bluuebunny/crossref_metadata_2025 huggingface dataset:
Cannabinoid-Mediated Modulation of Neuropathic Pain and Microglial Accumulation in a Model of Murine Type I Diabetic Peripheral Neuropathic Pain
Authors: Toth Cory C , Jedrzejewski Nicole M , Ellis Connie L , Frey William H
Published: March 2010

Background:

Despite the frequency of diabetes mellitus and its relationship to diabetic peripheral neuropathy (DPN) and neuropathic pain (NeP), our understanding of underlying mechanisms leading to chronic pain in diabetes remains poor. Recent evidence has demonstated a prominent role of microglial cells in neuropathic pain states. One potential therapeutic option gaining clinical acceptance is the cannabinoids, for which cannabinoid receptors (CB) are expressed on neurons and microglia. We studied the accumulation and activation of spinal and thalamic microglia in streptozotocin (STZ)-diabetic CD1 mice and the impact of cannabinoid receptor agonism/antagonism during the development of a chronic NeP state. We provided either intranasal or intraperitoneal cannabinoid agonists/antagonists at multiple doses both at the initiation of diabetes as well as after establishment of diabetes and its related NeP state.

Results:

Tactile allodynia and thermal hypersensitivity were observed over 8 months in diabetic mice without intervention. Microglial density increases were seen in the dorsal spinal cord and in thalamic nuclei and were accompanied by elevation of phosphorylated p38 MAPK, a marker of microglial activation. When initiated coincidentally with diabetes, moderate-high doses of intranasal cannabidiol (cannaboid receptor 2 agonist) and intraperitoneal cannabidiol attenuated the development of an NeP state, even after their discontinuation and without modification of the diabetic state. Cannabidiol was also associated with restriction in elevation of microglial density in the dorsal spinal cord and elevation in phosphorylated p38 MAPK. When initiated in an established DPN NeP state, both CB1 and CB2 agonists demonstrated an antinociceptive effect until their discontinuation. There were no pronociceptive effects demonstated for either CB1 or CB2 antagonists.

Conclusions:

The prevention of microglial accumulation and activation in the dorsal spinal cord was associated with limited development of a neuropathic pain state. Cannabinoids demonstrated antinociceptive effects in this mouse model of DPN. These results suggest that such interventions may also benefit humans with DPN, and their early introduction may also modify the development of the NeP state.
Automated detection of near falls: algorithm development and preliminary results
Authors: Weiss Aner , Shimkin Ilan , Giladi Nir , Hausdorff Jeffrey M
Published: March 2010

Background

Falls are a major source of morbidity and mortality among older adults. Unfortunately, self-report is, to a large degree, the gold-standard method for characterizing and quantifying fall frequency. A number of studies have demonstrated that near falls predict falls and that near falls may occur more frequently than falls. These studies suggest that near falls might be an appropriate fall risk measure. However, to date, such investigations have also relied on self-report. The purpose of the present study was to develop a method for automatic detection of near falls, potentially a sensitive, objectivemarker of fall risk and to demonstrate the ability to detect near falls using this approach.

Findings

15 healthy subjects wore a tri-axial accelerometer on the pelvis as they walked on a treadmill under different conditions. Near falls were induced by placing obstacles on the treadmill and were defined using observational analysis. Acceleration-derived parameters were examined as potential indicators of near falls, alone and in various combinations. 21 near falls were observed and compared to 668 "non-near falls" segments, consisting of normal and abnormal (but not near falls) gait. The best single method was based on the maximum peak-to-peak vertical acceleration derivative, with detection rates better than 85% sensitivity and specificity.

Conclusions

These findings suggest that tri-axial accelerometers may be used to successfully distinguish near falls from other gait patterns observed in the gait laboratory and may have the potential for improving the objective evaluation of fall risk, perhaps both in the lab and in at home-settings.
The loss of health status in rheumatoid arthritis and the effect of biologic therapy: a longitudinal observational study
Authors: Wolfe Frederick , Michaud Kaleb
Published: March 2010

Introduction

The long-term course of rheumatoid arthritis (RA) in terms of health status is not well understood, nor is the degree of effectiveness of biologic therapy in the community. We modeled the progression of loss of health status, and measured incremental costs and effectiveness of biologic therapy in the community.

Methods

We studied change in function and health status in 18,485 RA patients (135,731 observations) at six-month intervals for up to 11 years, including a group of 4,911 patients (59,630 observations) who switched to biologic therapy from non-biologic therapy. We measured the SF-36 Physical Component (PCS) and Mental Component (MCS) Summary scales, the EQ-5D health utility scale, and the Health Assessment Questionnaire (HAQ) disability scale; and we calculated treatment and direct medical costs.

Results

RA onset caused an immediate and substantial reduction in physical but not mental health status. Thereafter, the progression of dysfunction in RA was very slow (HAQ 0.016 units and PCS -0.125 units annually), only slightly worse than the age and sex-adjusted US population. We estimated biologic treatment to improve HAQ by 0.29 units, PCS by 5.3 units, and EQ-5D by 0.05 units over a 10-year period. The estimated incremental 10-year total direct medical cost for this benefit was $159,140.

