number of seeds per cob, 100-seed weight and seed yield by 55.6%, 66.5%, and 55.4%, respectively over Chromolaena and neem seed cake. Chromolaena and neem seed cake produced similar grain weight per plant, 100-seed weight, number of seed per cob, and seed yield. Poultry manure significantly enhanced the growth and seed yield characteristics of maize over Chromolaena and neem seed cake.

Conclusions

Integrated use of organic wastes and mineral NPK fertilizer showed promising potential for improving soil fertility, growth, and yield of maize in the Southern Guinea savanna agroecological zone of Nigeria. It is recommended that poultry manure at 7 t/ha plus NPK fertilizer at 200 kg/ha be adopted for maize cultivation in the study area.
Aggressive disease defined by cytogenetics is associated with cytokine dysregulation in CLL/SLL patients
Authors: Karmali Reem , Paganessi Laura A , Frank Robin R , Jagan Sucheta , Larson Melissa L , Venugopal Parameswaran , Gregory Stephanie A , Christopherson Kent W
Published: November 2012

Specific cytokine signatures correlate with genetic aberrations in CLL/SLL, reflecting a pattern of Th1/Th2/Treg dysregulation that may predict aggressive disease, and a need for therapy.

Early treatment of CLL/SLL does not impact survival-reflecting limitations in detecting progression early and identifying asymptomatic patients likely to benefit from early treatment. Improved understanding of CLL/SLL biology would identify better prognostic/predictive markers. This study attempts to address these issues by determining the relationship between cytokine aberrations and poor clinical outcomes in CLL/SLL in the context of a genetic–based prognostic model. Fifty-nine serum cytokines/chemokines were measured in 28 untreated CLL/SLL patients. Patients were stratified as GR or int/PR using cytogenetics. Comparison of CLL/SLL with 28 HCs revealed increased expression of Th2 cytokines (IL-10, IL-5, sIL-2Rα; P≤0.01) and decreased levels of Th1 cytokines (IL-17, IL-23, IFN-γ; P≤0.003). In a multivariate analysis of GR versus int/PR groups, differential expression of sIL-2Rα maintained significance with increased expression in int/PR CLL/SLL. With median follow-up of 54.3 months after diagnosis, four patients incurred disease progression, with an IL-17/sIL-2Rα model predicting need for treatment in all cases. In summary, specific cytokine signatures are associated with genetically defined aggressive disease and predict need for therapy. This suggests utility in detecting disease progression early, identifying those likely to incur a survival advantage with early treatment, and directing future therapy.
Current trends in inflammatory and immunomodulatory mediators in sepsis
Authors: Aziz Monowar , Jacob Asha , Yang Weng-Lang , Matsuda Akihisa , Wang Ping
Published: November 2012

Review on sepsis mediators, and roles in innate and adaptive immune systems, as well as implications for therapeutics.

Sepsis refers to severe systemic inflammation in response to invading pathogens. An overwhelming immune response, as mediated by the release of various inflammatory mediators, can lead to shock, multiple organ damage, and even death. Cytokines, proteases, lipid mediators, gaseous substances, vasoactive peptides, and cell stress markers play key roles in sepsis pathophysiology. Various adhesion molecules and chemokines sequester and activate neutrophils into the target organs, further augmenting inflammation and tissue damage. Although the anti-inflammatory substances counterbalance proinflammatory mediators, prolonged immune modulation may cause host susceptibility to concurrent infections, thus reflecting enormous challenge toward developing effective clinical therapy against sepsis. To understand the complex interplay between pro- and anti-inflammatory phenomenon in sepsis, there is still an unmet need to study newly characterized mediators. In addition, revealing the current trends of novel mediators will upgrade our understanding on their signal transduction, cross-talk, and synergistic and immunomodulating roles during sepsis. This review highlights the latest discoveries of the mediators in sepsis linking to innate and adaptive immune systems, which may lead to resolution of many unexplored queries.
The granulocyte-colony stimulating factor receptor (G-CSFR) interacts with retinoic acid receptors (RARs) in the regulation of myeloid differentiation
Authors: Chee Lynette C Y , Hendy Jean , Purton Louise E , McArthur Grant A
Published: November 2012

Residual granulopoiesis persists in mice lacking both G-CSFR and RARα, or RARγ; G-CSFR is required for granulopoietic expansion seen with loss of RARγ.

