bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive microRNA profiling in B-cells of human centenarians by massively parallel sequencing
Authors: Gombar Saurabh , Jung Hwa Jin , Dong Feng , Calder Brent , Atzmon Gil , Barzilai Nir , Tian Xiao-Li , Pothof Joris , Hoeijmakers Jan HJ , Campisi Judith , Vijg Jan , Suh Yousin
Published: July 2012

Background

MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression and play a critical role in development, homeostasis, and disease. Despite their demonstrated roles in age-associated pathologies, little is known about the role of miRNAs in human aging and longevity.

Results

We employed massively parallel sequencing technology to identify miRNAs expressed in B-cells from Ashkenazi Jewish centenarians, i.e., those living to a hundred and a human model of exceptional longevity, and younger controls without a family history of longevity. With data from 26.7 million reads comprising 9.4 × 108 bp from 3 centenarian and 3 control individuals, we discovered a total of 276 known miRNAs and 8 unknown miRNAs ranging several orders of magnitude in expression levels, a typical characteristics of saturated miRNA-sequencing. A total of 22 miRNAs were found to be significantly upregulated, with only 2 miRNAs downregulated, in centenarians as compared to controls. Gene Ontology analysis of the predicted and validated targets of the 24 differentially expressed miRNAs indicated enrichment of functional pathways involved in cell metabolism, cell cycle, cell signaling, and cell differentiation. A cross sectional expression analysis of the differentially expressed miRNAs in B-cells from Ashkenazi Jewish individuals between the 50th and 100th years of age indicated that expression levels of miR-363* declined significantly with age. Centenarians, however, maintained the youthful expression level. This result suggests that miR-363* may be a candidate longevity-associated miRNA.

Conclusion

Our comprehensive miRNA data provide a resource for further studies to identify genetic pathways associated with aging and longevity in humans.
The Arabidopsis apyrase AtAPY1 is localized in the Golgi instead of the extracellular space
Authors: Schiller Madlen , Massalski Carolin , Kurth Thomas , Steinebrunner Iris
Published: July 2012

Background

The two highly similar Arabidopsis apyrases AtAPY1 and AtAPY2 were previously shown to be involved in plant growth and development, evidently by regulating extracellular ATP signals. The subcellular localization of AtAPY1 was investigated to corroborate an extracellular function.

Results

Transgenic Arabidopsis lines expressing AtAPY1 fused to the SNAP-(O6-alkylguanine-DNA alkyltransferase)-tag were used for indirect immunofluorescence and AtAPY1 was detected in punctate structures within the cell. The same signal pattern was found in seedlings stably overexpressing AtAPY1-GFP by indirect immunofluorescence and live imaging. In order to identify the nature of the AtAPY1-positive structures, AtAPY1-GFP expressing seedlings were treated with the endocytic marker stain FM4-64 (N-(3-triethylammoniumpropyl)-4-(p-diethylaminophenyl-hexatrienyl)-pyridinium dibromide) and crossed with a transgenic line expressing the trans-Golgi marker Rab E1d. Neither FM4-64 nor Rab E1d co-localized with AtAPY1. However, live imaging of transgenic Arabidopsis lines expressing AtAPY1-GFP and either the fluorescent protein-tagged Golgi marker Membrin 12, Syntaxin of plants 32 or Golgi transport 1 protein homolog showed co-localization. The Golgi localization was confirmed by immunogold labeling of AtAPY1-GFP. There was no indication of extracellular AtAPY1 by indirect immunofluorescence using antibodies against SNAP and GFP, live imaging of AtAPY1-GFP and immunogold labeling of AtAPY1-GFP. Activity assays with AtAPY1-GFP revealed GDP, UDP and IDP as substrates, but neither ATP nor ADP. To determine if AtAPY1 is a soluble or membrane protein, microsomal membranes were isolated and treated with various solubilizing agents. Only SDS and urea (not alkaline or high salt conditions) were able to release the AtAPY1 protein from microsomal membranes.

Conclusions

AtAPY1 is an integral Golgi protein with the substrate specificity typical for Golgi apyrases. It is therefore not likely to regulate extracellular nucleotide signals as previously thought. We propose instead that AtAPY1 exerts its growth and developmental effects by possibly regulating glycosylation reactions in the Golgi.
Deletion of Foxp3+ regulatory T cells in genetically targeted mice supports development of intestinal inflammation
Authors: Boehm Franziska , Martin Maria , Kesselring Rebecca , Schiechl Gabriela , Geissler Edward K , Schlitt Hans-Jürgen , Fichtner-Feigl Stefan
Published: July 2012

Background

Mice lacking Foxp3+ regulatory T (Treg) cells develop severe tissue inflammation in lung, skin, and liver with premature death, whereas the intestine remains uninflamed. This study aims to demonstrate the importance of Foxp3+ Treg for the activation of T cells and the development of intestinal inflammation.

Methods

Foxp3-GFP-DTR (human diphtheria toxin receptor) C57BL/6 mice allow elimination of Foxp3+ Treg by treatment with Dx (diphtheria toxin). The influence of Foxp3+ Treg on intestinal inflammation was tested using the CD4+ T-cell transfer colitis model in Rag−/− C57BL/6 mice and the acute DSS-colitis model.