Conclusions

Biologic therapy retards RA progression, but its effect is far less than is seen in clinical trials. In the community, cost-effectiveness is substantially less than that estimated from clinical trial data. The study results represent the incremental benefit of adding biologic therapy to optimum non-biologic therapy.
TRAF1/C5polymorphism is not associated with increased mortality in rheumatoid arthritis: two large longitudinal studies
Authors: van Nies Jessica AB , Marques Rute B , Trompet Stella , de Jong Zuzana , Kurreeman Fina AS , Toes Rene EM , Jukema J Wouter , Huizinga Tom WJ , van der Helm-van Mil Annette HM
Published: March 2010

Introduction

Recently an association between a genetic variation in TRAF1/C5 and mortality from sepsis or cancer was found in rheumatoid arthritis (RA). The most prevalent cause of death, cardiovascular disease, may have been missed in that study, since patients were enrolled at an advanced disease stage. Therefore, we used an inception cohort of RA patients to investigate the association between TRAF1/C5 and cardiovascular mortality, and replicate the findings on all-cause mortality. As TRAF1/C5 associated mortality may not be restricted to RA, we also studied a large cohort of non-RA patients.

Methods

615 RA patients from the Leiden Early Arthritis Clinic (EAC) (mean follow-up 7.6 years) were genotyped for rs10818488. In addition 5634 persons enrolled in the PROspective Study of Pravastatin in the Elderly at Risk (mean follow-up 3.2 years) were genotyped for rs2416808 (R2 >0.99 with rs10818488). The life/death status was determined and for the deceased persons the cause of death was ascertained. Cox proportional hazards and regression models were used to assess hazard ratios (HR) and 95% confidence intervals (CI).

Results

Seventy-seven RA patients died. The main death causes in RA patients were cardiovascular diseases (37.7%), cancer (28.6%) and death due to infections (9.1%). No association was observed between the rs10818488 susceptible genotype AA and cardiovascular mortality (HR 1.08 95%CI 0.54 to 2.15) and all-cause mortality (HR 0.81 95%CI 0.27 to 2.43). Similar findings were observed for rs2416808 susceptible genotype GG in the non-RA cohort (HR 0.99; 95%CI 0.79 to 1.25 and HR 0.89; 95%CI 0.64 to 1.25, respectively).

Conclusions

The TRAF1/C5 region is not associated with an increased mortality risk.
Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus
Authors: Shah Kamini , Lee Won-Woo , Lee Seung-Hyun , Kim Sang Hyun , Kang Seong Wook , Craft Joe , Kang Insoo
Published: March 2010

Introduction

Interleukin (IL)-17 is a proinflammatory cytokine that is produced largely by a unique CD4+ T-helper (Th) subset called Th17 cells. The development of Th17 cells is suppressed by interferon (IFN)-γ produced by Th1 cells, suggesting cross-regulation between Th17 and Th1 cells. Thus, this study analyzed the balance of CD4+ Th17 and Th1 cell responses in peripheral blood from patients with systemic lupus erythematosus (SLE) and healthy subjects.

Methods

Twenty-five adult patients with SLE and 26 healthy subjects matched for gender and age (± 2 years) were recruited. Peripheral blood mononuclear cells (PBMCs) from patients and healthy subjects were stimulated for 4 h ex vivo with phorbol myristate acetate (PMA) and ionomycin. The frequency of CD4+ T cells producing IL-17 and/or IFN-γ was measured by using flow cytometry. Expression of Th17-associated chemokine receptors CCR4 and CCR6 on CD4+ T cells as well as plasma levels of Th17-polarizing cytokines were assessed. Disease activity was evaluated by the SLE disease activity index score (SLEDAI). Unpaired t test and Pearson correlation were used for statistical analyses.

Results

Patients with SLE had an increased frequency of CD4+IL-17+ T cells compared with healthy subjects. However, the frequency of CD4+IFN-γ+ T cells was similar between the two groups, indicating an altered balance of Th17 and Th1 cell responses in SLE. Patients with SLE also had an increased frequency of CD4+CCR4+CCR6+ T cells that are known to produce IL-17. The frequency of CD4+IL-17+ T cells and CD4+CCR4+CCR6+ T cells correlated with disease activity. In measuring plasma levels of the Th17-polarizing cytokines, levels of IL-6 were higher in patients with SLE than in healthy subjects, although levels of IL-1β, IL-21, IL-23, and transforming growth factor (TGF)-β were not different between the two groups.

Conclusions

We demonstrate an enhanced Th17 cell response that correlates with disease activity in patients with SLE, suggesting a role for IL-17 in the pathogenesis of lupus. Our data indicate that the mechanisms involved in balancing Th1 and Th17 regulation, as well as in producing IL-6, are aberrant in SLE, leading to an increased Th17 response. We suggest that CCR4 and CCR6 expression on CD4+ T cells should be considered as markers of disease activity, and that IL-17 blocking may offer a therapeutic target in SLE.
B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up open-label trial
Authors: Bosello Silvia , De Santis Maria , Lama Gina , Spanò Cristina , Angelucci Cristiana , Tolusso Barbara , Sica Gigliola , Ferraccioli Gianfranco
Published: March 2010

Introduction

An over-expression of CD19 has been shown in B cells of systemic sclerosis (SSc) and B cells are thought to contribute to the induction of skin fibrosis in the tight skin mouse model. The aim was to define the outcome on safety and the change in skin score after rituximab therapy in SSc patients and to correlate the clinical characteristics with the levels of interleukin (IL)-6 and with the immune cell infiltrate detected by immunohistochemistry.

Methods

Nine patients with SSc with mean age 40.9 ± 11.1 years were treated with anti-CD20, 1 g at time 0 and after 14 days. Skin biopsy was performed at baseline and during the follow-up. B-cell activating factor (BAFF) and IL-6 levels were also determined at the follow-up times.

