bluuebunny/crossref_metadata_2025 huggingface dataset:
CD4
+
CD25
+
Foxp3
+
Regulatory T Cells Protect the Proinflammatory Activation of Human Umbilical Vein Endothelial Cells
Authors: He Shaolin , Li Ming , Ma Xuming , Lin Jing , Li Dazhu
Published: October 2010

Objective—

To investigate the role of CD4
+
CD25
+
forkhead box P 3 (Foxp3)
+
T-regulatory cells (Tregs) in protecting the activation and function of human umbilical vein endothelial cells (HUVECs) induced by proinflammatory stimulus and the mechanisms of it.

Methods and Results—

ECs play a major role in atherogenic initiation, changing their quiescence into activated phenotypes to support every phase of the inflammatory process. HUVECs were incubated alone, with Tregs or CD4
+
CD25
−
T cells in the presence of anti–CD3 monoclonal antibodies for 48 hours, and then were stimulated with or without oxidized low-density lipoprotein/lipopolysaccharide for an additional 24 hours. Tregs are able to induce alternative expression of immune phenotypic markers of activated HUVECs by down modulating CD86 and to inhibit the adhesion molecule, such as vascular cell adhesion molecule-1 (VCAM-1) and proinflammatory cytokine (eg, monocyte chemoattractant protein-1 and interleukin 6), response of HUVECs to oxidized low-density lipoprotein/lipopolysaccharide. Moreover, Tregs downregulate proinflammatory factor nuclear factor-κB activation and induce resistance to suppression of anti-inflammatory factor Kruppellike factor 2 in HUVECs induced by a proinflammatory stimulus. Mechanism studies reveal that Treg-mediated suppression of HUVEC proinflammatory cytokines and adhesion molecule expression impaired by oxidized low-density lipoprotein/lipopolysaccharide require cell contact by cytotoxic T-lymphocyte antigen-4 and CD86 and by soluble factors (mainly interleukin 10 and transforming growth factor [TGF]-β).

Conclusion—

Tregs may exert their protective effects against atherogenesis in part through inducing an immune-inhibitory phenotype of ECs involving cytotoxic T-lymphocyte antigen-4–dependent cell-to-cell contact and also requiring soluble factors (mainly interleukin 10 and TGF-β).
Activation of Protease-Activated Receptors 3 and 4 Accelerates Tissue Factor–Induced Thrombin Generation on the Surface of Vascular Smooth Muscle Cells
Authors: Vidwan Param , Pathak Alokkumar , Sheth Samar , Huang Jianhua , Monroe Dougald M. , Stouffer George A.
Published: October 2010

Objective—

To determine factors regulating human aortic smooth muscle cells (HASMC) supported tissue factor-induced thrombin generation.

Methods and Results—

The addition of nonlipidated tissue factor and Ca
2+
to HASMCs maintained in reptilase-treated platelet-poor plasma resulted in the robust formation of thrombin after a lag phase of approximately 6 minutes. Pretreatment with low concentrations of α-thrombin before the addition of tissue factor and Ca
2+
accelerated the rate of thrombin generation (time to reach half of peak thrombin was reduced by [mean±SD] 42.0±2.2%;
P
<0.05) but had no effect on the amount of peak thrombin generated. Protease-activated receptor (PAR) 3 activating peptides (APs) or PAR-4 APs accelerated thrombin generation without affecting peak thrombin levels (time to half of peak thrombin decreased by 17.4±5.6% and 21.7±3.5%;
P
<0.05 with PAR-3 AP and PAR-4 AP, respectively). The addition of PAR-3 AP and PAR-4 AP together had an additive effect, with a reduction in time to half of peak thrombin of 43.9±4.0%. PAR-3 AP or PAR-4 AP enhanced tissue factor–induced factor Xa production and phosphatidylserine exposure on the surface of HASMCs. PAR-1 activation had no effect on thrombin generation, factor Xa production, or phosphatidylserine exposure.

Conclusion—

Low concentrations of α-thrombin accelerate tissue factor–induced thrombin generation on the surface of HASMCs, and this effect is mediated by PAR-3 and PAR-4.
Oral Administration of an Active Form of Vitamin D
3
(Calcitriol) Decreases Atherosclerosis in Mice by Inducing Regulatory T Cells and Immature Dendritic Cells With Tolerogenic Functions
Authors: Takeda Masafumi , Yamashita Tomoya , Sasaki Naoto , Nakajima Kenji , Kita Tomoyuki , Shinohara Masakazu , Ishida Tatsuro , Hirata Ken-ichi
Published: October 2010

Objective—

To determine whether the administration of an active form of vitamin D
3
(calcitriol) could prevent atherosclerosis through anti-inflammatory actions.

Methods and Results—

Recent clinical studies have shown that lack of vitamin D
3
is a risk factor for cardiovascular events. Oral calcitriol administration decreased atherosclerotic lesions, macrophage accumulation, and CD4
+
T-cell infiltration at the aortic sinus, when compared with the corresponding observations in control mice. We observed a significant increase in Foxp3
+
regulatory T cells and a decrease in CD80
+
CD86
+
dendritic cells (DCs) in the mesenteric lymph nodes, spleen, and atherosclerotic lesions in oral calcitriol–treated mice in association with increased interleukin 10 and decreased interleukin 12 mRNA expression. CD11c
+
DCs from the calcitriol group showed reduced proliferative activity of T lymphocytes, suggesting the suppression of DC maturation. Neutralization of CD25 in vivo revealed that calcitriol inhibited atherosclerosis mainly in a regulatory T cell–dependent manner but also partly because of a decrease in DC maturation.