The key roles of RARs and G-CSFR in the regulation of granulopoiesis have been well-documented. In this study, we sought to investigate the interaction between G-CSFR and RARs in myeloid differentiation of adult mice through conditional deletion of RARα or RARγ on a G-CSFR−/− background and by pharmacological intervention of WT and G-CSFR−/− mice with a pan-RAR inverse agonist, NRX194310. Our findings show that residual granulopoiesis still persists in mice doubly null for G-CSFR and RARα or RARγ, confirming that RARs and G-CSFR are dispensable in maintaining residual granulopoiesis. Moreover, an increase in mature myeloid cells was seen in the conditional RARγΔ/Δ mice and WT mice treated with NRX194310, likely mediated through increased G-CSF production. However, with the loss of G-CSFR, this expansion in granulopoiesis was attenuated, supporting the hypothesis that G-CSFR signaling interacts with RARs in the regulation of myeloid differentiation.
Nameless History Before and AfterLas Meninas: Luther Blissett's Archaeological Fiction
Authors: Ovan Sabrina
Published: November 2012

This article provides a comparative reading of “Las Meninas,” Michel Foucault's opening essay in The Order of Things, and the historical novel Q, written by the Italian collective known as Luther Blissett. Foucault's opening chapter, a close reading of Diego Velázquez's 1656 painting portraying the royal family of Spain, is the narration of an epistemological break through the analysis of an image. In a similar fashion, Q, composed in 1999 by the four writers of the Italian collective, the Luther Blissett Project, takes a fictionalized visual representation as a point of departure for a tale of historical and epistemological transformation. Following this idea, the article shows how the use of visual tropes to create meaning and definition (in a word, to name) is inherent to the narration of the epistemic rupture, and more specifically, it analyzes how this epistemic change, interpreted as if it were complete within the frames of Las Meninas, is still indeterminate and “in the making” during the age immediately preceding: the age narrated in Q. If Foucault's The Order of Things takes as a point of departure the closure of the episteme from the point of view of the new system of knowledge epitomized by Las Meninas, the collective novel Q concentrates on the passage from one age to another. The lack of a unified author for the novel reinforces this notion of displacement by multiplying the narratives, the characters, the historical references. The article furthermore reflects on the nature of these narratives as paradigmatic of the ages they strive to represent, particularly in their implied resonance on class and power structures: an age of nameless history, where individuality is characterized by blurred signifiers and collectivity is the founding element of everyday social relations, ends in an enclosed frame, a limited and specified space where names and signatures (and by extension power, property, hierarchy) become the domain of the individual.
Prdm14 acts upstream of islet2 transcription to regulate axon growth of primary motoneurons in zebrafish
Authors: Liu Chao , Ma Weirui , Su Wenjing , Zhang Jian
Published: November 2012

The precise formation of three-dimensional motor circuits is essential for movement control. Within these circuits, motoneurons (MNs) are specified from spinal progenitors by dorsoventral signals and distinct transcriptional programs. Different MN subpopulations have stereotypic cell body positions and show specific spatial axon trajectories. Our knowledge of MN axon outgrowth remains incomplete. Here, we report a zebrafish gene-trap mutant, short lightning (slg), in which prdm14 expression is disrupted. slg mutant embryos show shortened axons in caudal primary (CaP) MNs resulting in defective embryonic movement. Both the CaP neuronal defects and behavior abnormality of the mutants can be phenocopied by injection of a prdm14 morpholino into wild-type embryos. By removing a copy of the inserted transposon from homozygous mutants, prdm14 expression and normal embryonic movement were restored, confirming that loss of prdm14 expression accounts for the observed defects. Mechanistically, Prdm14 protein binds to the promoter region of islet2, a known transcription factor required for CaP development. Notably, disruption of islet2 function caused similar CaP axon outgrowth defects as observed in slg mutant embryos. Furthermore, overexpression of islet2 in slg mutant embryos rescued the shortened CaP axon phenotypes. Together, these data reveal that prdm14 regulates CaP axon outgrowth through activation of islet2 expression.
The PBAP remodeling complex is required for histone H3.3 replacement at chromatin boundaries and for boundary functions
Authors: Nakayama Takahiro , Shimojima Tsukasa , Hirose Susumu
Published: November 2012