Results

Continuous depletion of Foxp3+ Treg in Foxp3-GFP-DTR mice led to dramatic weight loss and death of mice by day 28. After 10 days of depletion of Foxp3+ Treg, isolated CD4+ T-cells were activated and produced extensive amounts of IFN-γ, IL-13, and IL-17A. Transfer of total CD4+ T-cells isolated from Foxp3-GFP-DTR mice did not result in any changes of intestinal homeostasis in Rag−/− C57BL/6 mice. However, administration of DTx between days 14 and 18 after T-cell reconstitution, lead to elimination of Foxp3+ Treg and to immediate weight loss due to intestinal inflammation. This pro-inflammatory effect of Foxp3+ Treg depletion consecutively increased inflammatory cytokine production. Further, the depletion of Foxp3+ Treg from Foxp3-GFP-DTR mice increased the severity of acute dSS-colitis accompanied by 80% lethality of Treg-depleted mice. CD4+ effector T-cells from Foxp3+ Treg-depleted mice produced significantly more pro-inflammatory cytokines.

Conclusion

Intermittent depletion of Foxp3+ Treg aggravates intestinal inflammatory responses demonstrating the importance of Foxp3+ Treg for the balance at the mucosal surface of the intestine.
Reduced rhinovirus-specific antibodies are associated with acute exacerbations of chronic obstructive pulmonary disease requiring hospitalisation
Authors: Yerkovich Stephanie T , Hales Belinda J , Carroll Melanie L , Burel Julie G , Towers Michelle A , Smith Daniel J , Thomas Wayne R , Upham John W
Published: July 2012

Background

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are often linked to respiratory infections. However, it is unknown if COPD patients who experience frequent exacerbations have impaired humoral immunity. The aim of this study was to determine if antibodies specific for common respiratory pathogens are associated with AECOPD.

Methods

Plasma was obtained from COPD patients when clinically stable. AECOPD requiring hospitalisation were recorded. IgG1 antibodies to H. Influenzae outer membrane protein 6 (P6), pneumococcal surface protein C (PspC) and the VP1 viral capsid protein of rhinovirus were measured.

Results

COPD patients who had an AECOPD (n = 32) had significantly lower anti-VP1 IgG1 antibody levels when stable compared to COPD patients who did not have an AECOPD (n = 28, p = 0.024). Furthermore, the number of hospitalisations was inversely proportional to anti-VP1 antibody levels (r = −0.331, p = 0.011). In contrast, antibodies specific for P6 and PspC were present at similar concentrations between groups. Plasma IL-21, a cytokine important for B-cell development and antibody synthesis, was also lower in COPD patients who had an AECOPD, than in stable COPD patients (p = 0.046).

Conclusion

Deficient humoral immunity specific for rhinoviruses is associated with AECOPD requiring hospitalisation, and may partly explain why some COPD patients have an increased exacerbation risk following respiratory viral infections.
Mononuclear cell therapy reverts cuff-induced thrombosis in apolipoprotein E-deficient mice
Authors: Lima Leandro C F , Porto Marcella L , Campagnaro Bianca P , Tonini Clarissa L , Nogueira Breno V , Pereira Thiago MC , Vasquez Elisardo C , Meyrelles Silvana S
Published: July 2012

Background

Stem/progenitor cell-based therapy has successfully been used as a novel therapeutic strategy for vascular diseases triggered by endothelial dysfunction. The aim of this study was to investigate the effects of mononuclear cell (MNC) therapy in situ on carotid cuff-induced occlusive thrombus in the apolipoprotein E knockout (apoE-/-) mouse.

Methods

Spleen-derived MNCs were isolated from green fluorescent protein (GFP)-transgenic mice for cell treatment. A cuff-induced thrombus model was produced by placing a nonconstrictive silastic collar around the left common carotid artery in 20-week-old female apoE-/- mice. After 10 days, the cuff was removed, and the animals received in situ MNCs (Cuff-MNC) or vehicle (Cuff-Vehicle) and were compared with sham-operated animals (Sham).

Results

The histological analysis showed that the MNC treatment reverted occlusive thrombus formation compared to the vehicle and the vessel lumen area to that observed in the Sham group (MNC, 50 ± 4; Vehicle, 20 ± 4; Sham, 55 ± 2 x103 μm2; p < 0.01). The animals that underwent the carotid cuff placement developed compensatory vessel enlargement, which was reduced by the MNC therapy. In addition, the treatment was able to reduce superoxide anion production, which likely contributed to the reduced apoptosis that was observed. Lastly, the immunofluorescence analysis revealed the presence of endothelial progenitor cells (EPCs) in the carotid endothelia of the apoE-/- mice.

Conclusion

In situ short-term MNC therapy was able to revert cuff-induced occlusive thrombi in the carotid arteries of apoE-/- mice, possibly through the homing of EPCs, reduction of oxidative stress and decreased apoptosis.
Dietary total antioxidant capacity and the occurrence of metabolic syndrome and its components after a 3-year follow-up in adults: Tehran Lipid and Glucose Study
Authors: Bahadoran Zahra , Golzarand Mahdieh , Mirmiran Parvin , Shiva Niloofar , Azizi Fereidoun
Published: July 2012

Background

There is growing evidence that dietary antioxidants could have favorable effects on the attenuation and prevention of metabolic disorders. In the current study we investigated the association of dietary total antioxidant capacity (TAC) and metabolic syndrome (MetS) components and the occurrence of the MetS during a 3-year follow-up.

Methods

This longitudinal study was conducted in the framework of Tehran Lipid and Glucose Study, between 2006–2008 and 2009–2011, on 1983 adults, aged 19–70 y. The usual intakes of participant were measured using a validated semi-quantitative food frequency questionnaire and dietary TAC was estimated at baseline. The MetS components were assessed at baseline and 3 years later. Multiple logistic regression models were used to estimate the occurrence of the MetS and its components according to dietary TAC quartile categories.