Conclusion—

Oral calcitriol treatment could prevent the development of atherosclerosis by changing the function or differentiation of DCs and regulatory T cells. These findings suggest that intestinal and systemic immune modulation by calcitriol may be a potentially valuable therapeutic approach against atherosclerosis.
Alcohol Inhibits Smooth Muscle Cell Proliferation via Regulation of the Notch Signaling Pathway
Authors: Morrow David , Cullen John P. , Liu Weimin , Cahill Paul A. , Redmond Eileen M.
Published: October 2010

Objective—To determine the role of Notch signaling in mediating alcohol’s inhibition of smooth muscle cell (SMC) proliferation.

Methods and Results—Treatment of human coronary artery SMCs with ethanol (EtOH) decreased Notch 1 mRNA and Notch 1 intracellular domain protein levels, in the absence of any effect on Notch 3. EtOH treatment also decreased C-promoter binding factor-1 (CBF-1)/recombination signal-binding protein (RBP)-jk promoter activity and Notch target gene (hairy related transcription factor [HRT-1] orHRT-2) expression. These effects were concomitant with an inhibitory effect of EtOH on SMC proliferation. Overexpression of constitutively active Notch 1 intracellular domain or human hairy related transcription factor-1 (hHRT-1) prevented the EtOH-induced inhibition of SMC proliferation. In vivo, Notch 1 and HRT-1 mRNA expression was increased after ligation-induced carotid artery remodeling. The vessel remodeling response was inhibited in mice that received “moderate” amounts of alcohol by gavage daily; intimal-medial thickening was markedly reduced, and medial and neointimal SMC proliferating cell nuclear antigen expression was decreased. Moreover, Notch 1 and HRT-1 expression, induced after ligation injury, was inhibited by moderate alcohol consumption.

Conclusion—EtOH inhibits Notch signaling and, subsequently, SMC proliferation, in vitro and in vivo. The modulation of Notch signaling in SMCs by EtOH may be relevant to the cardiovascular protective effects of moderate alcohol consumption purported by epidemiological studies.
n-3 Fatty Acids Decrease Arterial Low-Density Lipoprotein Cholesterol Delivery and Lipoprotein Lipase Levels in Insulin-Resistant Mice
Authors: Chang Chuchun L. , Seo Toru , Du Christine B. , Accili Domenico , Deckelbaum Richard J.
Published: October 2010

Objective—

To determine whether n-3 fatty acids (n-3) influence arterial cholesterol delivery and lipoprotein lipase (LpL) levels in insulin-resistant mice.

Methods and Results—

Insulin resistance contributes to risk of cardiovascular disease. It was previously reported that saturated fat (SAT) diets increased, but n-3 diets decreased, arterial low-density lipoprotein (LDL) cholesterol deposition from LDL total and selective uptake; this was associated with increased or decreased arterial LpL, respectively. Insulin receptor transgenic knockout mice (L1) were fed a chow, SAT, or n-3 diet for 12 weeks. Double-fluorescent boron dipyrromethene (BODIPY)–cholesteryl ester (CE) and Alexa dye-labeled human LDL were injected to separately trace LDL-CE and LDL–apolipoprotein B whole particle uptake. In contrast to SAT, n-3 diets markedly reduced all plasma lipids, ameliorating progression of insulin resistance. As opposed to SAT, n-3 reduced arterial LDL uptake, CE deposition, and selective uptake. Disparate patterns of CE deposition between diets were comparable with arterial LpL distribution; SAT induced high LpL levels throughout aortic media; LpL was limited only to intima in n-3–fed mice.

Conclusion—

n-3 diets diminish arterial LDL-cholesterol deposition in mice with insulin resistance, and this is associated with changes in arterial LpL levels and distribution.
Vascular Hospitalization Rates and Costs in Patients With Peripheral Artery Disease in the United States
Authors: Mahoney Elizabeth M. , Wang Kaijun , Keo Hong H. , Duval Sue , Smolderen Kim G. , Cohen David J. , Steg Gabriel , Bhatt Deepak L. , Hirsch Alan T. ,   on behalf of the Reduction of Atherothrombosis for Continued Health (REACH) Registry Investigators*
Published: October 2010

Background—

Peripheral artery disease (PAD) is common and imposes a high risk of major systemic and limb ischemic events. The
RE
duction of
A
therothrombosis for
C
ontinued
H
ealth (REACH) Registry is an international prospective registry of patients at risk of atherothrombosis caused by established arterial disease or the presence of ≥3 atherothrombotic risk factors.

Methods and Results—

We compared the 2-year rates of vascular-related hospitalizations and associated costs in US patients with established PAD across patient subgroups. Symptomatic PAD at enrollment was identified on the basis of current intermittent claudication with an ankle-brachial index (ABI) <0.90 or a history of lower-limb revascularization or amputation. Asymptomatic PAD was diagnosed on the basis of an enrollment ABI <0.90 in the absence of symptoms. Overall, 25 763 of the total 68 236–patient REACH cohort were enrolled from US sites; 2396 (9.3%) had symptomatic and 213 (0.8%) had asymptomatic PAD at baseline. One- and cumulative 2-year follow-up data were available for 2137 (82%) and 1677 (64%) of US REACH patients with either symptomatic or asymptomatic PAD, respectively. At 2 years, mean cumulative hospitalization costs, per patient, were $7445, $7000, $10 430, and $11 693 for patients with asymptomatic PAD, a history of claudication, lower-limb amputation, and revascularization, respectively (
P
=0.007). A history of peripheral intervention (lower-limb revascularization or amputation) was associated with higher rates of subsequent procedures at both 1 and 2 years.