Establishment and maintenance of epigenetic memories are essential for development. Replacement of canonical histone H3 by its variant H3.3 has been implicated in cellular memory. Drosophila sequence-specific DNA-binding protein GAGA factor and a chromatin factor FACT direct H3.3 replacement in conjunction with H3.3-specific chaperone HIRA at chromatin boundaries to counteract the spreading of silent chromatin. However, little is known about which ATP-driven chromatin remodeling factor is responsible for the H3.3 replacement at chromatin boundaries. Here, we report that GAGA factor associates with the Polybromo-associated Brm (PBAP) remodeling complex, which consists of many Trithorax group proteins, and recruits this complex to chromatin boundaries d1 (which is downstream of w), the Fab-7 DNase-hypersensitive site (HS) 1 of Abd-B and the bxd region of Ubx. Trl-encoding GAGA factor, brm and polybromo/bap180 mutations compromise the H3.3 replacement and boundary functions in a synergistic manner. Furthermore, Polybromo is necessary for generation of the DNase HS at d1, and HIRA functions to restore the alteration. Taken together, we propose that FACT and PBAP complexes are recruited to chromatin boundaries in a GAGA factor-dependent manner, and are needed for H3.3 replacement to execute boundary functions. Our results provide new insight into the function of the trithorax group during development.
Cell-autonomous Notch activity maintains the temporal specification potential of skeletal muscle stem cells
Authors: Mourikis Philippos , Gopalakrishnan Swetha , Sambasivan Ramkumar , Tajbakhsh Shahragim
Published: November 2012

During organogenesis, a continuum of founder stem cells produces temporally distinct progeny until development is complete. Similarly, in skeletal myogenesis, phenotypically and functionally distinct myoblasts and differentiated cells are generated during development. How this occurs in muscle and other tissues in vertebrates remains largely unclear. We showed previously that committed cells are required for maintaining muscle stem cells. Here we show that active Notch signalling specifies a subpopulation of myogenic cells with high Pax7 expression. By genetically modulating Notch activity, we demonstrate that activated Notch (NICD) blocks terminal differentiation in an Rbpj-dependent manner that is sufficient to sustain stem/progenitor cells throughout embryogenesis, despite the absence of committed progeny. Although arrested in lineage progression, NICD-expressing cells of embryonic origin progressively mature and adopt characteristics of foetal myogenic cells, including expression of the foetal myogenesis regulator Nfix. siRNA-mediated silencing of NICD promotes the temporally appropriate foetal myogenic fate in spite of expression of markers for multiple cell types. We uncover a differential effect of Notch, whereby high Notch activity is associated with stem/progenitor cell expansion in the mouse embryo, yet it promotes reversible cell cycle exit in the foetus and the appearance of an adult muscle stem cell state. We propose that active Notch signalling is sufficient to sustain an upstream population of muscle founder stem cells while suppressing differentiation. Significantly, Notch does not override other signals that promote temporal myogenic cell fates during ontology where spatiotemporal developmental cues produce distinct phenotypic classes of myoblasts.
Reduction of pro-tumorigenic activity of human prostate cancer-associated fibroblasts using Dlk1 or SCUBE1
Authors: Orr Brigid , Grace O. Cathal , Brown Pam , Riddick Antony C. P. , Stewart Grant D. , Franco Omar E. , Hayward Simon W. , Thomson Axel A.
Published: November 2012

Human prostatic cancer-associated fibroblasts (CAFs) can elicit malignant changes in initiated but non-tumorigenic human prostate epithelium, demonstrating that they possess pro-tumorigenic properties. We set out to reduce the pro-tumorigenic activity of patient CAFs using the Dlk1 and SCUBE1 molecules that we had previously identified in prostate development. Our hypothesis was that mesenchymally expressed molecules might reduce CAF pro-tumorigenic activity, either directly or indirectly. We isolated primary prostatic CAFs and characterised their expression of CAF markers, expression of Notch2, Dlk1 and SCUBE1 transcripts, and confirmed their ability to stimulate BPH1 epithelial cell proliferation. Next, we expressed Dlk1 or SCUBE1 in CAFs and determined their effects upon tumorigenesis in vivo following recombination with BPH1 epithelia and xenografting in SCID mice. Tumour size was reduced by about 75% and BPH1 proliferation was reduced by about 50% after expression of Dlk1 or SCUBE1 in CAFs, and there was also a reduction in invasion of BPH1 epithelia into the host kidney. Inhibition of Notch signalling, using inhibitor XIX, led to a reduction in BPH1 cell proliferation in CAF-BPH1 co-cultures, whereas inhibition of Dlk1 in NIH3T3-conditioned media led to an increase in BPH1 growth. Our results suggest that pro-tumorigenic CAF activity can be reduced by the expression of developmental pathways.
From encephalitis lethargica to cerebral cytoarchitectonics: the polymath talent of Constantin von Economo (1876-1931), pioneer neuroanatomist, neurophysiologist and military aviator
Authors: Demetriades A K
Published: November 2012

