bluuebunny/crossref_metadata_2025 huggingface dataset:
The prokineticin receptor agonist Bv8 decreases IL-10 and IL-4 production in mice splenocytes by activating prokineticin receptor-1
Authors: Franchi Silvia , Giannini Elisa , Lattuada Donatella , Lattanzi Roberta , Tian Hui , Melchiorri Pietro , Negri Lucia , Panerai Alberto E , Sacerdote Paola
Published: October 2008

Background

Bv8, prokineticin-1, or endocrine gland-vascular endothelial growth factor, and prokineticin-2 are recently isolated peptide agonists of two G protein-coupled receptors, prokineticin receptor-1 (PROKR 1) and PROKR 2, and have been described as affecting a number of myeloid cell functions. We evaluated the impact of Bv8 on lymphoid cells by investigating its ability to modulate T cell cytokine balance in mouse.

Results

The production of T-helper1 cytokines (IL-2, IFN-γ and IL-1β), the T-helper 2 cytokine IL-4, and the anti-inflammatory cytokine IL-10 by mouse splenocytes was evaluated after polyclonal stimulation or immunisation with the keyhole limpet hemocyanin protein antigen by measuring cytokine levels. When addedin vitroto Con-A-stimulated splenocytes, Bv8 significantly increased IL-1β and decreased IL-4 and IL-10; IL-2 and IFN-γ were not affected. Similar results were obtained when Bv8 was administeredin vivo. In KLH-immunised mice, splenocytes restimulatedin vitrowith KLH and Bv8 produced significantly smaller amounts of IL-4 and IL-10. KLH-induced IL-10 and IL-4 production was also significantly blunted in animals administered Bv8in vivoat the time of KLH immunisation or two weeks later. The Bv8-induced effects were lost in mice lacking the PROKR 1 gene, thus indicating that PROKR 1 is the receptor involved in the modulation of cytokines.

Conclusion

These findings indicate that Bv8/prokineticin-1 is a novel modulator of lymphoid functions, and may be a suitable target for new immunopharmacological strategies.
Design of the BRISC study: a multicentre controlled clinical trial to optimize the communication of breast cancer risks in genetic counselling
Authors: Ockhuysen-Vermey Caroline F , Henneman Lidewij , van Asperen Christi J , Oosterwijk Jan C , Menko Fred H , Timmermans Daniëlle RM
Published: October 2008

Background

Understanding risks is considered to be crucial for informed decision-making. Inaccurate risk perception is a common finding in women with a family history of breast cancer attending genetic counseling. As yet, it is unclear how risks should best be communicated in clinical practice. This study protocol describes the design and methods of the BRISC (Breast cancer RISk Communication) study evaluating the effect of different formats of risk communication on the counsellee's risk perception, psychological well-being and decision-making regarding preventive options for breast cancer.

Methods and design

The BRISC study is designed as a pre-post-test controlled group intervention trial with repeated measurements using questionnaires. The intervention-an additional risk consultation-consists of one of 5 conditions that differ in the way counsellee's breast cancer risk is communicated: 1) lifetime risk in numerical format (natural frequencies, i.e. X out of 100), 2) lifetime risk in both numerical format and graphical format (population figures), 3) lifetime risk and age-related risk in numerical format, 4) lifetime risk and age-related risk in both numerical format and graphical format, and 5) lifetime risk in percentages. Condition 6 is the control condition in which no intervention is given (usual care). Participants are unaffected women with a family history of breast cancer attending one of three participating clinical genetic centres in the Netherlands.

Discussion

The BRISC study allows for an evaluation of the effects of different formats of communicating breast cancer risks to counsellees. The results can be used to optimize risk communication in order to improve informed decision-making among women with a family history of breast cancer. They may also be useful for risk communication in other health-related services.