Conclusions—

The economic burden of PAD is high. Recurring hospitalizations and repeat revascularization procedures suggest that neither patients, physicians, nor healthcare systems should assume that a first admission for a lower-extremity PAD procedure serves as a permanent resolution of this costly and debilitating condition.
Improvements in Symptoms and Quality of Life in Patients With Paroxysmal Atrial Fibrillation Treated With Radiofrequency Catheter Ablation Versus Antiarrhythmic Drugs
Authors: Reynolds Matthew R. , Walczak Joshua , White Sarah A. , Cohen David J. , Wilber David J.
Published: October 2010

Background—

In patients with paroxysmal atrial fibrillation (AF), catheter ablation maintains sinus rhythm more effectively than antiarrhythmic drugs (AADs), but its effect on symptoms and quality of life (QOL) has not been fully characterized.

Methods and Results—

We evaluated symptoms and QOL in a multicenter, randomized trial comparing catheter ablation with AADs as second-line treatment for patients with paroxysmal AF. The Short Form (SF)-36 health survey and the AF Symptom Checklist were administered at baseline and 3, 6, and 9 months after a blanking or dose-titration period. The primary between-group comparisons were conducted at 3 months because of permitted crossover from AAD to ablation beyond this time. Additional analyses based on subsequent follow-up were performed, including the construction of mixed linear regression models to assess the impact of multiple factors on follow-up QOL scores.

At baseline in both the ablation (n=103) and the AAD (n=56) groups, 7 of 8 SF-36 scales were well below population norms, as were the physical (PCS) and mental (MCS) summary scores. At 3 months, the same 7 SF-36 scales were significantly (
P
<0.01) higher in the ablation than in the AAD group, as were the PCS (52.0±7.8 versus 47.1±10.6;
P
<0.01) and MCS (52.4±8.1 versus 46.6±9.8;
P
<0.01) scores, whereas symptom frequency (9.3±9.2 versus 19.0±12.6;
P
<0.001) and symptom severity (7.7±7.2 versus 16.2±10.0;
P
<0.001) were significantly reduced. In multivariable analysis, ablation and recurrent arrhythmias most strongly correlated with QOL changes over time.

Conclusions—

For second-line therapy of paroxysmal AF, ablation is superior to AAD treatment at improving symptoms and QOL.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00116428.
Lamb, Mutton, and Goat in the Babylonian Temple Economy
Authors: Kozuh Michael
Published: October 2010

In the mid-first millennium B.C.E., the Eanna temple of Uruk distributed the meat of sheep and goats to its associates and dependents. The meat of post-sacrificial lambs went to the Eanna’s prebend holding elite, while others received the meat of goats and older sheep without ceremony and on the hoof. Many assume this latter distribution worked to supply the Eanna’s lowest classes with substandard meat. I argue, instead, that there was nothing inherently substandard about this meat; moreover, there is little evidence that it was intended for the Eanna’s lowest classes. This paper then explores the distribution of meat to the Eanna’s sub-elite, especially in place of temple rations and payments of silver.
The Christians Whose Force is Hard: Non-Ecclesiastical Judicial Authorities in the Early Islamic Period
Authors: Simonsohn Uriel
Published: October 2010

This paper examines the context in which church leaders in the regions of Mesopotamia and the Fertile Crescent, during the first few centuries after the Arab conquest, were objecting to the appeal of the their coreligionists to judicial authorities outside ecclesiastical control. Rather than assuming that from the outset of the Islamic conquest Muslim judges served as immediate judicial alternatives, the paper shows that, at least in the early Islamic period, church leaders were often aiming their exhortations towards Christians who sought the authority of other Christian figures from outside ecclesiastical jurisdiction.
Animals as Property in Early Modern Ottoman Egypt
Authors: Mikhail Alan
Published: October 2010

Through an examination of the role of domesticated animals as forms of property in rural Ottoman Egypt, this article argues that historians of the early modern Muslim world must pay greater attention to the economic and social importance of animals. Based on the sharīa court records of multiple cities in both the Nile Delta and Upper Egypt, this study documents the role of animals as agricultural laborers, as means of transport, and as sources of food. It then analyzes several court cases in which the abilities of animals to move, die, and procreate serve to challenge notions of property and legal ownership in Ottoman Egypt.À travers l’examen du rôle que jouaient les animaux domestiques, en tant qu’objets de propriété, dans les campagnes de l’Égypte ottomane, cet article propose qu’une attention accrue devrait être prêtée à l’importance économique et sociale des animaux à l’époque moderne. Basée sur les registres de tribunaux religieux de nombreuses villes du Delta et de Haute Égypte, cette étude révèle le rôle des animaux en tant qu’ouvriers agricoles, moyens de transport et sources d’alimentation. Une série de procès menés devant ces tribunaux montre que la capacité des animaux à se déplacer, à mourir et à procréer servait à remettre en cause les notions de propriété et de possession légale dans l’Égypte ottomane.
Transgenic Rescue of Enamel Phenotype in Ambn Null Mice
Authors: Chun Y.-H.P. , Lu Y. , Hu Y. , Krebsbach P.H. , Yamada Y. , Hu J.C.-C. , Simmer J.P.
Published: October 2010