Results

After 6 months patients presented a median decrease of the skin score of 43.3% (range 21.1-64.0%), and a decrease in disease activity index and disease severity index. IL-6 levels decreased permanently during the follow up. After treatment, a complete depletion of peripheral blood B cells was observed in all but 2 patients. Only 3 patients presented CD20 positive cells in the biopsy of the involved skin at baseline.

Conclusions

Anti-CD20 treatment has been well tolerated and SSc patients experienced an improvement of the skin score and of clinical symptoms. The clear fall in IL-6 levels could contribute to the skin fibrosis improvement, while the presence of B cells in the skin seems to be irrelevant with respect to the outcome after B cell depletion.

Trial registration

ISRCTN77554566.
The release of microparticles by RAW 264.7 macrophage cells stimulated with TLR ligands
Authors: Gauley Julie , Pisetsky David S
Published: March 2010

TLR ligands induce microparticle release by macrophages and highlight the importance of nitric oxide.

MPs are small membrane-bound particles that originate from activated and dying cells and mediate intercellular communication. Once released from cells, MPs can serve as novel signaling elements in innate immunity, with levels elevated in immune-mediated diseases. This study tested the hypothesis that TLR stimulation can induce MP release by macrophages. In these experiments, using the RAW 264.7 murine macrophage cell line as a model, LPS, a TLR4 ligand, and poly(I:C), a TLR3 ligand, induced MP release effectively, as measured by flow cytometry; in contrast, a CpG oligonucleotide, which can stimulate TLR9, induced much lower levels of particle release. To determine the role of other mediators in this response, the effects of NO were tested. Thus, MP release from RAW 264.7 cells stimulated by LPS or poly(I:C) correlated with NO production, and treatment with the iNOS inhibitor 1400W decreased particle release and NO production. Furthermore, treatment of RAW 264.7 cells with NO donors induced MP production. As TLR ligands can induce apoptosis, the effect of caspase inhibition on MP release by stimulated cells was assessed. These experiments showed that the pan-caspase inhibitor, ZVAD, although decreasing NO production, increased MP release by stimulated cells. Together, these experiments demonstrate that TLR stimulation of macrophages can lead to MP release, and NO plays a key role in this response.
Regulation of the T helper cell type 2 (Th2)/T regulatory cell (Treg) balance by IL-4 and STAT6
Authors: Chapoval Svetlana , Dasgupta Preeta , Dorsey Nicolas J , Keegan Achsah D
Published: March 2010

Review discusses the regulation of Th2 cells by Tregs and vice versa and focuses on the interplay between the IL-4-activated STAT6/GATA3 pathway and Foxp3.

During the development of immune responses to pathogens, self-antigens, or environmental allergens, naive CD4+ T cells differentiate into subsets of effector cells including Th1, Th2, and Th17 cells. The differentiation into these subsets is controlled by specific transcription factors. The activity of these effector cells is limited by nTregs and iTregs, whose differentiation and maintenance are dependent on the transcription factor Foxp3. The regulation of autoimmune diseases mediated by Th1 and Th17 cells by Tregs has been studied and reviewed extensively. However, much less has been presented about the interplay between Tregs and Th2 cells and their contribution to allergic disease. In this perspective, we discuss the regulation of Th2 cells by Tregs and vice versa, focusing on the interplay between the IL-4-activated STAT6/GATA3 pathway and Foxp3.
Membrane fusion triggers rapid degradation of two gamete-specific, fusion-essential proteins in a membrane block to polygamy inChlamydomonas
Authors: Liu Yanjie , Misamore Michael J. , Snell William J.
Published: March 2010

The plasma membranes of gametes are specialized for fusion, yet, once fusion occurs, in many organisms the new zygote becomes incapable of further membrane fusion reactions. The molecular mechanisms that underlie this loss of fusion capacity (block to polygamy) remain unknown. During fertilization in the green alga Chlamydomonas, the plus gamete-specific membrane protein FUS1 is required for adhesion between the apically localized sites on the plasma membranes of plus and minus gametes that are specialized for fusion, and the minus-specific membrane protein HAP2 is essential for completion of the membrane fusion reaction. HAP2 (GCS1) family members are also required for fertilization in Arabidopsis, and for the membrane fusion reaction in the malaria organism Plasmodium berghei. Here, we tested whether Chlamydomonas gamete fusion triggers alterations in FUS1 and HAP2 and renders the plasma membranes of the cells incapable of subsequent fusion. We find that, even though the fusogenic sites support multi-cell adhesions, triploid zygotes are rare, indicating a fusion-triggered block to the membrane fusion reaction. Consistent with the extinction of fusogenic capacity, both FUS1 and HAP2 are degraded upon fusion. The rapid, fusion-triggered cleavage of HAP2 in zygotes is distinct from degradation occurring during constitutive turnover in gametes. Thus, gamete fusion triggers specific degradation of fusion-essential proteins and renders the zygote incapable of fusion. Our results provide the first molecular explanation for a membrane block to polygamy in any organism.
TheC. eleganshomolog of nucleoporin Nup98 is required for the integrity and function of germline P granules
Authors: Voronina Ekaterina , Seydoux Geraldine
Published: March 2010

