bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cannabinoids and bone: endocannabinoids modulate human osteoclast function in vitro
Authors: Whyte LS , Ford L , Ridge SA , Cameron GA , Rogers MJ , Ross RA 
Published: June 2011

BACKGROUND AND PURPOSE Both CB1 and CB2 cannabinoid receptors have been shown to play a role in bone metabolism. Crucially, previous studies have focussed on the effects of cannabinoid ligands in murine bone cells. This study aimed to investigate the effects of cannabinoids on human bone cells in vitro.EXPERIMENTAL APPROACH Quantitative RT‐PCR was used to determine expression of cannabinoid receptors and liquid chromatography‐electrospray ionization tandem mass spectrometry was used to determine the presence of endocannabinoids in human bone cells. The effect of cannabinoids on human osteoclast formation, polarization and resorption was determined by assessing the number of cells expressing αvβ3 or with F‐actin rings, or measurement of resorption area.KEY RESULTS Human osteoclasts express both CB1 and CB2 receptors. CB2 expression was significantly higher in human monocytes compared to differentiated osteoclasts. Furthermore, the differentiation of human osteoclasts from monocytes was associated with a reduction in 2‐AG levels and an increase in anandamide (AEA) levels. Treatment of osteoclasts with LPS significantly increased levels of AEA. Nanomolar concentrations of AEA and the synthetic agonists CP 55 940 and JWH015 stimulated human osteoclast polarization and resorption; these effects were attenuated in the presence of CB1 and/or CB2 antagonists.CONCLUSIONS AND IMPLICATIONS Low concentrations of cannabinoids activate human osteoclasts in vitro. There is a dynamic regulation of the expression of the CB2 receptor and the production of the endocannabinoids during the differentiation of human bone cells. These data suggest that small molecules modulating the endocannabinoid system could be important therapeutics in human bone disease.LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue‐8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue‐7
Noncontact low‐frequency ultrasound therapy in the treatment of chronic wounds: A meta‐analysis
Authors: Driver Vickie R. , Yao Min , Miller Christopher J. 
Published: June 2011

ABSTRACTOur objective was to summarize and quantify the effects of a noncontact low‐frequency ultrasound (NLFU) therapy on healing of chronic wounds. We performed a meta‐analysis of eight published studies reporting effects of NLFU on wound size and healing rate of chronic wounds in 444 NLFU‐treated patients. A search of the PubMed database was conducted in January 2010 and updated in October 2010. We used random‐effects linear regression models to estimate the proportional reductions in wound area and volume and the proportion of wounds healed from baseline to last follow‐up. In four studies (N=188) reporting change in wound area from baseline, NLFU was associated with 85.2% area reduction (95% CI 64.7%–97.6%) over a mean 7 weeks. In four studies (N=278) reporting reduction in wound volume, NLFU was associated with 79.7% volume reduction (95% CI 46.1%–98.8%) over a mean 12 weeks. In seven studies (N=429) reporting proportion of wounds healing by study end (mean time to healing 8.2 weeks; median 6.8 weeks), meta‐analyzed healing rates over time suggest 32.7% of wounds healed on average by 6 weeks (95% CI 23.3%–42.1%) and 41.7% by 12 weeks. NLFU for treatment of chronic wounds was associated with consistent and substantial wound size reductions, as well as favorable rates of healing.
Spinal Manipulations for Cervicogenic Headaches: A Systematic Review of Randomized Clinical Trials
Authors: Posadzki Paul , Ernst Edzard 
Published: June 2011

(Headache 2011;51:1132‐1139)The objective of this systematic review was to assess the effectiveness of spinal manipulations as a treatment option for cervicogenic headaches. Seven databases were searched from their inception to February 2011. All randomized trials which investigated spinal manipulations performed by any type of healthcare professional for treating cervicogenic headaches in human subjects were considered. The selection of studies, data extraction, and validation were performed independently by 2 reviewers. Nine randomized clinical trials (RCTs) met the inclusion criteria. Their methodological quality was mostly poor. Six RCTs suggested that spinal manipulation is more effective than physical therapy, gentle massage, drug therapy, or no intervention. Three RCTs showed no differences in pain, duration, and frequency of headaches compared to placebo, manipulation, physical therapy, massage, or wait list controls. Adequate control for placebo effect was achieved in 1 RCT only, and this trial showed no benefit of spinal manipulations beyond a placebo effect. The majority of RCTs failed to provide details of adverse effects. There are few rigorous RCTs testing the effectiveness of spinal manipulations for treating cervicogenic headaches. The results are mixed and the only trial accounting for placebo effects fails to be positive. Therefore, the therapeutic value of this approach remains uncertain.
A Clinical Index to Stratify Hospitalized Older Adults According to Risk for New‐Onset Disability
Authors: Mehta Kala M. , Pierluissi Edgar , Boscardin W. John , Kirby Katharine A. , Walter Louise C. , Chren Mary‐Margaret , Palmer Robert M. , Counsell Steven R. , Landefeld C. Seth 
Published: June 2011