Ameloblastin null mice fail to make an enamel layer, but the defects could be due to an absence of functional ameloblastin or to the secretion of a potentially toxic mutant ameloblastin. We hypothesized that the enamel phenotype could be rescued by the transgenic expression of normal ameloblastin in Ambn mutant mice. We established and analyzed 5 transgenic lines that expressed ameloblastin from the amelogenin ( AmelX) promoter and identified transgenic lines that express virtually no transgene, slightly less than normal (Tg+), somewhat higher than normal (Tg++), and much higher than normal (Tg+++) levels of ameloblastin. All lines expressing detectable levels of ameloblastin at least partially recovered the enamel phenotype. When ameloblastin expression was only somewhat higher than normal, the enamel covering the molars and incisors was of normal thickness, had clearly defined rod and interrod enamel, and held up well in function. We conclude that ameloblastin is essential for dental enamel formation.
Effect of Biofilm on the Repair Bond Strengths of Composites
Authors: Rinastiti M. , Özcan M. , Siswomihardjo W. , Busscher H.J. , van der Mei H.C.
Published: October 2010

Composite restorations degrade during wear, but it is unknown how wear affects the composite surface and influences composite-to-composite bonding in minimally invasive repair. Here, it is hypothesized that in vitro exposure of composites to oral biofilm yields clinically relevant degradation of composite surfaces, and its influence on composite-to-composite bonding is determined. Biofilms on composite surfaces in vitro increased their roughness and decreased filler particle exposure, except for a microhybrid composite, similar to effects of clinical wear in palatal appliances. Failure shear stresses after intermediate-adhesive-resin application were significantly lower after aging by in vitro exposure to biofilms, while silica-coating maintained the same failure stress levels as in non-aged composites. Failure modes were predominantly cohesive after silica-coating, while intermediate-adhesive-resin application yielded more adhesive failure. It is concluded that in vitro exposure to oral biofilm is a clinically relevant aging condition, and that silica-coating is to be preferred for the repair of aged composites.
Novel Molecular Events in Oral Carcinogenesis via Integrative Approaches
Authors: Wu R.Q. , Zhao X.F. , Wang Z.Y. , Zhou M. , Chen Q.M.
Published: October 2010

Cancer is now viewed as a systems biology disease, and oral squamous cell carcinoma (OSCC) can be viewed in a similar fashion. In this paper, we highlight some of the novel molecular events in OSCC, revealed through an integrative strategy of systems biology based on high-throughput omics analysis such as genomics and/or proteomics, the most powerful hypothesis-generating means available today. These approaches have resulted not only in the identification of novel genes for OSCC, but also in more comprehensive networks that describe the mechanisms by which those identified events work, with the promise of developing this knowledge into biomarkers for diagnosis, prognosis, and prediction of therapeutic responses in OSCC patients. Long-term, population-based prospective studies of OSCC patients, and those at high risk of developing OSCC, will then be needed to validate these biomarkers.
Expression of Osteoclastogenesis Inducers in a Tissue Model of Periodontal Ligament under Compression
Authors: Li Y. , Zheng W. , Liu J.-S. , Wang J. , Yang P. , Li M.-L. , Zhao Z.-H.
Published: October 2010

There is increasing interest in the development of new in vitro tissue models. In this study, a tissue model of periodontal ligament (PDL) was established by 3-D-culturing human PDL cells in a thin sheet of porous poly (lactic-co-glycolic acid) scaffold. Growth of the model was evidenced by MTT assay and various microscopies. After being subjected to static compression of 5 ~ 35 g/cm2 for 6 hrs, the RANKL mRNA expression was significantly up-regulated by force ≥ 25 g/cm2 in the model. After being subjected to static compression of 25 g/cm2 for 6 ~ 72 hrs, the mRNA expression of PTHrP, IL-11, IL-8, and FGF-2, potential osteoclastogenesis inducers, was significantly up-regulated in the model, which was further verified by the compression of human PDL in vivo. However, when human gingival fibroblasts were substituted for PDL cells in the model, almost no osteoclastogenesis inducers were up-regulated by compression. This tissue model can serve as an effective tool for the study of PDL mechanoresponse. Abbreviations: periodontal ligament, PDL; periodontal ligament cells, PDLCs; poly (lactic-co-glycolic acid), PLGA; orthodontic tooth movement, OTM; extracellular matrix, ECM.
Ethanol Wet-bonding Challenges Current Anti-degradation Strategy
Authors: Sadek F.T. , Braga R.R. , Muench A. , Liu Y. , Pashley D.H. , Tay F.R.
Published: October 2010

The long-term effectiveness of chlorhexidine as a matrix metalloproteinase (MMP) inhibitor may be compromised when water is incompletely removed during dentin bonding. This study challenged this anti-bond degradation strategy by testing the null hypothesis that wet-bonding with water or ethanol has no effect on the effectiveness of chlorhexidine in preventing hybrid layer degradation over an 18-month period. Acid-etched dentin was bonded under pulpal pressure simulation with Scotchbond MP and Single Bond 2, with water wet-bonding or with a hydrophobic adhesive with ethanol wet-bonding, with or without pre-treatment with chlorhexidine diacetate (CHD). Resin-dentin beams were prepared for bond strength and TEM evaluation after 24 hrs and after aging in artificial saliva for 9 and 18 mos. Bonds made to ethanol-saturated dentin did not change over time with preservation of hybrid layer integrity. Bonds made to CHD pre-treated acid-etched dentin with commercial adhesives with water wet-bonding were preserved after 9 mos but not after 18 mos, with severe hybrid layer degradation. The results led to rejection of the null hypothesis and highlight the concept of biomimetic water replacement from the collagen intrafibrillar compartments as the ultimate goal in extending the longevity of resin-dentin bonds.
Interaction between the MTHFR C677T Polymorphism and Alcohol—Impact on Oral Cancer Risk and Multiple DNA Methylation of Tumor-related Genes
Authors: Supic G. , Jovic N. , Kozomara R. , Zeljic K. , Magic Z.
Published: October 2010