Trial registration

Current Controlled Trials ISRCTN14566836.
Anti-proliferative effects of Bifidobacterium adolescentis SPM0212 extract on human colon cancer cell lines
Authors: Lee Do Kyung , Jang Seok , Kim Mi Jin , Kim Jung Hyun , Chung Myung Jun , Kim Kyung Jae , Ha Nam Joo
Published: October 2008

Background

Lactic acid bacteria (LAB) are beneficial probiotic organisms that contribute to improved nutrition, microbial balance, and immuno-enhancement of the intestinal tract, as well as anti-tumor activity. The aim of the present work was to study the growth inhibition of tumor cells by butanol extract ofBifidobacterium adolescentisisolated from healthy young Koreans.

Methods

The anti-proliferative activity ofB. adolescentisisolates was assessed by XTT assays on three human colon cancer cell lines (Caco-2, HT-29, and SW480). The effects ofB. adolescentisSPM0212 butanol extract on tumor necrosis factor-α (TNF-α) and nitric oxide (NO) production were tested using the murine macrophage RAW 264.7 cell line.

Results

The butanol extract ofB. adolescentisSPM0212 dose-dependently inhibited the growth of Caco-2, HT-29, and SW480 cells by 70%, 30%, and 40%, respectively, at 200 μg/mL. Additionally, the butanol extract ofB. adolescentisSPM0212 induced macrophage activation and significantly increased the production of TNF-α and NO, which regulate immune modulation and are cytotoxic to tumor cells.

Conclusion

The butanol extract ofB. adolescentisSPM0212 increased activity of the host immune system and may improve human health by helping to prevent colon cancer as a biological response modifier.
Selective translational repression of HIV-1 RNA by Sam68DeltaC occurs by altering PABP1 binding to unspliced viral RNA
Authors: Marsh Kim , Soros Vanessa , Cochrane Alan
Published: October 2008

HIV-1 structural proteins are translated from incompletely spliced 9 kb and 4 kb mRNAs, which are transported to the cytoplasm by Crm1. It has been assumed that once in the cytoplasm, translation of incompletely spliced HIV-1 mRNAs occurs in the same manner as host mRNAs. Previous analyses have demonstrated that Sam68 and a mutant thereof, Sam68ΔC, have dramatic effects on HIV gene expression, strongly enhancing and inhibiting viral structural protein synthesis, respectively. While investigating the inhibition of incompletely spliced HIV-1 mRNAs by Sam68ΔC, we determined that the effect was independent of the perinuclear bundling of the viral RNA. Inhibition was dependent upon the nuclear export pathway used, as translation of viral RNA exported via the Tap/CTE export pathway was not blocked by Sam68ΔC. We demonstrate that inhibition of HIV expression by Sam68ΔC is correlated with a loss of PABP1 binding with no attendant change in polyadenosine tail length of the affected RNAs. The capacity of Sam68ΔC to selectively inhibit translation of HIV-1 RNAs exported by Crm1 suggests that it is able to recognize unique characteristics of these viral RNPs, a property that could lead to new therapeutic approaches to controlling HIV-1 replication.
Evolution of the Randomized Controlled Trial in Oncology Over Three Decades
Authors: Booth Christopher M. , Cescon David W. , Wang Lisa , Tannock Ian F. , Krzyzanowska Monika K.
Published: October 2008

Purpose

The randomized controlled trial (RCT) is the gold standard for establishing new therapies in clinical oncology. Here we document changes with time in design, sponsorship, and outcomes of oncology RCTs.

Methods

Reports of RCTs evaluating systemic therapy for breast, colorectal (CRC), and non–small-cell lung cancer (NSCLC) published 1975 to 2004 in six major journals were reviewed. Two authors abstracted data regarding trial design, results, and conclusions. Conclusions of authors were graded using a 7-point Likert scale. For each study the effect size for the primary end point was converted to a summary measure.

Results

A total of 321 eligible RCTs were included (48% breast, 24% CRC, 28% NSCLC). Over time, the number and size of RCTs increased considerably. For-profit/mixed sponsorship increased substantially during the study period (4% to 57%; P < .001). There was increasing use of time-to-event measures (39% to 78%) and decreasing use of response rate (54% to 14%) as primary end point (P < .001). Effect size remained stable over the study period. Authors have become more likely to strongly endorse the experimental arm (P = .017). A significant P value for the primary end point and industry sponsorship were each independently associated with endorsement of the experimental agent (odds ratio [OR] = 19.6, 95% CI, 8.9 to 43.1, and OR = 3.5, 95% CI, 1.6 to 7.5, respectively).