Results

The mean age of participants was 40.4 ± 13.0 y, and mean BMI was 27.03 ± 4.9 kg/m2 at baseline. After adjustment for potential confounding variables, TAC was associated with MetS components at baseline. Participant with highest TAC score had lower weight and abdominal fat gain during the 3 year follow-up. The chance of having the MetS, abdominal obesity and hypertension after 3 years decreased across the increasing dietary TAC quartile (P for trend < 0.01). Dietary TAC more than 1080 μmolTE/100 g of food, resulted in a 38% decrease in the risk of central obesity (OR = 0.62, 95% CI = 0.38-0.99).

Conclusion

We demonstrated that higher dietary antioxidant intakes have favorable effects on metabolic disorders and, more interestingly, prevent subsequent weight and abdominal fat gain during a 3-year follow-up.
A reaction–diffusion mechanism influences cell lineage progression as a basis for formation, regeneration, and stability of intestinal crypts
Authors: Zhang Lei , Lander Arthur D , Nie Qing
Published: July 2012

Background

Colon crypts, a single sheet of epithelia cells, consist of a periodic pattern of stem cells, transit-amplifying cells, and terminally differentiated cells that constantly renew and turnover. Experimental evidence suggests that Wnt signaling promotes and regulates stem cell division, differentiation, and possible cell migrations while intestinal BMP signaling inhibits stem cell self-renewal and repression in crypt formation. As more molecular details on Wnt and BMP in crypts are being discovered, little is still known about how complex interactions among Wnt, BMP, and different types of cells, and surrounding environments may lead to de novo formation of multiple crypts or how such interactions affect regeneration and stability of crypts.

Results

We present a mathematical model that contains Wnt and BMP, a cell lineage, and their feedback regulations to study formation, regeneration, and stability of multiple crypts. The computational explorations and linear stability analysis of the model suggest a reaction–diffusion mechanism, which exhibits a short-range activation of Wnt plus a long-range inhibition with modulation of BMP signals in a growing tissue of cell lineage, can account for spontaneous formation of multiple crypts with the spatial and temporal pattern observed in experiments. Through this mechanism, the model can recapitulate some distinctive and important experimental findings such as crypt regeneration and crypt multiplication. BMP is important in maintaining stability of crypts and loss of BMP usually leads to crypt multiplication with a fingering pattern.

Conclusions

The study provides a mechanism for de novo formation of multiple intestinal crypts and demonstrates a synergetic role of Wnt and BMP in regeneration and stability of intestinal crypts. The proposed model presents a robust framework for studying spatial and temporal dynamics of cell lineages in growing tissues driven by multiple signaling molecules.
Human foreskin fibroblast produces interleukin-6 to support derivation and self-renewal of mouse embryonic stem cells
Authors: Ma Yu , Gu Junjie , Li Chunliang , Wei Xiaoyuan , Tang Fan , Shi Guilai , Jiang Jing , Kuang Ying , Li Jinsong , Wang Zhugang , Xie Xin , Jin Ying
Published: July 2012

Introduction

Embryonic stem cells (ESCs) provide an attractive cell source for basic research and disease treatment. Currently, the common culture system for mouse ESC requires mouse embryonic fibroblast (MEF) as a feeder layer supplemented with leukemia inhibitory factor (LIF). The drawbacks associated with MEF and the cost of LIF have motivated exploration of new feeder cell types to maintain self-renewal of mouse ESCs without the need of exogenous LIF. However, why these feeder cells could maintain ESCs at the undifferentiated state independent of exogenous LIF is unclear.

Methods

We derived mouse ESC lines using human foreskin fibroblast (HFF) in the absence of exogenous LIF. We also examined the dependence of HFF on the JAK-Stat3 pathway to maintain ESC identities and explored the potential molecular basis for HFF to support self-renewal of ESCs.

Results

HFF supported mouse ESC self-renewal superiorly to MEFs. Using the HFF system, multiple lines of mouse ESCs were successfully derived without addition of exogenous LIF and any small molecular inhibitors. These ESCs had capacities to self-renew for a long period of time and to differentiate into various cell types of the three germ layers both in vitro and in vivo. Moreover, the ESCs participated in embryonic development and contributed to germ cell lineages in the chimeric mouse. At a molecular level, HFF was dependent on the JAK-Stat3 pathway to maintain ESC self-renewal. The high level of interleukin-6 (IL-6) produced by HFF might be responsible for the exogenous LIF-independent effect.

Conclusion

This study describes an efficient, convenient and economic system to establish and maintain mouse ESC lines, and provides insights into the functional difference in the support of ESC culture between MEF and HFF.
Fragility Functions for Steel Plate Shear Walls
Authors: Baldvins Nicole M. , Berman Jeffery W. , Lowes Laura N. , Janes Todd M. , Low Natalie A.
Published: July 2012

Fragility functions are developed to predict the method of repair required for steel plate shear walls damaged due to earthquake loading. The results of previous experimental studies are used to develop empirical relationships between damage states and story drift. Damage states are proposed and linked deterministically with commonly employed methods of repair; these damage states are characterized by parameters such as yielding and tearing of the steel plate and yielding, buckling and fracture of frame members. Lognormal probability distributions are fit to the empirical data and evaluated using standard statistical methods. The results of this effort are families of fragility functions that predict the required method of repair for a damaged wall.
Randomized Trial of Radiation Therapy Plus Procarbazine, Lomustine, and Vincristine Chemotherapy for Supratentorial Adult Low-Grade Glioma: Initial Results of RTOG 9802
Authors: Shaw Edward G. , Wang Meihua , Coons Stephen W. , Brachman David G. , Buckner Jan C. , Stelzer Keith J. , Barger Geoffrey R. , Brown Paul D. , Gilbert Mark R. , Mehta Minesh P.
Published: July 2012

Purpose

A prior Radiation Therapy Oncology Group (RTOG) clinical trial in anaplastic oligodendroglioma suggested a progression-free survival benefit for procarbazine, lomustine, and vincristine (PCV) chemotherapy in addition to radiation therapy (RT), as have smaller trials in low-grade glioma (LGG).