BACKGROUND: Many older adults who are independent prior to hospitalization develop a new disability by hospital discharge. Early risk stratification for new‐onset disability may improve care. Thus, this study's objective was to develop and validate a clinical index to determine, at admission, risk for new‐onset disability among older, hospitalized adults at discharge.DESIGN: Data analyses derived from two prospective studies.SETTING: Two teaching hospitals in Ohio.PARTICIPANTS: Eight hundred eighty‐five patients aged 70 years and older were discharged from a general medical service at a tertiary care hospital (mean age 78, 59% female) and 753 patients discharged from a separate community teaching hospital (mean age 79, 63% female). All participants reported being independent in five activities of daily living (ADLs: bathing, dressing, transferring, toileting, and eating) 2 weeks before admission.MEASUREMENTS: New‐onset disability, defined as a new need for personal assistance in one or more ADLs at discharge in participants who were independent 2 weeks before hospital admission.RESULTS: Seven independent risk factors known on admission were identified and weighted using logistic regression: age (80–89, 1 point; ≥90, 2 points); dependence in three or more instrumental ADLs at baseline (2 points); impaired mobility at baseline (unable to run, 1 point; unable to climb stairs, 2 points); dependence in ADLs at admission (2–3 ADLs, 1 point; 4–5 ADLs, 3 points); acute stroke or metastatic cancer (2 points); severe cognitive impairment (1 point); and albumin less than 3.0 g/dL (2 points). New‐onset disability occurred in 6%, 13%, 18%, 34%, 35%, 45%, 50%, and 87% of participants with 0, 1, 2, 3, 4, 5, 6, and 7 or more points, respectively, in the derivation cohort (area under the receiver operating characteristic curve (AUC)=0.784), and in 8%, 10%, 27%, 38%, 44%, 45%, 58%, and 83%, respectively, in the validation cohort (AUC=0.784). The risk score also predicted (P<.001) disability severity, nursing home placement, and long‐term survival.CONCLUSION: This clinical index determines risk for new‐onset disability in hospitalized older adults and may inform clinical care.
Response of iron overload to deferasirox in rare transfusion‐dependent anaemias: equivalent effects on serum ferritin and labile plasma iron for haemolytic or production anaemias
Authors: Porter John B. , Lin Kai‐Hsin , Beris Photis , Forni Gian Luca , Taher Ali , Habr Dany , Domokos Gabor , Roubert Bernard , Thein Swee Lay ,   on behalf of the EPIC study investigators
Published: June 2011

AbstractObjectives:  It is widely assumed that, at matched transfusional iron‐loading rates, responses to chelation therapy are similar, irrespective of the underlying condition. However, data are limited for rare transfusion‐dependent anaemias, and it remains to be elucidated if response differs, depending on whether the anaemia has a primary haemolytic or production mechanism.Methods:  The efficacy and safety of deferasirox (Exjade®) in rare transfusion‐dependent anaemias were evaluated over 1 yr, with change in serum ferritin as the primary efficacy endpoint. Initial deferasirox doses were 10–30 mg/kg/d, depending on transfusion requirements; 34 patients had production anaemias, and 23 had haemolytic anaemias.Results:  Patients with production anaemias or haemolytic anaemias had comparable transfusional iron‐loading rates (0.31 vs. 0.30 mL red blood cells/kg/d), mean deferasirox dosing (19.3 vs. 19.0 mg/kg/d) and baseline median serum ferritin (2926 vs. 2682 ng/mL). Baseline labile plasma iron (LPI) levels correlated significantly with the transfusional iron‐loading rates and with serum ferritin levels in both cohorts. Reductions in median serum ferritin levels were initially faster in the production than the haemolytic anaemias, but at 1 yr, similar significant reductions of 940 and 617 ng/mL were attained, respectively (−26.0% overall). Mean LPI decreased significantly in patients with production (P < 0.0001) and haemolytic (P = 0.037) anaemias after the first dose and was maintained at normal mean levels (<0.4 μm) subsequently. The most common drug‐related, investigator‐assessed adverse events were diarrhoea (n = 16) and nausea (n = 12).Conclusions:  At matched transfusional iron‐loading rates, the responses of rare transfusion‐dependent anaemias to deferasirox are similar at 1 yr, irrespective of the underlying pathogenic mechanism.
The Membrane-Activated Chelator Stroke Intervention (MACSI) Trial of DP-b99 in Acute Ischemic Stroke: A Randomized, Double-Blind, Placebo-Controlled, Multinational Pivotal Phase III Study
Authors: Rosenberg Gilad , Bornstein Natan , Diener Hans-Christoph , Gorelick Philip B. , Shuaib Ashfaq , Lees Kennedy ,   for the MACSI investigators
Published: June 2011