Several studies have reported Oral Squamous Cell Carcinoma ( OSCC) association with etiological factors, such as smoking and alcohol. The aim of the present study was to establish whether the methylenetetrahydrofolate reductase ( MTHFR) C677T genotype and a high alcohol intake, solely or in interaction, have an impact on the oral cancer risk, DNA methylation, or multiple methylation of tumor-related genes. MTHFR C677T genetic polymorphism was determined by the PCR/RFLP method, and DNA methylation was assessed by nested methylation-specific PCR. The risk for multiple methylation was significantly increased in heavy-drinking patients with the TT genotype, compared with CC and CT patients (OR = 10.873; 95% CI, 1.134-104.24). Multiple methylation was significantly associated with tumor stage ( p = 0.018), and showed a trend of association with the presence of nodal metastases ( p = 0.058). A significant association was found between TT genotype and methylation status of the RASSF1A gene in OSCC patients ( p = 0.012). Heavy-drinking individuals with the TT genotype showed increased oral cancer risk compared with the CC genotype (OR = 3.601; 95% CI, 1.036-12.513), and compared with the CC and CT genotypes (OR = 4.288; 95% CI, 1.325-13.877). Our study suggested gene-environment interactions between high alcohol intake and the MTHFR 677TT genotype for elevated oral cancer risk, with a significant impact on multiple methylation of cancer-related genes.
Two Algorithms for Relaxed Structural Balance Partitioning: Linking Theory, Models, and Data to Understand Social Network Phenomena
Authors: Brusco Michael , Doreian Patrick , Mrvar Andrej , Steinley Douglas
Published: October 2010

Understanding social phenomena with the help of mathematical models requires a coherent combination of theory, models, and data together with using valid data analytic methods. The study of social networks through the use of mathematical models is no exception. The intuitions of structural balance were formalized and led to a pair of remarkable theorems giving the nature of partition structures for balanced signed networks. Algorithms for partitioning signed networks, informed by these formal results, were developed and applied empirically. More recently, ‘‘structural balance’’ was generalized to ‘‘relaxed structural balance,’’ and a modified partitioning algorithm was proposed. Given the critical interplay of theory, models, and data, it is important that methods for the partitioning of signed networks in terms of relaxed structural balance model are appropriate. The authors consider two algorithms for establishing partitions of signed networks in terms of relaxed structural balance. One is an older heuristic relocation algorithm, and the other is a new exact solution procedure. The former can be used both inductively and deductively. When used deductively, this requires some prespecification incorporating substantive insights. The new branch-and-bound algorithm is used inductively and requires no prespecification of an image matrix in terms of ideal blocks. Both procedures are demonstrated using several examples from the literature, and their contributions are discussed. Together, the two algorithms provide a sound foundation for partitioning signed networks and yield optimal partitions. Issues of network size and density are considered in terms of their consequences for algorithm performance.
Population Pharmacokinetic Model of Human Insulin Following Different Routes of Administration
Authors: Potocka Elizabeth , Baughman Robert A. , Derendorf Hartmut
Published: October 2010

Multiple‐compartment disposition of insulin has been demonstrated following intravenous administration; however, because of slow absorption and flip‐flop kinetics, meal‐time insulin pharmacokinetics have been described by a 1‐compartment model. Technosphere insulin (TI) is an inhaled human insulin with rapid absorption and a distinct second compartment in its pharmacokinetics. The aim of this analysis was to develop a pharmacokinetic model for insulin administered via the intravenous, subcutaneous, and inhalation routes. A 2‐compartment pharmacokinetic model with 1 (inhaled) or 2 sequential (subcutaneous) first‐order absorption processes and first‐order elimination was developed using data from 2 studies with a total of 651 concentrations from 16 healthy volunteers. Insulin was administered intravenously (5 U), subcutaneously (10 U), and via inhalation (25, 50, and 100 U). The data were modeled simultaneously with NONMEM VI, using ADVAN6 subroutine with FO. Typical values were clearance, 43.4 L/h; volume of distribution in the central compartment, 5.0 L; intercompartmental clearance, 23.9 L/h; volume of distribution in the peripheral compartment 30.7 L; TI first‐order absorption rate constant, 2.35 h−1; and first‐order absorption rate constants associated with subcutaneously administered insulin, 0.63 and 1.04 h−1, respectively. Absorption rate after subcutaneous dosing was found to decrease with increasing body mass index. Insulin pharmacokinetics were found to be consistent with 2‐compartment disposition, regardless of route of administration, with insulin curve differences attributable to absorption differences.
Offender Experiences and Opinions of Mixed-Gender Group Work in the Community
Authors: Burrowes Nina , Day Jo
Published: October 2010