Patients and Methods

Eligibility criteria included supratentorial WHO grade 2 LGG, age 18 to 39 years with subtotal resection/biopsy, or age ≥ 40 years with any extent resection. Patients were randomly assigned to RT alone or RT followed by six cycles of PCV. Survival was compared by using the modified Wilcoxon and log-rank tests.

Results

In all, 251 patients were accrued from 1998 to 2002. Median overall survival (OS) time and 5-year OS rates for RT versus RT + PCV were 7.5 years versus not reached and 63% versus 72%, respectively (hazard ratio [HR]; 0.72; 95% CI, 0.47 to 1.10; P = .33; log-rank P = .13). Median progression-free survival (PFS) time and 5-year PFS rates for RT versus RT + PCV were 4.4 years versus not reached and 46% versus 63%, respectively (HR, 0.6; 95% CI, 0.41 to 0.86; P = .06; log-rank P = .005). OS and PFS were similar for all patients between years 0 and 2. After 2 years, OS and PFS curves separated significantly, favoring RT + PCV. For 2-year survivors (n = 211), the probability of OS for an additional 5 years was 74% with RT + PCV versus 59% with RT alone (HR, 0.52; 95% CI, 0.30 to 0.90; log-rank P = .02).

Conclusion

PFS but not OS was improved for adult patients with LGG receiving RT + PCV versus RT alone. On post hoc analysis, for 2-year survivors, the addition of PCV to RT conferred a survival advantage, suggesting a delayed benefit for chemotherapy.
The Audacity to Strong-Arm the Generals: Paulo Maluf and the 1978 São Paulo Gubernatorial Contest
Authors: Pitts Bryan
Published: July 2012

In 1978, as striking metalworkers, students, and a revitalized political opposition challenged the Brazilian military regime from without, a stunning rebellion by the regime’s civilian allies in São Paulo undermined it from within. Dealing the regime a shocking political defeat, the delegates to the regime-allied political party’s state convention rejected the generals’ anointed gubernatorial candidate and narrowly nominated the rebel Paulo Maluf, who would go on to be confirmed by a manipulated electoral college. Although Maluf and the delegates did not challenge the regime on ideological grounds, the mix of resentment, regionalism, and personal rivalries that drove their insurrection and the generals’ reluctant tolerance of it highlight the fragility of the regime’s support among those who were thought to be its most stalwart allies. Moreover, Maluf’s selection demonstrates key differences between the Brazilian military regime and its Southern Cone counterparts and expands our understanding of how authoritarian regimes placed constraints upon and were in turn constrained by civilian political elites.
The last rRNA methyltransferase of E. coli revealed: The yhiR gene encodes adenine-N6 methyltransferase specific for modification of A2030 of 23S ribosomal RNA
Authors: Golovina Anna Y. , Dzama Margarita M. , Osterman Ilya A. , Sergiev Petr V. , Serebryakova Marina V. , Bogdanov Alexey A. , Dontsova Olga A.
Published: July 2012

The ribosomal RNA (rRNA) of Escherichia coli contains 24 methylated residues. A set of 22 methyltransferases responsible for modification of 23 residues has been described previously. Herein we report the identification of the yhiR gene as encoding the enzyme that modifies the 23S rRNA nucleotide A2030, the last methylated rRNA nucleotide whose modification enzyme was not known. YhiR prefers protein-free 23S rRNA to ribonucleoprotein particles containing only part of the 50S subunit proteins and does not methylate the assembled 50S subunit. We suggest renaming the yhiR gene to rlmJ according to the rRNA methyltransferase nomenclature. The phenotype of yhiR knockout gene is very mild under various growth conditions and at the stationary phase, except for a small growth advantage at anaerobic conditions. Only minor changes in the total E. coli proteome could be observed in a cell devoid of the 23S rRNA nucleotide A2030 methylation.
EU membership and the Europeanization of Spanish political parties
Authors: Pardo Ramon Pacheco
Published: July 2012

This article explores the extent to which Spanish political parties have been affected by the pro-European views of a wide majority of the Spanish electorate and by EU membership. It suggests that Spain's two main political parties, the Partido Socialista Obrero Español (PSOE)
and the Partido Popular (PP), have become Europeanized as a result of both phenomena. Hence, socialists and conservatives have adapted their political discourse to reflect and satisfy the pro-European stance of most Spaniards and the demands related to EU membership. To prove the Europeanization
of these parties, I analyse the electoral manifestos that the PSOE and the PP have used to communicate their political agenda to the Spanish electorate in national elections dating back to the restoration of democracy.
HE4 in gynecological cancers: report of a European investigators and experts meeting
Authors: Plebani Mario ,   on behalf of the HE4 Study Group
Published: July 2012