Conclusion

RCTs in oncology have become larger and are more likely to be sponsored by industry. Authors of modern RCTs are more likely to strongly endorse novel therapies. For-profit sponsorship and statistically significant results are independently associated with endorsement of the experimental arm.
Fertility Preservation in Girls with Turner Syndrome: Prognostic Signs of the Presence of Ovarian Follicles
Authors: Birgit Borgström , Julius Hreinsson , Carsten Rasmussen , Maryam Sheikhi , Gabriel Fried , Victoria Keros , Margareta Fridström , Outi Hovatta
Published: October 2008

Context: Many girls with Turner syndrome have follicles in their ovaries at adolescence.

Objective: Our objective was to study which girls might benefit from ovarian tissue freezing for fertility preservation.

Design: Clinical and laboratory parameters and ovarian follicle counts were analyzed among girls referred by 25 pediatric endocrinologists.

Subjects and Setting: Fifty-seven girls with Turner syndrome, aged 8–19.8 yr, were studied at a university hospital.

Interventions: Ovarian tissue was biopsied laparoscopically, studied for the presence of follicles, and cryopreserved. Blood samples were drawn for hormone measurements.

Main Outcome Measures: Presence of follicles in the biopsied tissue related to age, signs of spontaneous puberty, karyotype, and serum concentrations of gonadotropins and anti-Müllerian hormone were assessed.

Results: Ovarian biopsy was feasible in 47 of the 57 girls. In 15 of the 57 girls (26%), there were follicles in the tissue piece analyzed histologically. Six of seven girls (86%) with mosaicism, six of 22 (27%) with structural chromosomal abnormalities, and three of 28 with karyotype 45X (10.7%) had follicles. Eight of the 13 girls (62%) with spontaneous menarche had follicles, and 11 of the 19 girls (58%) who had signs of spontaneous puberty had follicles. The age group 12–16 yr had the highest proportion of girls with follicles. Normal FSH and anti-Müllerian hormone concentrations for age and pubertal stage were more frequent in girls with follicles.

Conclusions: Signs of spontaneous puberty, mosaicism, and normal hormone concentrations were positive and statistically significant but not exclusive prognostic factors as regards finding follicles.
Maturation of Luteinizing Hormone (Gonadotropin-Releasing Hormone) Secretion across Puberty: Evidence for Altered Regulation in Obese Peripubertal Girls
Authors: McCartney Christopher R. , Prendergast Kathleen A. , Blank Susan K. , Helm Kristin D. , Chhabra Sandhya , Marshall John C.
Published: October 2008

Context: Peripubertal obesity (body mass index-for-age ≥ 95%) in girls is associated with hyperandrogenemia. LH likely contributes to this relationship, but overnight LH secretion in obese girls is poorly characterized.

Objective: The aim of the study was to evaluate LH pulse characteristics in obese girls throughout pubertal maturation.

Design: We conducted a cross-sectional analysis.

Setting: The study was performed in a general clinical research center.

Participants: Eight nonobese and five obese Tanner 1–2 girls participated, as well as 32 nonobese and 12 obese Tanner 3–5 girls.

Intervention: Blood samples were collected every 10 min overnight (from 1900 to 0700 h).

Main Outcome Measures: LH pulse frequency, amplitude, and mean LH were measured in three 4-h time blocks (block 1, 1900–2300 h; block 2, 2300–0300 h; and block 3, 0300–0700 h).

Results: Tanner stage 1–2 nonobese girls demonstrated nocturnal increases of LH frequency (P < 0.01, block 1 vs. 2) and mean LH (P < 0.05, block 1 vs. 2 and 3). Obese Tanner 1–2 girls had lower 12-h LH frequency and LH amplitude (P < 0.05 for both), with no overnight changes of LH pulse parameters. Compared to normal, LH frequency was elevated in Tanner 3–5 obese girls (P < 0.01 in all blocks), whereas LH amplitude was low (P < 0.05 in all blocks). Overnight increases of LH amplitude were observed in nonobese Tanner 3–5 girls (P < 0.0001), but not in obese Tanner 3–5 girls.