The National Probation Service in England and Wales currently delivers community-based accredited offending behavior programs in mixed-gender groups. There is at present a lack of research on the potential impact of mixed-gender group work on female offenders, who are often the minority within the group. This study aimed to improve our understanding of the area using qualitative methods. Sixteen offenders who had participated in a mixed-gender offending behavior program were interviewed as part of this study. Themes from the interviews were analyzed using Grounded Theory techniques. The findings illustrated an overall preference among all participants for mixed-gender rather than single-gender group work. The specific advantages of mixed-gender group work included increased learning about the opposite sex and a more relaxed atmosphere within the group. Although this study reflects positive attitudes to mixed-gender group work, the findings need to be tested further using empirical methodology.
Population geographies and climate change
Authors: Bailey Adrian J.
Published: October 2010

This review considers how population geographies currently contribute, and might further contribute, to understanding how populations are connected to climate change. Progress has been made in understanding the empirical and theoretical dimensions of climate change through research on the demographics of climate change, theories of vulnerability and adaptation, and frameworks concerned with risk, and governmentality. I conclude with a call to reflect upon and develop policy and activist strategies sensitive to the increasingly important role of global networks.
Asthenopia (eyestrain) in working children of gem-polishing industries
Authors: Tiwari Rajnarayan R , Saha Asim , Parikh Jagdish R
Published: October 2010

Working children of gem-polishing units are exposed to poor illumination and improper workstations. Also processes require lot of visual and mental concentration for precision. This may result in eyestrain. The study included 432 exposed and 569 comparison group subjects. Self-reported eyestrain was recorded through personal interview. Eyestrain included symptoms like itching, burning, or irritated eyes; tired or heavy eyes; difficulty seeing clearly (including blurred or double vision); and headache. The study variables included age, gender, daily working hours, and duration of exposure. The prevalence of eyestrain in child labourers was 32.2%, which was significantly more than the comparison group subjects. Also, the working children of gem-polishing units were at 1.4 times higher risk of developing eyestrain. Age 314 years and female gender were significantly associated with the eyestrain. The prevalence of eyestrain in child labourers was 32.2% and was associated with age 314 years and female gender.
Variation in the von Willebrand factor gene is associated with von Willebrand factor levels and with the risk for cardiovascular disease
Authors: van Schie Marianne C. , de Maat Moniek P. M. , Isaacs Aaron , van Duijn Cornelia M. , Deckers Jaap W. , Dippel Diederik W. J. , Leebeek Frank W. G.
Published: October 2010

High levels of von Willebrand factor (VWF) are associated with an increased risk for cardiovascular disease (CVD). Although VWF levels are strongly heritable and genetic susceptibility is an important risk factor for CVD, information on the contribution of common VWF gene variants to VWF levels and CVD risk is limited. In a case-control study of 421 young patients with a first event of acute coronary heart disease (CHD) or ischemic stroke (IS), and 409 healthy control participants (men aged ≤ 45 years, women aged ≤ 55 years), 27 haplotype-tagging single-nucleotide polymorphisms (ht-SNPs), covering the total common VWF gene variation, were selected and genotyped. The associations between these SNPs, VWF antigen (VWF:Ag) levels, VWF collagen-binding (VWF:CB) activity, and CVD risk was investigated. Two new associations were identified. For ht-SNP rs4764478 (intron 45), the increase in VWF:Ag levels and VWF:CB activity per minor allele was 0.082 (± 0.026) IU/mL (P = .001) and 0.096 (± 0.030) IU/mL (P = .002), respectively. ht-SNP rs216293 (intron 17) was associated with CVD risk (odds ratio, 1.44; 95% confidence interval [CI], 1.12-1.86 per minor allele). We confirmed the association between rs1063857 and CVD risk. Our data show that common variants in the VWF gene are associated with VWF levels and with the risk for CVD.
The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemia
Authors: Herishanu Yair , Pérez-Galán Patricia , Liu Delong , Biancotto Angélique , Pittaluga Stefania , Vire Berengere , Gibellini Federica , Njuguna Ndegwa , Lee Elinor , Stennett Lawrence , Raghavachari Nalini , Liu Poching , McCoy J. Philip , Raffeld Mark , Stetler-Stevenson Maryalice , Yuan Constance , Sherry Richard , Arthur Diane C. , Maric Irina , White Therese , Marti Gerald E. , Munson Peter , Wilson Wyndham H. , Wiestner Adrian
Published: October 2010

Chronic lymphocytic leukemia (CLL), an incurable malignancy of mature B lymphocytes, involves blood, bone marrow, and secondary lymphoid organs such as the lymph nodes (LN). A role of the tissue microenvironment in the pathogenesis of CLL is hypothesized based on in vitro observations, but its contribution in vivo remains ill-defined. To elucidate the effects of tumor-host interactions in vivo, we purified tumor cells from 24 treatment-naive patients. Samples were obtained concurrently from blood, bone marrow, and/or LN and analyzed by gene expression profiling. We identified the LN as a key site in CLL pathogenesis. CLL cells in the LN showed up-regulation of gene signatures, indicating B-cell receptor (BCR) and nuclear factor-κB activation. Consistent with antigen-dependent BCR signaling and canonical nuclear factor-κB activation, we detected phosphorylation of SYK and IκBα, respectively. Expression of BCR target genes was stronger in clinically more aggressive CLL, indicating more effective BCR signaling in this subtype in vivo. Tumor proliferation, quantified by the expression of the E2F and c-MYC target genes and verified with Ki67 staining by flow cytometry, was highest in the LN and was correlated with clinical disease progression. These data identify the disruption of tumor microenvironment interactions and the inhibition of BCR signaling as promising therapeutic strategies in CLL. This study is registered at http://clinicaltrials.gov as NCT00019370.
Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine
Authors: Itzykson Raphael , Thépot Sylvain , Quesnel Bruno , Dreyfus Francois , Beyne-Rauzy Odile , Turlure Pascal , Vey Norbert , Recher Christian , Dartigeas Caroline , Legros Laurence , Delaunay Jacques , Salanoubat Célia , Visanica Sorin , Stamatoullas Aspasia , Isnard Francoise , Marfaing-Koka Anne , de Botton Stephane , Chelghoum Youcef , Taksin Anne-Laure , Plantier Isabelle , Ame Shanti , Boehrer Simone , Gardin Claude , Beach C. L. , Adès Lionel , Fenaux Pierre ,   on behalf of the Groupe Francophone des Myelodysplasies (GFM)
Published: October 2010

