bluuebunny/crossref_metadata_2025_split 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

Abstract

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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.
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

SUMMARYBiallelic 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.
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

Abstract

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

Abstract
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

Abstract
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.