Conclusions: Obesity in prepubertal and early pubertal girls is associated with reduced LH secretion and reduced nocturnal changes of LH. In later pubertal girls, obesity is linked with reduced LH amplitude, but elevated LH frequency; the latter may reflect effects of hyperandrogenemia.
Effect of Weight Loss on Liver Free Fatty Acid Uptake and Hepatic Insulin Resistance
Authors: Viljanen Antti P. M. , Iozzo Patricia , Borra Ronald , Kankaanpää Mikko , Karmi Anna , Lautamäki Riikka , Järvisalo Mikko , Parkkola Riitta , Rönnemaa Tapani , Guiducci Letizia , Lehtimäki Terho , Raitakari Olli T. , Mari Andrea , Nuutila Pirjo
Published: October 2008

Objective: Weight loss has been shown to decrease liver fat content and whole-body insulin resistance. The current study was conducted to investigate the simultaneous effects of rapid weight reduction with a very-low-calorie diet on liver glucose and fatty acid metabolism and liver adiposity.

Hypothesis: We hypothesized that liver insulin resistance and free fatty acid uptake would decrease after weight loss and that they are associated with reduction of liver fat content.

Design: Thirty-four healthy obese subjects (body mass index, 33.7 ± 8.0 kg/m2) were studied before and after a very-low-calorie diet for 6 wk. Hepatic glucose uptake and endogenous glucose production were measured with [18F]fluorodeoxyglucose during hyperinsulinemic euglycemia and fasting hepatic fatty acid uptake with [18F]fluoro-6-thia-heptadecanoic acid and positron emission tomography. Liver volume and fat content were measured using magnetic resonance imaging and spectroscopy.

Results: Subjects lost weight (11.2 ± 2.9 kg; P < 0.0001). Liver volume decreased by 11% (P < 0.002), which was partly explained by decreased liver fat content (P < 0.0001). Liver free fatty acid uptake was 26% lower after weight loss (P < 0.003) and correlated with the decrement in liver fat content (r = 0.54; P < 0.03). Hepatic glucose uptake during insulin stimulation was unchanged, but the endogenous glucose production decreased by 40% (P < 0.04), and hepatic insulin resistance by 40% (P < 0.05).

Conclusions: The liver responds to a 6-wk period of calorie restriction with a parallel reduction in lipid uptake and storage, accompanied by enhancement of hepatic insulin sensitivity and clearance.
Epithelial-to-mesenchymal transition of peritoneal mesothelial cells is regulated by an ERK/NF-κB/Snail1 pathway
Authors: Strippoli Raffaele , Benedicto Ignacio , Pérez Lozano Maria Luisa , Cerezo Ana , López-Cabrera Manuel , del Pozo Miguel A.
Published: October 2008

Epithelial-to-mesenchymal transition (EMT) occurs in fibrotic diseases affecting the kidney, liver and lung, and in the peritoneum of patients undergoing peritoneal dialysis. EMT in the peritoneum is linked to peritoneal membrane dysfunction, and its establishment limits the effectiveness of peritoneal dialysis. The molecular regulation of EMT in the peritoneum is thus of interest from basic and clinical perspectives. Treatment of primary human mesothelial cells (MCs) with effluent from patients undergoing peritoneal dialysis induced a genuine EMT, characterized by downregulated E-cadherin and cytokeratin expression, cell scattering, and spindle-like morphology. This EMT was replicated by co-stimulation with transforming growth factor (TGF)-β1 and interleukin (IL)-1β. Retroviral overexpression of a mutant inhibitor of kappaB (IκB) demonstrated that NF-κB activation is required for E-cadherin and cytokeratin downregulation during EMT. Pre-treatment with the MAP kinase kinase (MEK)-1/2 inhibitor U0126 showed that cytokine-triggered NF-κB nuclear translocation and transcriptional activity are mediated by activation of extracellular regulated kinase (ERK). Cytokine-mediated induction of mRNA expression of the transcription factor Snail1, a repressor of E-cadherin expression and a potent inducer of EMT, was prevented by blockade of ERK or NF-κB. Finally, blockade of ERK/NF-κB signaling in ex vivo MCs that were cultured from peritoneal dialysis effluents reverted cells to an epithelioid morphology, upregulated E-cadherin and cytokeratin expression, and downregulated Snail1 expression. Modulation of the ERK/NF-κB/Snail1 pathway may provide a means of counteracting the progressive structural and functional deterioration of the peritoneal membrane during peritoneal dialysis.
Therapeutic Strategy for Treatment of Metastatic Non-Small Cell Lung Cancer
Authors: Berhoune Malik , Banu Eugeniu , Scotte Florian , Prognon Patrice , Oudard Stephane , Bonan Brigitte
Published: October 2008