C. elegans P granules are conserved cytoplasmic ribonucleoprotein complexes that are unique to the germline and essential for fertility. During most of germline development, P granules are perinuclear and associate with clusters of nuclear pores. In an RNAi screen against nucleoporins, we have identified a specific nucleoporin essential for P granule integrity and function. The C. elegans homolog of vertebrate Nup98 (CeNup98) is enriched in P granules and associates with the translationally repressed, P granule-enriched mRNA nos-2 (nanos homolog). Loss of CeNup98 causes P granules to disperse in the cytoplasm and to release nos-2 mRNA. Embryos depleted for CeNup98 express a nos-2 3′UTR reporter prematurely. In the mouse, Nup98 immunoprecipitates with the germ granule component MVH. Our findings suggest that, in germ cells, the function of Nup98 extends beyond transport at the nuclear pore to include mRNA regulation in the cytoplasm.
von Hippel-Lindau tumor suppressor mutants faithfully model pathological hypoxia-driven angiogenesis and vascular retinopathies in zebrafish
Authors: van Rooijen Ellen , Voest Emile E. , Logister Ive , Bussmann Jeroen , Korving Jeroen , van Eeden Fredericus J. , Giles Rachel H. , Schulte-Merker Stefan
Published: March 2010

Biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene predisposes human patients to the development of highly vascularized neoplasms in multiple organ systems. We show that zebrafish vhl mutants display a marked increase in blood vessel formation throughout the embryo, starting at 2 days post-fertilization. The most severe neovascularization is observed in distinct areas that overlap with high vegfa mRNA expression, including the vhl mutant brain and eye. Real-time quantitative PCR revealed increased expression of the duplicated VEGFA orthologs vegfaa and vegfab, and of vegfb and its receptors flt1, kdr and kdr-like, indicating increased vascular endothelial growth factor (Vegf) signaling in vhl mutants. Similar to VHL-associated retinal neoplasms, diabetic retinopathy and age-related macular degeneration, we show, by tetramethyl rhodamine-dextran angiography, that vascular abnormalities in the vhl−/− retina lead to vascular leakage, severe macular edema and retinal detachment. Significantly, vessels in the brain and eye express cxcr4a, a marker gene expressed by tumor and vascular cells in VHL-associated hemangioblastomas and renal cell carcinomas. VEGF receptor (VEGFR) tyrosine kinase inhibition (through exposure to sunitinib and 676475) blocked vhl−/−-induced angiogenesis in all affected tissues, demonstrating that Vegfaa, Vegfab and Vegfb are key effectors of the vhl−/− angiogenic phenotype through Flt1, Kdr and Kdr-like signaling. Since we show that the vhl−/− angiogenic phenotype shares distinct characteristics with VHL-associated vascular neoplasms, zebrafish vhl mutants provide a valuable in vivo vertebrate model to elucidate underlying mechanisms contributing to the development of these lesions. Furthermore, vhl mutant zebrafish embryos carrying blood vessel-specific transgenes represent a unique and clinically relevant model for tissue-specific, hypoxia-induced pathological angiogenesis and vascular retinopathies. Importantly, they will allow for a cost-effective, non-invasive and efficient way to screen for novel pharmacological agents and combinatorial treatments.
Analysis of Page Replacement Policies in the Fluid Limit
Authors: Hirade Ryo , Osogami Takayuki
Published: March 2010

The performance of storage systems and database systems depends significantly on the page replacement policies. Although many page replacement policies have been discussed in the literature, their performances are not fully understood. We introduce analytical techniques for evaluating the performances of page replacement policies including two queue (2Q), which manages two buffers to capture both the recency and frequency of requests. We derive an exact expression for the probability that a requested item is found (the hit probability) in a buffer managed by 2Q in the fluid limit, where the number of items is scaled by n, the size of items is scaled by 1/n, and n approaches infinity. The hit probability in the fluid limit approximates the hit probability in the original system, and we find that the relative error in the approximation is typically within 1%. Our analysis also illuminates several fundamental properties of 2Q useful for system designers.
On Choosing Parameters in Retrospective-Approximation Algorithms for Stochastic Root Finding and Simulation Optimization
Authors: Pasupathy Raghu
Published: March 2010

The stochastic root-finding problem is that of finding a zero of a vector-valued function known only through a stochastic simulation. The simulation-optimization problem is that of locating a real-valued function's minimum, again with only a stochastic simulation that generates function estimates. Retrospective approximation (RA) is a sample-path technique for solving such problems, where the solution to the underlying problem is approached via solutions to a sequence of approximate deterministic problems, each of which is generated using a specified sample size, and solved to a specified error tolerance. Our primary focus, in this paper, is providing guidance on choosing the sequence of sample sizes and error tolerances in RA algorithms. We first present an overview of the conditions that guarantee the correct convergence of RA's iterates. Then we characterize a class of error-tolerance and sample-size sequences that are superior to others in a certain precisely defined sense. We also identify and recommend members of this class and provide a numerical example illustrating the key results.
Differential Characteristics of Efficient Frontiers in Data Envelopment Analysis
Authors: Podinovski Victor V. , Førsund Finn R.
Published: March 2010

The implicit definition and nondifferentiability of efficient frontiers used in data envelopment analysis are two major obstacles to obtaining their differential characteristics, including various elasticity measures and marginal rates of substitution. In this paper we invoke the theorem of the directional derivative of the optimal value function and show how this can be used to define and calculate the required elasticities without any simplifying assumptions. This approach allows us to extend the known elasticity measures and introduce new ones to the entire efficient frontier, including all its extreme points, in one single development. We also construct linear programs that are required for the calculation of elasticity measures. Our main development is undertaken in the variable returns-to-scale technology but extends to other polyhedral technologies of efficiency analysis.
The ‘I know you’ and the ‘You know me’ of mutual goal knowledge in partnerships: Differential associations with partnership satisfaction and sense of closeness over time
Authors: Riediger Michaela , Rauers Antje
Published: March 2010