The HE4 protein, which belongs to the “four disulfide” acid protein group, has emerged as one of the most promising biomarkers in gynecologic oncology. An expert meeting on the analytical and clinical performance of the quantitative determination of HE4 was held in November 2011, involving 25 clinical and laboratory specialists from 16 European countries. The aim of the meeting was to present and discuss the results of recent studies on the use of HE4 and on the Risk of Ovarian Malignancy Algorithm (ROMA), which combines the results of HE4 and CA 125. The meeting was structured in separate sessions focusing on ovarian cancer risk stratification, differential diagnosis, prognosis and monitoring and with diagnosis and monitoring of endometrial cancer. We present here a summary of the data and evidence, presented, together with consensus statements on the different topics, where available, and suggestions for further studies and evaluations required to establish optimal use of HE4, either alone or in combination with other markers, for diagnostic and prognostic purposes in gynecological malignancies. Available evidences support the utility of this new cancer biomarker for risk stratification, prognosis and monitoring of epithelial ovarian cancer and of endometrial cancer.
Human Research Ethics Committees: Examining Their Roles and Practices
Authors: Guillemin Marilys , Gillam Lynn , Rosenthal Doreen , Bolitho Annie
Published: July 2012

Considerable time and resources are invested in the ethics review process. We present qualitative data on how human research ethics committee members and health researchers perceive the role and function of the committee. The findings are based on interviews with 34 Australian ethics committee members and 54 health researchers. Although all participants agreed that the primary role of the ethics committee was to protect participants, there was disagreement regarding the additional roles undertaken by committees. Of particular concern were the perceptions from some ethics committee members and researchers that ethics committees were working to protect the institution's interests, as well as being over-protective toward research participants. This has the potential to lead to poor relations and mistrust between ethics committees and researchers.
Effects of mitotane treatment on human steroid metabolism: implications for patient management
Authors: Ghataore L , Chakraborti I , Aylwin S J , Schulte K-M , Dworakowska D , Coskeran P , Taylor N F
Published: July 2012

Mitotane (o,p'-DDD), an oral adrenolytic agent for treatment of advanced adrenocortical carcinoma (ACC), is reported to inhibit cortisol biosynthesis in vitro and enhance production from exogenous cortisol of urinary 6β-hydroxycortisol and unidentified polar unconjugated metabolites. We examined urinary steroid profiles by gas chromatography–mass spectrometry of patients with histologically confirmed ACC following surgery, receiving a) hydrocortisone alone (three males and three females) and b) mitotane and hydrocortisone (six males and 11 females). Samples were collected after plasma mitotane had reached the therapeutic range of 14–20 mg/l. Increased excretion of polar unconjugated steroids during mitotane treatment was confirmed, with 6β-hydroxycortisol and 6β-hydroxy-20-dihydrocortisols predominating. The proportion of additionally hydroxylated metabolites was <2% in untreated controls and 52, 35–52% (mean, range) in the mitotane plus hydrocortisone group. Ratios of 5α-/5β- and 20β-/20α-metabolites of administered cortisol were decreased 50-, 15-fold, and 14-, 8-fold respectively (males, females – mean values) but with no change in metabolite ratios that reflect oxidoreduction at C11 or C20. Patterns of decrease in 5α- relative to 5β-reduced metabolites were similar to those of patients with 5α-reductase 2 deficiency or on treatment with the 5α-reductase 2 inhibitor finasteride but different from those of patients on dutasteride, indicating specific inhibition of 5α-reductase 2. We conclude that mitotane causes consistent changes in cortisol catabolism, most of which have not been previously recognised. These need not interfere with early detection of ACC recurrence. Induction of 6β-hydroxylation offers an explanation for a reported decrease in cortisol bioavailability. Mitotane also has potential as a unique steroid metabolic probe for 20β-reduction.
Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center
Authors: Baudry Camille , Coste Joël , Bou Khalil Roula , Silvera Stéphane , Guignat Laurence , Guibourdenche Jean , Abbas Halim , Legmann Paul , Bertagna Xavier , Bertherat Jérôme
Published: July 2012

Context

Alternatives to transsphenoidal pituitary surgery may be required in Cushing's disease (CD) as a first- or second-line treatment. Mitotane is a potent anti-cortisolic drug but has been rarely investigated in the treatment of CD.

Objective

Evaluation of the efficacy and tolerance of mitotane in CD patients.

Design and setting

Retrospective analysis of 76 patients treated with mitotane from 219 patients diagnosed with CD between 1993 and 2009 in a single center.

Main outcome measure

Remission was defined as normalization of 24-h urinary free cortisol (24-h-UFC).

Results

Remission was achieved in 48 (72%) of the 67 long-term treated patients, after a median time of 6.7 (5.2–8.2) months. Mean plasma mitotane concentration at the time of remission was 10.5±8.9 mg/l, with a mean daily dose of 2.6±1.1 g. A negative linear relationship was observed between plasma mitotane concentration and 24-h-UFC (P<0.0001). Seventeen of 24 (71%) patients with durable remission subsequently experienced recurrence, after a median time of 13.2 (5.0–67.9) months. At the time of treatment discontinuation, ACTH concentration was statistically associated with a lower recurrence probability (hazard ratios 0.57 (0.32–1.00), P=0.05). Intolerance leading to treatment discontinuation occurred in 19 patients (29%). A pituitary adenoma became identifiable during mitotane treatment in 12 (25%) of the 48 patients with initial negative pituitary imaging allowing subsequent transsphenoidal surgery.

Conclusion

Mitotane is useful at different stages of CD. Mitotane dose adjustment based on plasma concentration monitoring and side effects could control hypercortisolism in the majority of CD patients.
Body compositional and cardiometabolic effects of testosterone therapy in obese men with severe obstructive sleep apnoea: a randomised placebo-controlled trial
Authors: Hoyos Camilla M , Yee Brendon J , Phillips Craig L , Machan Elizabeth A , Grunstein Ronald R , Liu Peter Y
Published: July 2012

Background

The combination of male gender, obstructive sleep apnoea (OSA) and obesity magnifies cardiometabolic risk. There has been no systematic study evaluating whether testosterone therapy can improve cardiometabolic health in obese men with OSA by improving body composition, visceral abdominal fat and insulin sensitivity.