Born in Romania of Greek parents and raised in Trieste, Constantin von Economo was educated and influenced by Vienna's medical and scientific tradition. Better known for his description of encephalitis lethargica, a disease bearing his name, he made several contributions to as varied themes as the cytoarchitecture of the cerebral cortex, sleep regulation, evolutionary brain development and, outside medicine, in aviation. While still a student he showed an aptitude for meticulous accuracy and a skill in combining animal experiments with microanatomical techniques. Nurtured in the formidable environment of Viennese histology he produced a monumental account of the cytoarchitecture of the human cerebral cortex. This, in an attempt to correlate structure and function, was unique in its quality of accuracy and paved the way for subsequent achievements two decades later. Despite an untimely death at 55 years, he remains one of the most talented pioneers of modern neuroscience.
Sacral nerve stimulation for urinary dysfunction: the first year of the Scottish national service
Authors: Hilmy M , Tatarov O , Mcqueen L , Small D , Granitsiotis P , Conn I G
Published: November 2012

Sacral nerve stimulation (SNS) has become an established treatment option for patients with intractable detrusor overactivity and non-obstructive urinary retention. The Scottish Sacral Nerve Stimulation service was established in April 2010 to provide a service for the population of Scotland. We report our experience from the first year of this new national service. All patients referred for SNS from the inception of the service in April 2010 until the end of March 2011 were studied. During the one-year period, there were 50 referrals. Thirty-three percutaneous nerve evaluations, eight tined lead tests and 16 permanent implantation procedures were performed during this period. Morbidity was low and both incontinence and quality-of-life questionnaires demonstrated statistically significant improvements (International Consultation on Incontinence Questionnaire [ICIQ-SF], P = 0.005; Incontinence Impact Questionnaire [IIQ 7], P = 0.0007; Urogenital Distress Inventory [UDI 6], P = 0.0002). Referral pattern was skewed towards the west of Scotland with some health boards producing no referrals during the year. Results from the first year of the service have shown that it is a safe and efficient procedure with significant improvement in incontinence, voluntary voiding and quality-of-life parameters. The limitation of funding for permanent implants inevitably impacts on the role of the technique as a management option in these patients.
Scotland's Knowledge Network: translating knowledge into action to improve quality of care
Authors: Awales A , Graham S , Rooney K , Crawford A
Published: November 2012

The Knowledge Network ( www.knowledge.scot.nhs.uk ) is Scotland's online knowledge service for health and social care. It is designed to support practitioners to apply knowledge in frontline delivery of care, helping to translate knowledge into better health-care outcomes through safe, effective, person-centred care. The Knowledge Network helps to combine the worlds of evidence-based practice and quality improvement by providing access to knowledge about the effectiveness of clinical interventions (‘know-what’) and knowledge about how to implement this knowledge to support individual patients in working health-care environments (‘know-how’). An ‘evidence and guidance’ search enables clinicians to quickly access quality-assured evidence and best practice, while point of care and mobile solutions provide knowledge in actionable formats to embed in clinical workflow. This research-based knowledge is complemented by social networking services and improvement tools which support the capture and exchange of knowledge from experience, facilitating practice change and systems improvement. In these cases, the Knowledge Network supports key components of the knowledge-to-action cycle – acquiring, creating, sharing and disseminating knowledge to improve performance and innovate. It provides a vehicle for implementing the recommendations of the national Knowledge into Action review, which outlines a new national approach to embedding knowledge in frontline practice and systems improvement.
The organization of tissue banking in Scotland
Authors: Galea G
Published: November 2012

Tissue banking in Scotland has developed significantly over the past 20 years or so. The range of issues procured has increased and so have their numbers. Initially, bone from live donors was the only tissue banked; later, tissues from multiorgan donors were procured; this was finally followed by the collection of tissues from donors following cardiac death. Bones, tendons, heart valves and skin are the main tissue types collected, stored and issued for clinical use. Much of our activity is based on identification of donors in two major accident and emergency departments followed by retrievals that take place in a dedicated mortuary by fully-trained staff. Tissues are released according to clinical need for Scottish patients and beyond. All of the tissue banking activity in Scotland takes place within the Scottish National Blood Transfusion Service, which is the preferred provider of tissues for Scottish patients. There is very close cooperation between our teams, the transplant teams and other clinical colleagues, including pathologists and anatomical technicians. The achievements in issue banking in Scotland are outlined along with the main clinical indications of the tissue procured. Diversification is now taking place into cellular therapy with the establishment of an islet processing programme and cell culturing techniques. The future is very exciting.
Measuring Eco-Inefficiency: A New Frontier Approach
Authors: Chen Chien-Ming , Delmas Magali A.
Published: November 2012