Rationale Zinc is both a direct neurotoxin and a signaling mediator in multiple early and late detrimental processes following ischemia. DP-b99, a lipophilic moderate-affinity chelator of zinc, is a first-in-class multitargeted neuroprotective agent for ischemic stroke. DP-b99 has completed several Phase I studies and two double-blind placebo-controlled Phase II trials, which supported the safety of DP-b99 and were consistent with a beneficial effect on poststroke recuperation. Aim: Membrane-Activated Chelator Stroke Intervention is a Phase III study. The primary objective is to evaluate the safety and therapeutic effects of intravenous 1·0 mg/kg/day DP-b99, initiated within nine-hours of stroke onset in patients with moderately severe hemispheric acute ischemic stroke, through the analysis across the whole distribution of scores of the primary efficacy endpoint of the modified Rankin Scale, 90 days after the stroke. Methods The Membrane-Activated Chelator Stroke Intervention study is a randomized, double-blind, placebo-controlled, multicenter, multinational, parallel-arm trial comparing a placebo group to a group treated with intravenous DP-b99 for four consecutive days. Non-rtPA-treated acute ischemic stroke patients – with a baseline NIHSS score of 10–16 and a clinical syndrome that includes language dysfunction, visual field defect and/or neglect–will be stratified on a 1:1 basis to one of the two treatments. Half will be randomized within 0–4·5 h of stroke onset. Follow-up after the four treatment days will occur on days 12, 30 and 90. An interim futility analysis will be performed after primary endpoint data have been collected for 50% of 770 subjects planned to be enrolled. A data and safety monitoring board will assess safety data and will oversee the interim analysis. Conclusion This Phase III Membrane-Activated Chelator Stroke Intervention trial is based on promising data derived from previous Phase I and II DP-b99 trials and capitalizes on lessons learned from failures of past stroke studies in relation to neuroprotection, patient selection and data analysis.
Seizures and Epilepsy in Alzheimer's Disease
Authors: Friedman Daniel , Honig Lawrence S. , Scarmeas Nikolaos 
Published: June 2011

SUMMARYMany studies have shown that patients with Alzheimer's disease (AD) are at increased risk for developing seizures and epilepsy. However, reported prevalence and incidence of seizures and relationship of seizures to disease measures such as severity, outcome, and progression vary widely between studies. We performed a literature review of the available clinical and epidemiological data on the topic of seizures in patients with AD. We review seizure rates and types, risk factors for seizures, electroencephalogram (EEG) studies, and treatment responses. Finally, we consider limitations and methodological issues. There is considerable variability in the reported prevalence and incidence of seizures in patients with AD—with reported lifetime prevalence rates of 1.5–64%. More recent, prospective, and larger studies in general report lower rates. Some, but not all, studies have noted increased seizure risk with increasing dementia severity or with younger age of AD onset. Generalized convulsive seizures are the most commonly reported type, but often historical information is the only basis used to determine seizure type and the manifestation of seizures may be difficult to distinguish from other behaviors common in demented patients. EEG has infrequently been performed and reported. Data on treatment of seizures in AD are extremely limited. Similarly, the relationship between seizures and cognitive impairment in AD is unclear. We conclude that the literature on seizures and epilepsy in AD, including diagnosis, risk factors, and response to treatment suffers from methodological limitations and gaps.
The Base Component of 3′-Azido-2′,3′-Dideoxynucleosides Influences Resistance Mutations Selected in HIV-1 Reverse Transcriptase
Authors: Meteer Jeffrey D. , Koontz Dianna , Asif Ghazia , Zhang Hong-wang , Detorio Mervi , Solomon Sarah , Coats Steven J. , Sluis-Cremer Nicolas , Schinazi Raymond F. , Mellors John W. 
Published: June 2011