Personal goals, that is, ideas of what one wants to maintain, attain, or avoid in the future, are pursued within social contexts and may influence the social systems a person belongs to. Focusing on romantic partnerships as one of the most important social contexts in adulthood, this longitudinal study investigated the role of partners' mutual goal knowledge for partnership development (T1: N =69 couples; T2: N =47). Partners described their own personal goals and the goals they assumed their partners to have. Trained coders rated the overlap between the self‐reported and the ascribed goals. Actor–partner interdependence models showed that knowing one's partner's goals was associated with a higher level of partnership satisfaction after about 16 months, controlling for initial partnership satisfaction. Having a partner who knows one's goals, by contrast, predicted greater feelings of closeness to that partner after the same period of time, controlling for initial levels of closeness; and this association could not be attributed to a greater similarity between both partners' goals. Overall, this research shows that both the ‘I know you’ and the ‘You know me’ components contribute to positive partnership development, and that their specific implications vary for different facets of partnership quality.
Beneficial effects of 2 years of administration of parenteral testosterone undecanoate on the metabolic syndrome and on non-alcoholic liver steatosis and C-reactive protein
Authors: Haider Ahmad , Gooren Louis J.G. , Padungtod Pawin , Saad Farid
Published: March 2010

Background: Elderly men often show a concurrence of a decline of testosterone with attributes of the metabolic syndrome. This study tested the effects of normalization of testosterone.

Materials and methods: A total of 122 hypogonadal men (18–83 years, mean 59.6±8.0 years; n=11<45 years, n=25<55 years, n=53<65 years) were included in the study. Their baseline testosterone levels were between 0.14 and 4.51 ng/mL (n>4.90 ng/mL) and were treated with parenteral testosterone undecanoate for 2 years as the sole intervention (administration at 0 and 6 weeks, and thereafter every 12 weeks).

Results: Plasma testosterone increased from 3.3±1.9 ng/mL to 4.1±1.5 ng/mL (p<0.01) at 3 months, and then stabilized at 6.8±1.3 ng/mL after the first 6 months. There was a remarkable progressive linear decline in body weight, body mass index, and waist circumference over the entire study period. Plasma cholesterol decreased significantly over the first 12 months, and then stabilized. Plasma glucose, triglycerides, low-density lipoprotein cholesterol, and C-reactive protein decreased significantly and high-density lipoprotein cholesterol increased significantly over the 24-month study period in a non-linear manner. There was a significant decrease in aspartate aminotransferase and alanine aminotransferase levels over the first 9 and 12 months, and then values leveled off. Changes in variables were largely correlated with changes in testosterone levels. At baseline, 47 out of 122 subjects fulfilled the metabolic syndrome criteria as defined by the National Cholesterol Education Program (2001); after 2 years of testosterone treatment, this number had declined to 11 out of 122 subjects.

Conclusion: With testosterone treatment over 2 years, the most significant improvement of the metabolic syndrome was noted over the first 12 months, but over the following 12 months further improvement was also observed. With regard to safety of testosterone administration to mainly elderly men, a number of safety measures were carried out.
Therapeutic implications of brain steroidogenesis
Authors: Azcoitia Iñigo , DonCarlos Lydia L. , Arevalo Maria-Angeles , Garcia-Segura Luis M.
Published: March 2010

The nervous system is a steroidogenic tissue and several steroids synthesized locally in the brain, such as pregnenolone, progesterone and estradiol, modulate neuronal and glial physiology and are neuroprotective. The brain upregulates steroidogenesis at sites of injury as part of a program triggered by neural tissue to cope with neurodegenerative insults. Pharmacological targets to increase brain steroidogenesis and promote neuroprotection include the molecules that transport cholesterol to the inner mitochondrial membrane, where the first enzyme for steroidogenesis is located. Furthermore, the human gene encoding aromatase, the enzyme that synthesizes estradiol, is under the control of different tissue-specific promoters, and it is therefore conceivable that selective aromatase modulators can be developed that will enhance the expression of the enzyme and the consequent increase in estrogen formation in the brain but not in other tissues.
Estrogen-induced breast cancer is the result of disruption of asymmetric cell division of the stem cell
Authors: Russo Jose , Snider Kara , Pereira Julia S. , Russo Irma H.
Published: March 2010

Stem cells have the unique potential to divide asymmetrically to generate daughters with distinct fates, one which remains a stem cell and the other which turns into a cell committed to differentiation. By dividing asymmetrically, stem cells maintain the stem cell pool and simultaneously generate committed cells that reconstitute the organ, for example, to prepare the breast for a new pregnancy after involution from a previous pregnancy and lactation process. In addition to the in vivo models of mammary morphogenesis, there are in vitro systems that make the ductulogenic pattern of breast epithelia growth more amenable to study in critically determined conditions. The human breast epithelial cells MCF-10F formed tubules when grown in type I collagen and we demonstrated that treatment of these cells with 17β-estradiol (E2) induces phenotypical changes indicative of neoplastic transformation. The transformation of MCF-10F by E2 is associated with impaired ductal morphogenesis caused by an alteration of the stem cells unique potential to divide asymmetrically, inducing formation of solid masses and mimicking intraductal carcinoma that progresses into an invasive and tumorigenic phenotype. In the present work, we present evidence for the mechanism of cell asymmetry which leads to normal ductulogenesis and show how the normal stem cell is transformed into a cancer stem cell by altering this process. Furthermore, we demonstrate that the carcinogenic agent, in this case E2, induces a defect in the asymmetric cell division program of the normal mammary stem cell.
Structural rearrangement of SULT2A1: effects on dehydroepiandrosterone and raloxifene sulfation
Authors: Cook Ian T. , Leyh Thomas S. , Kadlubar Susan A. , Falany Charles N.
Published: March 2010