Objective

To assess body compositional and cardiometabolic effects of testosterone treatment in obese men with severe OSA.

Design

An 18-week randomised, double-blind, placebo-controlled and parallel group trial in 67 men.

Methods

Participants (age=49±12 years, apnoea hypopnoea index=39.9±17.7 events/h, BMI=31.3±5.2 kg/m2) were placed on a hypocaloric diet and received i.m. injections of either 1000 mg testosterone undecanoate (n=33) or placebo (n=34) for 18 weeks. Outcomes were the changes in body composition (total muscle mass, total and abdominal fat, total body dual-energy X-ray absorptiometry and computerised tomography (CT)), weight, insulin sensitivity (homeostasis model assessment), abdominal liver fat (CT), arterial stiffness (pulse wave analysis), resting metabolic rate and respiratory quotient (indirect calorimetry) and blood lipids and metabolic syndrome from baseline to week 18.

Results

After 18 weeks, testosterone treatment increased insulin sensitivity (−1.14 units, 95% confidence interval (95% CI) −2.27 to −0.01,P<0.05), reduced liver fat (0.09 Hounsfield attenuation ratio, 95% CI 0.009 to 0.17,P=0.03) and increased muscle mass (1.6 kg, 95% CI 0.69 to 2.5,P=0.0009) to a greater extent than placebo. Other measures of body composition and regional adiposity as well as the number of participants with metabolic syndrome did not change. Testosterone also decreased arterial stiffness (augmentation index) by 3.2% (95% CI −6.01 to −0.46%,P=0.02) and decreased the respiratory quotient (95% CI −0.04, −0.08 to −0.001,P=0.04) after 18 weeks compared with placebo.

Conclusion

Eighteen weeks of testosterone therapy in obese men with OSA improved several important cardiometabolic parameters but did not differentially reduce overall weight or the metabolic syndrome. Longer term studies are required.
Cutoff value of time to prostate-specific antigen nadir is inversely correlated with disease progression in advanced prostate cancer
Authors: Sasaki Takeshi , Onishi Takehisa , Hoshina Akira
Published: July 2012

To identify the early predictor of progression to castration-resistant prostate cancer (CRPC) for different stage of advanced PC patients, we focused on time to prostate-specific antigen (PSA) nadir following primary androgen deprivation therapy (PADT). We reviewed 184 advanced (locally advanced and metastatic) PC patients (101 patients with bone metastasis (BM) and 83 patients without BM at presentation) who had received PADT at our institution. We evaluated laboratory data, pathological results, and the influence of PSA kinetics impact on disease progression. The progression rates were analyzed with reference to the nadir PSA level and time to PSA nadir (TTN) following PADT by Kaplan–Meier method. In all, 103 patients (56%) progressed to CRPC. Nadir PSA lower than 0.2 ng/ml (nadir ≤0.2) during PADT was observed in 114 patients (62%). Median TTN was 8.5 months in patients with BM and 11.5 months in patients without BM. Multivariate analysis revealed that nadir ≤0.2 following PADT (P<0.001), longer TTN (>8 months) (P<0.001), extent of disease on bone scan grade (P=0.02), and T stage (P=0.04) in BM group and nadir ≤0.2 following PADT (P<0.001), longer TTN (>11 months) (P<0.001), and T stage (P=0.03) in without BM group were independent prognostic factors for progression. In both groups, longer TTN identified patients with prolonged progression-free survival in both nadir ≤0.2 and >0.2 nadir levels. Longer TTN is strongly associated with a low risk of disease progression, and the cutoff value of TTN could be inversely correlated with disease progression.
Searching for ways to switch on brown fat: are we getting warmer?
Authors: Whittle Andrew
Published: July 2012

Obesity rates are increasing alongside those of its co-morbidities, placing a huge strain on health systems across the globe. Evidence points to inappropriate levels of ectopic lipid accumulation outside of adipose tissue being a major factor in the progression of many of these diseases. Brown adipose tissue (BAT) has a huge capacity to remove lipids from the circulatory system to fuel thermogenesis. Multiple studies have now confirmed the existence of active BAT in adult humans, making strategies aimed at activating it a potential therapeutic option in obese subjects. In recent years, researchers working in murine models have found a wide range of endogenous molecules with specific roles regulating BAT. These findings place BAT firmly within the wider network of physiological regulation covering global metabolism. They also highlight the possibility of targeting thermogenesis in a safe and specific manner to remove potentially harmful lipids released from stressed or failing white adipose tissue in obese states.
Escherichia coli lipopolysaccharide administration transiently suppresses luteal structure and function in diestrous cows
Authors: Herzog K , Strüve K , Kastelic J P , Piechotta M , Ulbrich S E , Pfarrer C , Shirasuna K , Shimizu T , Miyamoto A , Bollwein H
Published: July 2012