ABSTRACT

We recently reported that HIV-1 resistant to 3′-azido-3′-deoxythymidine (AZT) is not cross-resistant to 3′-azido-2′,3′-dideoxypurines. This finding suggested that the nucleoside base is a major determinant of HIV-1 resistance to nucleoside analogs. To further explore this hypothesis, we conducted
in vitro
selection experiments by serial passage of HIV-1
LAI
in MT-2 cells in increasing concentrations of 3′-azido-2′,3′-dideoxyguanosine (3′-azido-ddG), 3′-azido-2′,3′-dideoxycytidine (3′-azido-ddC), or 3′-azido-2′,3′-dideoxyadenosine (3′-azido-ddA). 3′-Azido-ddG selected for virus that was 5.3-fold resistant to 3′-azido-ddG compared to wild-type HIV-1
LAI
passaged in the absence of drug. Population sequencing of the entire reverse transcriptase (RT) gene identified L74V, F77L, and L214F mutations in the polymerase domain and K476N and V518I mutations in the RNase H domain. However, when introduced into HIV-1 by site-directed mutagenesis, these 5 mutations only conferred ∼2.0-fold resistance. Single-genome sequencing analyses of the selected virus revealed a complex population of mutants that all contained L74V and L214F linked to other mutations, including ones not identified during population sequencing. Recombinant HIV-1 clones containing RT derived from single sequences exhibited 3.2- to 4.0-fold 3′-azido-ddG resistance. In contrast to 3′-azido-ddG, 3′-azido-ddC selected for the V75I mutation in HIV-1 RT that conferred 5.9-fold resistance, compared to the wild-type virus. Interestingly, we were unable to select HIV-1 that was resistant to 3′-azido-ddA, even at concentrations of 3′-azido-ddA that yielded high intracellular levels of 3′-azido-ddA-5′-triphosphate. Taken together, these findings show that the nucleoside base is a major determinant of HIV-1 resistance mechanisms that can be exploited in the design of novel nucleoside RT inhibitors.
The Toll-Like Receptor 4 Agonist Monophosphoryl Lipid A Augments Innate Host Resistance to Systemic Bacterial Infection
Authors: Romero Christopher D. , Varma Tushar K. , Hobbs Jason B. , Reyes Aimee , Driver Brandon , Sherwood Edward R. 
Published: June 2011

ABSTRACT

Monophosphoryl lipid A (MPLA) is a Toll-like receptor 4 (TLR4) agonist that is currently used as a vaccine adjuvant in humans. In this study, we evaluated the effect of MPLA treatment on the innate immune response to systemic bacterial infections in mice. Mice treated with MPLA after burn injury showed improved survival and less local and systemic dissemination of bacteria in a model of
Pseudomonas aeruginosa
burn wound infection. Prophylactic treatment with MPLA significantly enhanced bacterial clearance at the site of infection and reduced systemic dissemination of bacteria despite causing attenuation of proinflammatory cytokine production during acute intra-abdominal infection caused by cecal ligation and puncture. Administration of MPLA at 1 h after CLP also improved bacterial clearance but did not alter cytokine production. MPLA treatment increased the numbers of granulocytes, double-positive myeloid cells, and macrophages at sites of infection and increased the percentage and total numbers of myeloid cells mediating phagocytosis of bacteria. Depletion of Ly6G
+
neutrophils, but not macrophages, eliminated the ability of MPLA treatment to improve bacterial clearance. The immunomodulatory effects of MPLA were absent in TLR4-deficient mice. In conclusion, these studies show that MPLA treatment significantly augments the innate immune response to bacterial infection by enhancing bacterial clearance despite the attenuation of proinflammatory cytokine production. The enhanced bacterial clearance is mediated, in part, by increased numbers of myeloid cells with effective phagocytic functions at sites of infection and is TLR4 dependent.
Pivotal Role of Innate and Adaptive Immunity in Anthracycline Chemotherapy of Established Tumors
Authors: Mattarollo Stephen R. , Loi Sherene , Duret Helene , Ma Yuting , Zitvogel Laurence , Smyth Mark J. 
Published: June 2011