Objective:

To review the current practices for metastatic non–small cell lung cancer (NSCLC) management and highlight the latest progress.

Data Sources:

A literature review using HighWire Press (1960–May 2008) was conducted using the following key words: non–small cell lung cancer, chemotherapy. supportive care, therapeutic strategy, quality of life (QOL), and targeted therapies.

Study Selection and Data Extraction:

Review articles, clinical trials, and case reports, as well as the references of those articles, were reviewed. Statistical significance and number of patients included in the studies were some of the aspects that were considered seriously. Response rates, overall survival, and progression-free survival were the major data considered.

Data Synthesis:

The therapeutic management of metastatic NSCLC has undergone a profound evolution over the past 10 years. The positive impact of chemotherapy on survival compared with supportive care atone has been demonstrated by several meta-analyses. The development of third-generation agents with better efficacy/toxicity ratios, such as vinorelbine, paclitaxel, docetaxel, gemcitabine, and pemetrexed, has led to improved therapeutic management of NSCLC, especially when tailored to patients' comorbidities and performance status. First-line platinum-based combinations remain the standard of care, with median survival 8 months and 1-year survival 35%, but no particular combination has yet shown superiority. First-line platinum regimens in combination with bevacizumab, a targeted inhibitor of vascular endothelial growth factor, have further improved NSCLC median survival. Moreover, second- and third-line treatments have evolved. The addition of small-molecule epidermal growth factor inhibitors and other targeted therapies has modified the pattern of NSCLC treatment. Specific management of the elderly and patients with poor performance status should be applied.

Conclusions:

Although there has been progress in the treatment of NSCLC, the gain in terms of clinical response and survival is still modest. Maintaining QOL and tailoring therapy for patients based on age, performance status, comorbidities, and toxicities, remain the first priority for clinicians.
Long-Acting Bronchodilator Therapy for the Treatment of Chronic Obstructive Pulmonary Disease
Authors: Chen Andrea M , Bollmeier Suzanne G , Finnegan Patrick M
Published: October 2008

Objective:

To review clinical data on the use of long-acting bronchodilator agents as monotherapy and in combination for the treatment of moderate-to-severe chronic obstructive pulmonary disease (COPD).

Data Sources:

A literature search was performed via MEDLINE (1966–April 2008). In addition, references from publications identified were reviewed. These searches were limited to human data published in the English language. Searches used the following terms: COPD, long-acting β2-agonisls, long-acting anticholinergics, combination therapy, pharmacoeconomics, safety, tiotropium, salmeterol, and formoterol.

Study Selection and Data Extraction:

Relevant information on the pharmacology, safety, efficacy, pharmacoeconomics, adherence, and available agents used in the treatment of COPD was selected. Randomized clinical trials and retrospective reviews were included.

Data Synthesis:

The Global Initiative for Chronic Obstructive Lung Disease guidelines provide general management recommendations to guide providers regarding treatment choices for COPD; however, they lack clarity regarding which long-acting bronchodilator to use and when combining agents becomes appropriate. Prospective trials evaluating short-acting anticholinergics and long-acting β2-agonists have utilized spirometric endpoints that relate most to short-term symptomatic relief. Tiotropium trials have focused more on patient-oriented outcomes, with data being reported for one year. Tiotropium significantly lowers exacerbation rates and improves health resource usage as well as health-related quality of life. Tiotropium also provides superior bronchodilation and improvement in dyspnea at all timo points, although onset of bronchodilation is slower than with long-acting β2-agonists. Combining these agents has been shown to decrease daytime rescue inhaler use, improve morning and evening peak expiratory flow rates, and improve bronchodilator efficacy compared with monotherapy. Pharmacoeconomic data lend support to the recommendation of tiotropium as a first-line long-acting agent.