Growing social concerns over the environmental externalities associated with business activities are pushing firms to identify activities that create economic value with less environmental impact and to become more eco-efficient. Over the past two decades, researchers have increasingly used frontier efficiency models to evaluate productive efficiency in the presence of undesirable outputs, such as greenhouse gas emissions or toxic emissions. In this paper, we identify critical flaws in existing frontier models and show that these models can identify eco-inefficient firms as eco-efficient. We develop a new eco-inefficiency frontier model that rectifies these problems. Our model calculates an eco-inefficiency score for each firm and improvements in outputs necessary to attain eco-efficiency. We demonstrate through a Monte Carlo experiment that our eco-inefficiency model provides a more reliable measurement of corporate eco-inefficiency than the existing frontier models. We also extend the single-output Cobb-Douglas production function to multiple desirable and undesirable outputs. This extension allows for greater flexibility in the simulation analysis of frontier models.
An Overloaded Multiclass FIFO Queue with Abandonments
Authors: Jennings Otis B. , Reed Josh E.
Published: November 2012

In this paper we consider a single-server queue fed by K independent renewal arrival streams, each representing a different job class. Jobs are processed in a FIFO fashion, regardless of class. The total amount of work arriving to the system exceeds the server's capacity. That is, the nominal traffic intensity of the system is assumed to be greater than one. Jobs arriving to the system grow impatient and abandon the queue after a random amount of time if service has not yet begun. Interarrival, service, and abandonment times are assumed to be generally distributed and class specific.

We approximate this system using both fluid and diffusion limits. To this end, we consider a sequence of systems indexed by n in which the arrival and service rates are proportional to n; the abandonment distribution remains fixed across the sequence. In our first main result, we show that in the limit as n tends to infinity, the virtual waiting time process converges to a limiting deterministic process. This limit may be characterized as the solution to a first-order ordinary differential equation (ODE). Specific examples are then presented for which the ODE may be explicitly solved. In our second main result, we refine the deterministic fluid approximation by showing that the fluid-centered and diffusion-scaled virtual waiting time process weakly converges to an Ornstein-Uhlenbeck process whose drift and infinitesimal variance both vary over time. This process may also be solved for explicitly, thus yielding approximations to the transient as well as steady-state behavior of the virtual waiting time process.
Pancreatitis: A Potential Complication of Liraglutide?
Authors: Franks Andrea S , Lee Phillip H , George Christa M
Published: November 2012

OBJECTIVE:

To review the evidence surrounding a potential association between liraglutide and pancreatitis.

DATA SOURCES:

A literature search was conducted in MEDLINE (1948-July 12, 2012) and EMBASE (1974-week 27, 2012) using the search terms pancreatitis, liraglutide, and glucagon-like peptide 1/adverse effects. Reference citations from identified publications were reviewed. The manufacturer was contacted and regulatory documents from the Food and Drug Administration website were reviewed for unpublished data related to cases of pancreatitis associated with liraglutide use.

STUDY SELECTION AND DATA EXTRACTION:

All identified sources that were published in English were considered for inclusion.

DATA SYNTHESIS:

Eleven cases of pancreatitis have been reported in patients taking liraglutide. Seven were from the LEAD (Liraglutide Effect and Action in Diabetes) studies, 1 was reported in the extension of a clinical trial, and 1 was in an unpublished obesity trial. Two were published postmarketing case reports. Nine of the cases reported were diagnosed as acute pancreatitis, while 2 were classified as chronic pancreatitis. The mean age of the patients was 57.5 years and mean body mass index was 33.92 kg/m2. Six of the 11 cases occurred in male patients. Nine of the patients were white and 1 was African American. In 7 of the cases, onset occurred at liraglutide doses at or above 1.8 mg daily. Common comorbidities included history of pancreatitis, cholelithiasis, and diabetes. One case was fatal.