Abstract
We show, in a series of established experimental breast adenocarcinomas and fibrosarcomas induced by carcinogen de novo in mice, that the therapeutic efficacy of doxorubicin treatment is dependent on CD8 T cells and IFN-γ production. Doxorubicin treatment enhances tumor antigen–specific proliferation of CD8 T cells in tumor-draining lymph nodes and promotes tumor infiltration of activated, IFN-γ–producing CD8 T cells. Optimal doxorubicin treatment outcome also requires both interleukin (IL)-1β and IL-17 cytokines, as blockade of IL-1β/IL-1R or IL-17A/IL-17Rα signaling abrogated the therapeutic effect. IL-23p19 had no observed role. The presence of γδ T cells, but not Jα18+ natural killer T cells, at the time of doxorubicin treatment was also important. In tumor samples taken from breast cancer patients prior to treatment with anthracycline chemotherapy, a correlation between CD8α, CD8β, and IFN-γ gene expression levels and clinical response was observed, supporting their role in the therapeutic efficacy of anthracyclines in humans. Overall, these data strongly support the pivotal contribution of both innate and adaptive immunity in treatment outcomes of anthracycline chemotherapy. Cancer Res; 71(14); 4809–20. ©2011 AACR.
Novel Changes in Glycosylation of Serum Apo-J in Patients with Hepatocellular Carcinoma
Authors: Comunale Mary Ann , Wang Mengjun , Rodemich-Betesh Lucy , Hafner Julie , Lamontagne Anne , Klein Andrew , Marrero Jorge , Di Bisceglie Adrian M. , Gish Robert , Block Timothy , Mehta Anand 
Published: June 2011

Abstract
Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the occurrence of HCC has more than doubled in the United States in the past decade. Early detection is considered key to reducing the mortality of HCC.
Methods: Using two-dimensional gel electrophoresis and high-performance liquid chromatography we have analyzed the glycosylation of Apo-J from healthy controls, patients with liver cirrhosis, or those with HCC.
Results: Apo-J in the serum from patients with HCC had decreased levels of (β-1,4) triantennary N-linked glycan compared with the healthy controls or patients with liver cirrhosis. We analyzed this change in an independent cohort of 76 patients with HCC, 32 with cirrhosis, and 43 infected with hepatitis C virus using the Datura stramonium lectin (DSL), which binds to (β-1,4) triantennary N-linked glycan. The level of DSL-reactive Apo-J allowed us to differentiate HCC from cirrhosis with an area under the receiver operating characteristic curve (AUROC) of 0.852. When Apo-J was combined with other serum biomarkers such as α-fetoprotein (AFP) and fucosylated kininogen by using a multivariate logistic regression model, the AUROC increased to 0.944, a value much greater than that observed with AFP alone (AUROC of 0.765).
Conclusions: The glycosylation of Apo-J is a useful marker when used alone or in combination with outer makers for the early detection of HCC.
Impact: The potential use of a combination of AFP, DSL-reactive Apo-J, and fucosylated kininogen as a biomarker of HCC would have great value in the management of patients with liver disease. Cancer Epidemiol Biomarkers Prev; 20(6); 1222–9. ©2011 AACR.
Genome-wide Association Study Identifies a Genetic Variant Associated with Risk for More Aggressive Prostate Cancer
Authors: FitzGerald Liesel M. , Kwon Erika M. , Conomos Matthew P. , Kolb Suzanne , Holt Sarah K. , Levine David , Feng Ziding , Ostrander Elaine A. , Stanford Janet L. 
Published: June 2011

Abstract
Background: Of the 200,000 U.S. men annually diagnosed with prostate cancer, approximately 20% to 30% will have clinically aggressive disease. Although factors such as Gleason score and tumor stage are used to assess prognosis, there are no biomarkers to identify men at greater risk for developing aggressive prostate cancer. We therefore undertook a search for genetic variants associated with risk of more aggressive disease.
Methods: A genome-wide scan was conducted in 202 prostate cancer cases with a more aggressive phenotype and 100 randomly sampled, age-matched prostate-specific antigen screened negative controls. Analysis of 387,384 autosomal single nucleotide polymorphisms (SNPs) was followed by validation testing in an independent set of 527 cases with more aggressive and 595 cases with less aggressive prostate cancer, and 1,167 age-matched controls.
Results: A variant on 15q13, rs6497287, was confirmed to be most strongly associated with more aggressive (Pdiscovery = 5.20 × 10−5, Pvalidation = 0.004) than less aggressive disease (P = 0.14). Another SNP on 3q26, rs3774315, was found to be associated with prostate cancer risk; however, the association was not stronger for more aggressive disease.
Conclusions: This study provides suggestive evidence for a genetic predisposition to more aggressive prostate cancer and highlights the fact that larger studies are warranted to confirm this supposition and identify further risk variants.
Impact: These findings raise the possibility that assessment of genetic variation may one day be useful to discern men at higher risk for developing clinically significant prostate cancer. Cancer Epidemiol Biomarkers Prev; 20(6); 1196–203. ©2011 AACR.