The objective was to characterize the effects of Escherichia coli lipopolysaccharide (LPS) endotoxin (given i.v.) on luteal structure and function. Seven nonlactating German Holstein cows, 5.1±0.8 years old (mean±s.e.m.), were given 10 ml saline on day 10 (ovulation=day 1) of a control estrous cycle. On day 10 of a subsequent cycle, they were given 0.5 μg/kg LPS. Luteal size decreased (from 5.2 to 3.8 cm2, P≤0.05) within 24 h after LPS treatment and remained smaller throughout the remainder of the cycle. Luteal blood flow decreased by 34% (P≤0.05) within 3 h after LPS and remained lower for 72 h. Plasma progesterone (P4) concentrations increased (P≤0.05) within the first 3 h after LPS but subsequently declined. Following LPS treatment, plasma prostaglandin (PG) F metabolites concentrations were approximately tenfold higher in LPS-treated compared with control cows (9.2 vs 0.8 ng/ml, P≤0.05) within 30 min, whereas plasma PGE concentrations were nearly double (P≤0.05) at 1 h after LPS. At 12 h after treatment, levels of mRNA encoding Caspase-3 in biopsies of the corpus luteum (CL) were increased (P≤0.05), whereas those encoding StAR were decreased (P≤0.05) in cattle given LPS vs saline. The CASP3 protein was localized in the cytoplasm and/or nuclei of luteal cells, whereas StAR was detected in the cytosol of luteal cells. In the estrous cycle following treatment with either saline or LPS, there were no significant differences between groups on luteal size, plasma P4 concentrations, or gene expression. In conclusion, LPS treatment of diestrus cows transiently suppressed both the structure and function of the CL.
A Cytoplasmic Suppressor of a Nuclear Mutation Affecting Mitochondrial Functions inDrosophila
Authors: Chen Shanjun , Oliveira Marcos T , Sanz Alberto , Kemppainen Esko , Fukuoh Atsushi , Schlicht Barbara , Kaguni Laurie S , Jacobs Howard T
Published: July 2012

Phenotypes relevant to oxidative phosphorylation (OXPHOS) in eukaryotes are jointly determined by nuclear and mitochondrial DNA (mtDNA). Thus, in humans, the variable clinical presentations of mitochondrial disease patients bearing the same primary mutation, whether in nuclear or mitochondrial DNA, have been attributed to putative genetic determinants carried in the “other” genome, though their identity and the molecular mechanism(s) by which they might act remain elusive. Here we demonstrate cytoplasmic suppression of the mitochondrial disease-like phenotype of the Drosophila melanogaster nuclear mutant tko25t, which includes developmental delay, seizure sensitivity, and defective male courtship. The tko25t strain carries a mutation in a mitoribosomal protein gene, causing OXPHOS deficiency due to defective intramitochondrial protein synthesis. Phenotypic suppression was associated with increased mtDNA copy number and increased mitochondrial biogenesis, as measured by the expression levels of porin voltage dependent anion channel and Spargel (PGC1α). Ubiquitous overexpression of Spargel in tko25t flies phenocopied the suppressor, identifying it as a key mechanistic target thereof. Suppressor-strain mtDNAs differed from related nonsuppressor strain mtDNAs by several coding-region polymorphisms and by length and sequence variation in the noncoding region (NCR), in which the origin of mtDNA replication is located. Cytoplasm from four of five originally Wolbachia-infected strains showed the same suppressor effect, whereas that from neither of two uninfected strains did so, suggesting that the stress of chronic Wolbachia infection may provide evolutionary selection for improved mitochondrial fitness under metabolic stress. Our findings provide a paradigm for understanding the role of mtDNA genotype in human disease.
A Redundant Function for the N-Terminal Tail of Ndc80 in Kinetochore–Microtubule Interaction in Saccharomyces cerevisiae
Authors: Demirel Pinar B , Keyes Brice E , Chatterjee Mandovi , Remington Courtney E , Burke Daniel J
Published: July 2012

The N-terminal tail of Ndc80 is essential for kinetochore–microtubule binding in human cells but is not required for viability in yeast. We show that the yeast Ndc80 tail is required for timely mitotic progression and accurate chromosome segregation. The tail is essential when cells are limited for Dam1, demonstrating a redundant function for the Ndc80 and Dam1 complexes in vivo.
Evaluating the National Health Insurance database of Hungary from the aspect of a health insurance specialist
Authors: Gresz Miklós
Published: July 2012

There is currently only one national database in the Hungarian health care system: the financial database of the National Health Insurance Fund. It includes all patients’ data of state-funded services since 2000, those for pharmaceuticals, health spas and suppliers for patient transport. Any information for scientific research purposes can be obtained from this database. The database for inpatient records is complicated, and it is difficult to make queries. On the basis of his ten-year-experience, the author outlines the typical errors, which hinder a correct query. Orv. Hetil., 2012, 153, 1234–1239.
Functionalization of carbon nanotubes with arenedyazonium salts in urea
Authors: Kharissova Oxana V. , Leija H. , de Casas-Ortiz E.G.
Published: July 2012

The functionalization of single wall carbon nanotubes (SWCNT) with arenediazonium salts, formed in situ from anilines as dimethyl-5-aminoisophthalate, sulfanilamide and p-anisidine, using the environmentally solvent urea. The functionalized SWNTs were then characterized using spectroscopic and microscopic methods along with thermogravimetric analysis (TGA). According to enhance solubility in solvents after that introduce them into the industrial processes. The molecules added appear on the nanotubes like chemical anchors.
Low Temperature Growth of CaTiO3: Pr Phosphor Thin Film on Flexible Substrate by Photo- induced Chemical Solution Process
Authors: Tsuchiya Tetsuo , Nakajima Tomohiko , Shinoda Kentaro
Published: July 2012