Prognostic factors for response and survival in higher-risk myelodysplastic syndrome patients treated with azacitidine (AZA) remain largely unknown. Two hundred eighty-two consecutive high or intermediate-2 risk myelodysplastic syndrome patients received AZA in a compassionate, patient-named program. Diagnosis was RA/RARS/RCMD in 4%, RAEB-1 in 20%, RAEB-2 in 54%, and RAEB-t (AML with 21%-30% marrow blasts) in 22%. Cytogenetic risk was good in 31%, intermediate in 17%, and poor in 47%. Patients received AZA for a median of 6 cycles (1-52). Previous low-dose cytosine arabinoside treatment (P = .009), bone marrow blasts > 15% (P = .004), and abnormal karyotype (P = .03) independently predicted lower response rates. Complex karyotype predicted shorter responses (P = .0003). Performance status ≥ 2, intermediate- and poor-risk cytogenetics, presence of circulating blasts, and red blood cell transfusion dependency ≥ 4 units/8 weeks (all P < 10−4) independently predicted poorer overall survival (OS). A prognostic score based on those factors discriminated 3 risk groups with median OS not reached, 15.0 and 6.1 months, respectively (P < 10−4). This prognostic score was validated in an independent set of patients receiving AZA in the AZA-001 trial (P = .003). Achievement of hematological improvement in patients who did not obtain complete or partial remission was associated with improved OS (P < 10−4). In conclusion, routine tests can identify subgroups of patients with distinct prognosis with AZA treatment.
Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6
Authors: Lenoir Anne , Deschemin Jean-Christophe , Kautz Léon , Ramsay Andrew J. , Roth Marie-Paule , Lopez-Otin Carlos , Vaulont Sophie , Nicolas Gaël
Published: October 2010

Hepcidin is the master regulator of iron homeostasis. In the liver, iron-dependent hepcidin activation is regulated through Bmp6 and its membrane receptor hemojuvelin (Hjv), whereas, in response to iron deficiency, hepcidin repression seems to be controlled by a pathway involving the serine protease matriptase-2 (encoded by Tmprss6). To determine the relationship between Bmp6 and matriptase-2 pathways, Tmprss6−/− mice (characterized by increased hepcidin levels and anemia) and Bmp6−/− mice (exhibiting severe iron overload because of hepcidin deficiency) were intercrossed. We showed that loss of Bmp6 decreased hepcidin levels; increased hepatic iron; and, importantly, corrected hematologic abnormalities in Tmprss6−/− mice. This finding suggests that elevated hepcidin levels in patients with familial iron-refractory, iron-deficiency anemia are the result of excess signaling through the Bmp6/Hjv pathway.
Trimming of mammalian transcriptional networks using network component analysis
Authors: Tran Linh M , Hyduke Daniel R , Liao James C
Published: October 2010

Background

Network Component Analysis (NCA) has been used to deduce the activities of transcription factors (TFs) from gene expression data and the TF-gene binding relationship. However, the TF-gene interaction varies in different environmental conditions and tissues, but such information is rarely available and cannot be predicted simply by motif analysis. Thus, it is beneficial to identify key TF-gene interactions under the experimental condition based on transcriptome data. Such information would be useful in identifying key regulatory pathways and gene markers of TFs in further studies.

Results

We developed an algorithm to trim network connectivity such that the important regulatory interactions between the TFs and the genes were retained and the regulatory signals were deduced. Theoretical studies demonstrated that the regulatory signals were accurately reconstructed even in the case where only three independent transcriptome datasets were available. At least 80% of the main target genes were correctly predicted in the extreme condition of high noise level and small number of datasets. Our algorithm was tested with transcriptome data taken from mice under rapamycin treatment. The initial network topology from the literature contains 70 TFs, 778 genes, and 1423 edges between the TFs and genes. Our method retained 1074 edges (i.e. 75% of the original edge number) and identified 17 TFs as being significantly perturbed under the experimental condition. Twelve of these TFs are involved in MAPK signaling or myeloid leukemia pathways defined in the KEGG database, or are known to physically interact with each other. Additionally, four of these TFs, which are Hif1a, Cebpb, Nfkb1, and Atf1, are known targets of rapamycin. Furthermore, the trimmed network was able to predictEno1as an important target of Hif1a; this key interaction could not be detected without trimming the regulatory network.