Background: Human cytosoloic sulfotransferase (SULT) 2A1 is a major hepatic isoform and sulfates hydroxyl groups in structurally diverse sterols and xenobiotics. SULT2A1 crystal structures resolved in the presence and absence of 3′,5′-diphosphoadenosine (PAP) or dehydropeiandrosterone (DHEA) suggest a significant rearrangement of the peptide that forms the surface of the active site in the presence of PAP.

Materials and methods: Molecular modeling was used to examine the effects of the rearrangement in SULT2A1 associated with 3′-phosphoadenosine 5′-phosphosulfate (PAPS) binding on the binding of DHEA and raloxifene. The kinetics of DHEA and raloxifene sulfation was analyzed to investigate the effects of the rearrangement on SULT2A1 activity.

Results: Molecular models indicate that DHEA is able to bind to SULT2A1 in both conformations (open, without PAP; closed, with PAP) in a catalytic configuration, whereas raloxifene bound in a catalytic conformation only in the open structure. Raloxifene did not bind in the smaller, closed substrate binding pocket. Kinetic analysis of DHEA sulfation was consistent with a random Bi-Bi reaction mechanism, whereas raloxifene sulfation was more indicative of an ordered reaction mechanism with raloxifene binding first. Initial burst kinetics with DHEA yielded similar results after preincubation of SULT2A1 with DHEA or PAPS. Preincubation of SULT2A1 with raloxifene showed a burst of raloxifene sulfate formation with the addition of PAPS. In contrast, little raloxifene sulfate was formed if SULT2A1 was preincubated with PAPS and the reaction initiated with raloxifene.

Conclusions: The structural rearrangements in SULT2A1 caused by PAPS binding can alter the sulfation mechanism and kinetics of different substrates.
Are estradiol metabolites involved in gynaecological carcinogenesis?
Authors: Seeger Harald , Mueck Alfred O.
Published: March 2010

Certain estradiol metabolites are biologically active, sometimes several times more potent than their parent substance. Highly sophisticated laboratory methods allow us to understand oestrogenic effects as a net effect of the corresponding metabolite pattern. Currently, research is focused on the anticancerogenic effects of 2-hydroxyestrone and particularly 2-methoxyestradiol, as well as the possible carcinogenic properties of 4-hydroxyoestrogens and 16α-hydroxyestrone. The clinical relevance of these activities, demonstrated in in-vitro and animal experiments, remains unclear – it is proven, however, that the metabolite production can be altered in certain malignancies such as endometrial-, breast- and cervical carcinoma. Clinical studies, including our studies, have demonstrated a negative correlation between the ratio of 2-hydroxyestrone to 16α-hydroxyestrone and breast cancer risk. However, the design and interpretation of such studies should consider factors influencing metabolic pattern such as diet, physical activity, smoking, as well as internal diseases and certain drugs.
Effect of toremifene and ospemifene, compared to acolbifene, on estrogen-sensitive parameters in rat and human uterine tissues
Authors: Labrie Fernand , Martel Céline , Gauthier Sylvain , Pelletier Georges , Sancéau Jean-Yves
Published: March 2010

Background: Although the first generation selective estrogen receptor modulator (SERM) tamoxifen (TAM) is well known for its uterotrophic activity, this study compares the stimulatory effect of the TAM derivatives toremifene (TORE) and ospemifene (OSPE) on estrogen-sensitive parameters in rat and human uterine tissues.

Material and methods: Ovariectomized female rats were treated daily orally for 10 days with 0.75 mg/rat of TORE, OSPE or acolbifene (ACOL, a pure estrogen antagonist in the uterus and mammary gland), which was used for comparison. Human endometrial carcinoma Ishikawa cells were incubated for 5 days with increasing doses of compounds, in the absence or presence of 1 nM estradiol (E2).

Results: TORE and OSPE revealed 52% and 56% increases, respectively, in uterine weight, whereas ACOL had no effect. Similar effects were observed on vaginal weight. Endometrial epithelial height increased from 15.82±0.20 to 48.94± 2.12 and 42.14±1.95 μm with TORE and OSPE, respectively, whereas ACOL had no effect. Alkaline phosphatase activity, an estrogen-sensitive parameter in Ishikawa cells, was increased by 144% and 135% with OH-TORE and OH-OSPE, respectively. Owing to their intrinsic estrogenic activity, at maximal concentrations, OH-TORE and OH-OSPE blocked the stimulatory effect of E2 by only 89% compared to 100% with ACOL.