CONCLUSIONS:

Pancreatitis is a potential complication with liraglutide therapy. Liraglutide should be used cautiously in patients at risk of pancreatitis (eg, alcohol abuse, history of pancreatitis, cholelithiasis).
New Agents for the Management of Castration-Resistant Prostate Cancer
Authors: Cersosimo Robert J
Published: November 2012

OBJECTIVE:

To review the activity of 3 new agents approved for the management of advanced castration-resistant prostate cancer (CRPC): sipuleucel-T, cabazitaxel, and abiraterone acetate.

DATA SOURCES:

Literature was accessed through MEDLINE (1977-June 2012) and abstracts from the American Society of Clinical Oncology (2000–2012) using the terms castration-resistant and hormone-refractory prostate cancer, sipuleucel-T, cabazitaxel, abiraterone, Provenge, Jevtana, and Zytiga. Reference citations from publications identified were also reviewed.

STUDY SELECTION AND DATA EXTRACTION:

Articles identified from the data sources in English on human subjects were evaluated.

DATA SYNTHESIS:

Options for patients with CRPC have been limited, with little to offer those who failed or could not tolerate docetaxel-based therapy. Three new drugs, with very different mechanisms of action, have changed that and will undoubtedly change the treatment paradigm for these patients. Each agent has demonstrated an impact on patient survival. Sipuleucel-T, the first immunotherapy approved for treatment of CRPC, improved median overall survival by 4.1 months and reduced the risk of death by 22% in a placebo-controlled trial of asymptomatic patients. Sipuleucel-T can be administered prior to docetaxel-based therapy. Cabazitaxel, a taxane chemotherapy agent, improved median overall survival by 2.4 months and reduced the risk of death by 30% in a Phase 3 trial of patients whose cancer progressed during or after docetaxel-based therapy. Abiraterone acetate, a hormonal therapy, improved median overall survival by 3.9 months and reduced the risk of death by 35% in patients with relapse during or after docetaxel-based therapy.

CONCLUSIONS:

The advent of new agents for the management of advanced CRPC has increased the choices for patients whose options were limited. Additional experience will determine the optimal sequencing of these agents, their roles in combination therapy, and their activity in patients with earlier disease.
Thiazide Diuretics as Chronic Antihypertensive Therapy in Patients with Severe Renal Disease—Is There a Role in the Absence of Diuresis?
Authors: Chan Cynthia Y , Peterson Evan J , Ng Tien MH
Published: November 2012

OBJECTIVE:

To determine whether thiazides have a chronic antihypertensive effect, in the absence of diuresis, in patients with severe renal disease (creatinine clearance <30 mL/min) or in those receiving dialysis.

DATA SOURCES:

A search was performed in PubMed, CENTRAL, and International Pharmaceutical Abstracts, using MeSH terms and/or key words. MeSH terms included kidney failure, chronic and exploded terms hydrochlorothiazide, renal dialysis, and thiazides. Key words included thiazide*, hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, metolazone, methyclothiazide, bendroflumethiazide, hemodialysis, dialysis, kidney failure, renal failure, renal insufficiency, hypertension, vasodilation, vascular, and diuretics.

STUDY SELECTION AND DATA EXTRACTION:

All relevant English-language publications were evaluated. Studies evaluating the efficacy of thiazides in renal insufficiency or dialysis were limited to those that included blood pressure measurements. Studies were included only if treatment duration was at least 4 weeks to evaluate chronic antihypertensive effects.

DATA SYNTHESIS:

Thiazide diuretics are associated with a chronic reduction in peripheral vascular resistance secondary to a purported vasodilatory effect. However, few clinical studies have evaluated the chronic antihypertensive efficacy of thiazide and thiazide-like diuretics in patients with severe renal disease or those on dialysis. Agents studied include hydrochlorothiazide, chlorothiazide, indapamide, and metolazone, with results varying by drug and patient population. Hydrochlorothiazide 25–200 mg daily, chlorothiazide 500 mg twice daily, and indapamide 2.5 mg daily provided long-term blood pressure reduction in patients with severe renal disease who were not on dialysis. In studies involving patients on dialysis, hydrochlorothiazide 50 mg daily and metolazone 5 mg daily did not affect blood pressure; however, 1 study suggested that indapamide 2.5 mg daily may confer an antihypertensive effect. All studies were small (≤12 subjects) and had methodological limitations.

CONCLUSIONS:

Thiazide diuretics may decrease peripheral vascular resistance independent of natriuresis. However, because current clinical data are inconclusive as to the efficacy of these agents at chronically lowering blood pressure in patients with severe renal disease or in those on dialysis, thiazide diuretics cannot be routinely recommended for this indication.