Conclusions

The advantage of our new algorithm, relative to the original NCA, is that our algorithm can identify the important TF-gene interactions. Identifying the important TF-gene interactions is crucial for understanding the roles of pleiotropic global regulators, such as p53. Also, our algorithm has been developed to overcome NCA's inability to analyze large networks where multiple TFs regulate a single gene. Thus, our algorithm extends the applicability of NCA to the realm of mammalian regulatory network analysis.
Evolutionary history of the poly(ADP-ribose) polymerase gene family in eukaryotes
Authors: Citarelli Matteo , Teotia Sachin , Lamb Rebecca S
Published: October 2010

Background

The Poly(ADP-ribose)polymerase (PARP) superfamily was originally identified as enzymes that catalyze the attachment of ADP-ribose subunits to target proteins using NAD+ as a substrate. The family is characterized by the catalytic site, termed the PARP signature. While these proteins can be found in a range of eukaryotes, they have been best studied in mammals. In these organisms, PARPs have key functions in DNA repair, genome integrity and epigenetic regulation. More recently it has been found that proteins within the PARP superfamily have altered catalytic sites, and have mono(ADP-ribose) transferase (mART) activity or are enzymatically inactive. These findings suggest that the PARP signature has a broader range of functions that initially predicted. In this study, we investigate the evolutionary history of PARP genes across the eukaryotes.

Results

We identified in silico 236 PARP proteins from 77 species across five of the six eukaryotic supergroups. We performed extensive phylogenetic analyses of the identified PARPs. They are found in all eukaryotic supergroups for which sequence is available, but some individual lineages within supergroups have independently lost these genes. The PARP superfamily can be subdivided into six clades. Two of these clades were likely found in the last common eukaryotic ancestor. In addition, we have identified PARPs in organisms in which they have not previously been described.

Conclusions

Three main conclusions can be drawn from our study. First, the broad distribution and pattern of representation of PARP genes indicates that the ancestor of all extant eukaryotes encoded proteins of this type. Second, the ancestral PARP proteins had different functions and activities. One of these proteins was similar to human PARP1 and likely functioned in DNA damage response. The second of the ancestral PARPs had already evolved differences in its catalytic domain that suggest that these proteins may not have possessed poly(ADP-ribosyl)ation activity. Third, the diversity of the PARP superfamily is larger than previously documented, suggesting as more eukaryotic genomes become available, this gene family will grow in both number and type.
Variance heterogeneity analysis for detection of potentially interacting genetic loci: method and its limitations
Authors: Struchalin Maksim V , Dehghan Abbas , Witteman Jacqueline CM , van Duijn Cornelia , Aulchenko Yurii S
Published: October 2010

Background

Presence of interaction between a genotype and certain factor in determination of a trait's value, it is expected that the trait's variance is increased in the group of subjects having this genotype. Thus, test of heterogeneity of variances can be used as a test to screen for potentially interacting single-nucleotide polymorphisms (SNPs). In this work, we evaluated statistical properties of variance heterogeneity analysis in respect to the detection of potentially interacting SNPs in a case when an interaction variable is unknown.

Results

Through simulations, we investigated type I error for Bartlett's test, Bartlett's test with prior rank transformation of a trait to normality, and Levene's test for different genetic models. Additionally, we derived an analytical expression for power estimation. We showed that Bartlett's test has acceptable type I error in the case of trait following a normal distribution, whereas Levene's test kept nominal Type I error under all scenarios investigated. For the power of variance homogeneity test, we showed (as opposed to the power of direct test which uses information about known interacting factor) that, given the same interaction effect, the power can vary widely depending on the non-estimable direct effect of the unobserved interacting variable. Thus, for a given interaction effect, only very wide limits of power of the variance homogeneity test can be estimated. Also we applied Levene's approach to test genome-wide homogeneity of variances of the C-reactive protein in the Rotterdam Study population (n = 5959). In this analysis, we replicate previous results of Pare and colleagues (2010) for the SNP rs12753193 (n = 21, 799).

Conclusions

Screening for differences in variances among genotypes of a SNP is a promising approach as a number of biologically interesting models may lead to the heterogeneity of variances. However, it should be kept in mind that the absence of variance heterogeneity for a SNP can not be interpreted as the absence of involvement of the SNP in the interaction network.
Characterization of the rainbow trout transcriptome using Sanger and 454-pyrosequencing approaches
Authors: Salem Mohamed , Rexroad Caird E , Wang Jiannan , Thorgaard Gary H , Yao Jianbo
Published: October 2010

Background

Rainbow trout are important fish for aquaculture and recreational fisheries and serves as a model species for research investigations associated with carcinogenesis, comparative immunology, toxicology and evolutionary biology. However, to date there is no genome reference sequence to facilitate the development of molecular technologies that utilize high-throughput characterizations of gene expression and genetic variation. Alternatively, transcriptome sequencing is a rapid and efficient means for gene discovery and genetic marker development. Although a large number (258,973) of EST sequences are publicly available, the nature of rainbow trout duplicated genome hinders assembly and complicates annotation.

Results

High-throughput deep sequencing of the Swanson rainbow trout doubled-haploid transcriptome using 454-pyrosequencing technology yielded ~1.3 million reads with an average length of 344 bp, a total of 447 million bases. De novo assembly of the sequences yielded 151,847 Tentative Consensus (TC) sequences (average length of 662 bp) and 224,391 singletons. A combination assembly of both the 454-pyrosequencing ESTs and the pre-existing sequences resulted in 161,818 TCs (average length of 758 bp) and 261,071 singletons. Gene Ontology analysis of the combination assembly showed high similarities to transcriptomes of other fish species with known genome sequences.

Conclusion

The 454 library significantly increased the suite of ESTs available for rainbow trout, allowing improved assembly and annotation of the transcriptome. Furthermore, the 454 sequencing enables functional genome research in rainbow trout, providing a wealth of sequence data to serve as a reference transcriptome for future studies including identification of paralogous sequences and/or allelic variation, digital gene expression and proteomic research.