Conclusions: The present in vitro and in vivo data show similar stimulatory effects of 4-hydroxytoremifene (OH-TORE) and OH-OSPE on estrogen-sensitive parameters. ACOL, a third generation SERM, has no effect on any of these parameters. Such data add to the potential uterine safety limitations of triphenylethylene-derived SERMs for long-term use in humans.
The use of peptide analogs for the treatment of gastrointestinal, pancreatic, liver and urinary bladder cancers
Authors: Szepeshazi Karoly , Block Norman L. , Schally Andrew V.
Published: March 2010

Peptide hormones can influence the development and growth of many cancers which are not considered classical hormone-dependent tumors. Analogs of somatostatin, bombesin/gastrin-releasing peptide (GRP), luteinizing hormone-releasing hormone (LH-RH) and growth hormone-releasing hormone (GH-RH) can interfere with receptors on tumor cells or intracellular pathways that are important in cell proliferation and in this way inhibit tumor growth. The first part of this review explains how these peptide hormones and their analogs affect tumors. The second part of this review describes how various hormone analogs can be used for the treatment of gastric, colorectal, pancreatic, liver and urinary bladder cancers. These tumors are major health problems worldwide and their treatment remains a great challenge. Receptors for somatostatin, bombesin/GRP, LH-RH and GH-RH are present in a large percentage of these cancers. We have developed a series of cytotoxic peptides based on doxorubicin or its derivative 2-pyrrolino-doxorubicin coupled to an analog of LH-RH, somatostatin or bombesin. This new class of targeted analogs might provide a more effective therapy for various cancers that express receptors for these carrier peptides, while producing significantly reduced peripheral toxicity. Under experimental conditions, these peptide hormone analogs strongly inhibited the growth of these tumors. Cytotoxic analogs were particularly effective on tumors that express the specific peptide receptors and acted more powerfully than the carrier peptide or the cytotoxic compound alone. Clinical trials on these peptide analogs are in progress.
Fatigue Crack Propagation in SAW Seam Welds of API 5L X42 Steel Pipe in the Radial Short Direction
Authors: Herrera D. Angeles , Velázquez J. L. González , Ramírez A. de J. Morales
Published: March 2010

Fatigue crack propagation (FCP) rates in submerged arc welding (SAW) seam welds of 1524 steel (API 5L X42) pipe were measured by using an arc-shaped bend specimen with the same radius of curvature of the body of the pipe so the material did not have to be cold worked to get a flat shape nor extensively machined. The test direction was girth radial and the stress intensity factor (K) function was calibrated for this type of nonstandard specimen. The FCP tests were carried out in air at room temperature, testing the three zones: The base metal, the deposited metal, and the heat affected zone (HAZ). A fractographic analysis was done to analyze the role of the microstructure in the FCP in the three zones. It was found that the zone of greater resistance to FCP was the base metal, whereas the deposited metal showed the least resistance to crack propagation. FCP in the deposited metal and the HAZ behaved according to the Paris law, unlike the base metal, which showed a high data dispersion. The behavior in the base metal was attributed to the propagation of the crack in the transverse direction of the preferential alignment of the microstructure, while the deposited metal and the HAZ had a more homogeneous microstructure.
FSHR gene polymorphisms influence bone mineral density and bone turnover in postmenopausal women
Authors: Rendina Domenico , Gianfrancesco Fernando , De Filippo Gianpaolo , Merlotti Daniela , Esposito Teresa , Mingione Alessandra , Nuti Ranuccio , Strazzullo Pasquale , Mossetti Giuseppe , Gennari Luigi
Published: March 2010

Objective

FSH, via its receptor (FSHR), influences bone remodeling and osteoclast proliferation and activity. The aim of this study was to evaluate the influence of two single nucleotide polymorphisms (SNPs) of theFSHRgene on bone mineral density (BMD) and bone turnover markers (bone alkaline phosphatase and type I collagen C-telopeptides) in postmenopausal women.

Methods

Two hundred and eighty-nine unrelated postmenopausal women were genotyped for the SNPs rs1394205 and rs6166. BMD was estimated using dual-energy X-ray absorptiometry and quantitative ultrasound (QUS) methodologies.

Results

AA rs6166 women showed a lower BMD (femoral neck and total body), lower stiffness index (calcaneal QUS), and higher serum levels of bone turnover markers compared to GG rs6166 women. The prevalence of osteoporosis was significantly higher in AA rs6166 women compared with GG rs6166 women. These results were not influenced by circulating levels of FSH and estrogens.

Conclusion

The SNP rs6166 of theFSHRgene significantly influences BMD in postmenopausal women. In particular, AA rs6166 women are at increased risk of postmenopausal osteoporosis compared with GG rs6166 women, independently of circulating levels of FSH and estrogens. Previous studies have demonstrated that this SNP influences cell and tissue response to hyperstimulation of FSHRin vivoandin vitro. Our study results appear in agreement with these experimental data and with known biological actions of FSH/FSHR system in bone homeostasis.
Neuroticism and Intensity of Religious Affect among Practising British Pagans
Authors: Francis Leslie J. , Williams Emyr , Billington Ursula
Published: March 2010

The Williams Scale of Attitude toward Paganism (as a particularised measure of the affective dimension of religion) was completed by seventy-five participants at a Pagan camp in celebration of the Midsummer Festival, together with the abbreviated form of the Revised Eysenck Personality Questionnaire (including a recognised measure of neuroticism). The data demonstrated that, after controlling for sex differences (routinely found in indices of neuroticism), more positive religious affect was significantly associated with higher neuroticism scores, but was not significantly associated with extraversion scores, psychoticism scores, or lie scale scores. These findings from research conducted in a (specific) Pagan context are contrasted with the consensus from studies (employing a comparable measure of religious affect) that have tended to find that more positive religious affect was associated with lower neuroticism scores in a Christian context.
Gender Essentialism in Matriarchalist Utopian Fantasies: Are popular novels vehicles of sacred stories, or purely propaganda?
Authors: Kraemer Christine Hoff
Published: March 2010