Preparation of the CaTiO3:Pr (CTO:Pr) phosphor thin film on PET substrate was investigated by using the excimer laser-assisted metal organic decomposition(ELAMOD) and photo reaction of nano-particles (PRNP) process. The effects of the substrate material, starting materials, and UV sources on photoluminescence (PL) were investigated. By using the BaTiO3(BTO) nano-particles buffer layer and the CTO: Pr nano-particles as a starting material, CTO: Pr thin film on the PET substrate was successfully obtained by using the KrF laser and excimer lamp irradiation at 25°C. It was found that excimer lamp irradiation is effective for improving the PL of the films.
Application of the Helium Ion Microscope as a Sculpting Tool for Nanosamples
Authors: Rudneva Maria , van Veldhoven Emile , Malladi Sairam , Maas Diederik , Zandbergen Henny W.
Published: July 2012

In this paper we propose a few helium ion microscope (HIM)-based methods for sample preparation and modification. In particular we report the use of the HIM to make thin wedge SrTiO3 samples without significant artifacts, the possibility to reshape thin metal lines on an electron transparent membrane and the new method of HIM sample preparation by in situ heating of the samples during He-beam illumination.
Long‐term demographic consequences of habitat fragmentation to a tropical understory bird community
Authors: Korfanta Nicole M. , Newmark William D. , Kauffman Matthew J.
Published: July 2012

Tropical deforestation continues to cause population declines and local extinctions in centers of avian diversity and endemism. Although local species extinctions stem from reductions in demographic rates, little is known about how habitat fragmentation influences survival of tropical bird populations or the relative importance of survival and fecundity in ultimately shaping communities. We analyzed 22 years of mark–recapture data to assess how fragmentation influenced apparent survival, recruitment, and realized population growth rate within 22 forest understory bird species in the Usambara Mountains, Tanzania. This represents the first such effort, in either tropical or temperate systems, to characterize the effect of deforestation on avian survival across such a broad suite of species. Long‐term demographic analysis of this suite of species experiencing the same fragmented environment revealed considerable variability in species' responses to fragmentation, in addition to general patterns that emerged from comparison among species. Across the understory bird community as a whole, we found significantly lower apparent survival and realized population growth rate in small fragments relative to large, demonstrating fragmentation effects to demographic rates long after habitat loss. Demographic rates were depressed across five feeding guilds, suggesting that fragmentation sensitivity was not limited to insectivores. Seniority analyses, together with a positive effect of fragmentation on recruitment, indicated that depressed apparent survival was the primary driver of population declines and observed extinctions. We also found a landscape effect, with lower vital rates in one mountain range relative to another, suggesting that fragmentation effects may add to other large‐scale drivers of population decline. Overall, realized population growth rate (λ) estimates were <1 for most species, suggesting that future population persistence, even within large forest fragments, is uncertain in this biodiversity hotspot.
Dual Effects of Bilirubin on the Proliferation of Rat Renal NRK52E Cells and its Association with Gap Junctions
Authors: Wang Yanling , Zhu Qiongfang , Luo Chenfang , Zhang Ailan , Hei Ziqing , Su Guangjie , Xia Zhengyuan , Irwin Michael G.
Published: July 2012

Objective

The effect of bilirubin on renal pathophysiology is controversial. This study aimed to observe the effects of bilirubin on the proliferation of normal rat renal tubular epithelial cell line (NRK52E) and its potential interplay with gap junction function.

Methods

Cultured NRK52E cells, seeded respectively at high- or low- densities, were treated with varying concentrations of bilirubin for 24 hours. Cell injury was assessed by measuring cell viability and proliferation, and gap junction function was assessed by Parachute dye-coupling assay. Connexin 43 protein was assessed by Western blotting.

Results

At doses from 17.1 to 513μmol/L, bilirubin dose-dependently enhanced cell viability and colony-formation rates when cells were seeded at either high- or low- densities (all p<0.05 vs. solvent group) accompanied with enhanced intercellular fluorescence transmission and increased Cx43 protein expression in high-density cells. However, the above effects of BR were gradually reversed when its concentration increased from 684 to 1026μmol/L. In high-density cells, gap junction inhibitor 12-O-tetradecanoylphorbol 13-acetate attenuated bilirubin-induced enhancement of colony-formation and fluorescence transmission. However, in the presence of high concentration bilirubin (1026μmol/L), activation of gap junction with retinoid acid decreased colony-formation rates.

Conclusion

Bilirubin can confer biphasic effects on renal NRK52E cell proliferation potentially by differentially affecting gap junction functions.
Incorporating Low-Dose Epidemiology Data in a Chlorpyrifos Risk Assessment
Authors: Goodman Julie E. , Prueitt Robyn L. , Rhomberg Lorenz R.
Published: July 2012

USEPA assessed whether epidemiology data suggest that fetal or early-life chlorpyrifos exposure causes neurodevelopmental effects and, if so, whether they occur at exposures below those causing the current most sensitive endpoint, 10% inhibition of blood acetyl-cholinesterase (AChE). We previously conducted a hypothesis-based weight-of-evidence analysis and found that a proposed causal association between chlorpyrifos exposure and neurodevelopmental effects in the absence of AChE inhibition does not have a substantial basis in existing animal or in vitro studies, and there is no plausible basis for invoking such effects in humans at their far lower exposure levels. The epidemiology studies fail to show consistent patterns; the few associations are likely attributable to alternative explanations. Human data are inappropriate for a dose-response assessment because biomarkers were only measured at one time point, may reflect exposure to other pesticides, and many values are at or below limits of quantification. When considered with pharmacokinetic data, however, these biomarkers provide information on exposure levels relative to those in experimental studies and indicate a margin of exposure of at least 1,000. Because animal data take into account the most sensitive lifestages, the use of AChE inhibition as a regulatory endpoint is protective of adverse effects in sensitive populations.