In The Myth of Matriarchal Prehistory: Why an Invented Past Won’t Give Women a Future (2000), Cynthia Eller attacks feminist narratives of a peaceful, egalitarian, Goddess-worshipping Neolithic Europe. She argues that they are too gender essentialist to be socially liberating to women. Popular novelists, who play a powerful role in spreading these narratives, however, resist the essentialism of more expository accounts of prehistoric matriarchy. Instead, their fictional accounts present more nuanced views of women’s roles in imagined Goddess societies, and suggest ways in which the myth might be successfully used as a liberating sacred story.
Field Report: Doing Ritual, Doing Time
Authors: Griffin Wendy
Published: March 2010

According to Susan Van Baalen, former Director of the Federal Prison Chaplaincy Program, most women in prison have never seen a “free” Pagan, one who is not and has never been incarcerated. Yet, she states that Pagan Spirituality, in particular Wicca, is a growing phenomenon in women’s prisons in the United States. This paper explores the spiritual needs of Pagan women prisoners and is based on interviews with Pagan prison chaplains and the author’s self-reflective, ethnographic field notes from a visit inside a medium security federal penitentiary where Pagan women have created “sacred space” and perform rituals invoking the Goddess.
A Management Strategy for Sedentary Nearshore Species that Uses Marine Protected Areas as a Reference
Authors: Wilson Jono R. , Prince Jeremy D. , Lenihan Hunter S.
Published: March 2010

Classical approaches to fisheries stock assessment rely on methods that are not conducive to managing data-poor stocks. Moreover, many nearshore rocky reef species exhibit spatial variation in harvest pressure and demographic rates, further limiting traditional stock assessment approaches. Novel management strategies to overcome data limitations and account for spatial variability are needed. With the ever-increasing implementation of no-take marine protected areas (MPAs), there is great potential for improving decision making in management through comparisons of fished populations with populations in MPAs at spatially explicit scales. We developed a management strategy that uses a combination of data-based indicators sampled inside and outside of MPAs as well as model-based reference points for data-poor, sedentary nearshore species. We performed a management strategy evaluation of this MPA-based decision tree model for a hypothetical population of grass rockfish Sebastes rastrelliger in California. We introduced process, observation, and model uncertainty in numerous scenarios and compared these scenarios with the precautionary approach currently used to manage data-poor species. Our model consistently improved total catches while maintaining the biomass and spawning potential ratio at levels well within acceptable thresholds of management. We suggest further exploration of this MPA-based management approach, and we outline a collaborative research program in the California Channel Islands that may well be suited for testing an experimental management procedure.
Models of Parent Involvement
Authors: Kindervater Terry
Published: March 2010

In this article a literacy lead teacher tells the story what happened when kindergarteners were taught to link certain sounds with particular hand and body gestures. Many children were so intrigued with “using the motions” that they shared these procedures with their parents. Terry Kindervater explains how this happened and describes some of the benefits of children teaching their parents about how to play with sounds.

يحكي في هذه المقالة معلم قائد في معرفة القراءة والكتابة الحكاية التي حدثت عندما تعلم طلاب روضة كيف بإمكانهم تعليق أصوات معينة بحركات يدوية وجسمية معينة. واسترعى ((استخدام الحركات)) انتباه بعض الأولاد إلى درجة أنهم نقلوا هذه الإجراءات إلى والديهم. ويشرح تيري كندرواتر كيف حصل هذا ويصف بعض فوائد تعليم الأولاد آباءهم التلاعب بالأصوات.

在本文中，一位读写教学领导教师讲述教授幼儿园学生的经验，这位领导教师教授学生把某些读音与特定的手势及身体姿势连接起来。很多小孩子都对这种「使用动作」感到兴趣，以至与他们的父母一起分享这些读音动作游戏的过程。本文作者解释这情况是怎样发生的，并说明小孩子通过教他们的父母如何玩这种读音动作游戏而获得的裨益。

Dans cet article, un enseignant champion en littératie raconte ce qui s'est produit quand on a enseigné à des enfants de maternelle à associer certains sons à des mouvements particuliers de la main ou du corps. Beaucoup d'enfants furent si intrigués par le fait de « faire des mouvements » qu'ils partagèrent ces procédures avec leurs parents. Terry Kindervater explique comment ceci s'est produit et décrit les bénéfices pour les enfants d'enseigner à leurs parents comment jouer avec des sons.

Учительница, занимающийся становлением грамотности у дошкольников, вспоминает, как она однажды предложила детям передавать некоторые звуки определенными жестами и телодвижениями. Дети, воодушевившись, привлекли к этому веселому занятию своих родителей. Автор объясняет, как организовать такую деятельность и почему так важно, чтобы родители принимали участие в становлении грамотности своих детей – в частности, в работе со звуками.

En este artículo, una maestra líder de alfabetización narra lo que pasó cuando se les enseño a estudiantes de un kindergarten a relacionar ciertos sonidos con movimientos de sus manos y su cuerpo. A tantos estudiantes les interesó tanto “usar los movimientos” que les enseñaron dichos procedimientos a sus padres. Ferry Kindervater explica cómo pasó esto y describe algunos de los beneficios de tener a los niños enseñándoles a sus padres juegos basados en sonidos.