Conclusions:

Tiotropium appears to be the best option as a first-line drug for patients with moderate-to-severe COPD because of its ability to sustain bronchodilator effect, improve quality of life, reduce COPD exacerbations, and reduce health resource usage. Patients who remain symptomatic may benefit from the addition of a long-acting β2-agonist to tiotropium monotherapy.
Tocilizumab: An lnterleukin-6 Receptor Inhibitor for the Treatment of Rheumatoid Arthritis
Authors: Plushner Susyn L
Published: October 2008

Objective:

To review the pharmacology, pharmacokinetics, clinical trial data, and safety profile of tocilizumab, a new biologic agent targeting the lnterleukin-6 cytokine receptor.

Data Sources:

A systematic search of MEDLINE (1998–June 2008) and International Pharmaceutical Abstracts (1970–June 2008) was performed to identify published clinical trials and review articles. Key search terms were tocilizumab, MRA, interleukin-6/receptors, interleukln-6/immunology, and rheumatoid arthritis. The search was limited to studies in humans that were published in the English language. References from articles located during this search were evaluated for other relevant citations. Abstracts from national and international rheumatology meetings (American College of Rheumatology and European League Against Rheumatism) and from unpublished Phase 3 clinical trials in progress (using www.clinicaltrials.gov ) were also reviewed.

Study Selection and Data Extraction:

All available human studies describing the pharmacology, pharmacokinetics, efficacy, safety, and adverse effects of tocilizumab were included.

Data Synthesis:

At doses greater than 4 mg/kg, tocilizumab use has resulted In significant improvement in clinical outcomes, including the American College of Rheumatology parameters indicating a patient's level of improvements and disease remission. Improvements were noted when tocilizumab was used as monotherapy or in combination with methotrexate or other disease-modifying antirheumatic drugs. The most effective dose of tocilizumab appears to be 8 mg/kg, which has shown significant improvements in radiographic measures of joint damage. The most common adverse effects have included abnormal results of liver function tests, hyperlipidemia, neutropenia, infections, nasopharyngitis, gastrointestinal complaints, musculoskeletal disorders, headache, rash, and pruritus.

Conclusions:

Tocilizumab represents a promising new treatment for rheumatoid arthritis. Additional research is warranted to confirm its radiographic benefits, clarify its safely profile, and identify its place in rheumatoid arthritis treatment relative to current biologic agents.
The international relations in the politics of the Partido Africano da Independncia da Guin e Cabo Verde
Authors: Gomes Patricia
Published: October 2008

The end of colonialism in Africa, and the establishment of the independent states, was reached variously through peaceful ways or violent ones. In the Guinean case, the establishment of the nation-state was made possible by the development of an armed struggle for national liberation,
in which the Partido Africano da Independncia da Guin e Cabo Verde (PAIGC) played a crucial role. The victories that were achieved in the Guinean territory were largely possible due to the diplomatic efforts requested by the PAIGC representatives. The exhaustive information sent throughout
these years to the United Nations Committee on Decolonisation, and the presence of PAIGC representatives in international organisations, contributed to the positive evolution of the liberation struggle. The aim of the present article is to analyse the manner and the context in which the PAIGC
obtained international support and its significance for the process of self-determination in Guinea-Bissau.
Up-Regulation of P2X4Receptors in Spinal Microglia after Peripheral Nerve Injury Mediates BDNF Release and Neuropathic Pain
Authors: Ulmann Lauriane , Hatcher Jon P. , Hughes Jane P. , Chaumont Séverine , Green Paula J. , Conquet François , Buell Gary N. , Reeve Alison J. , Chessell Iain P. , Rassendren Francois
Published: October 2008

ATP is a known mediator of inflammatory and neuropathic pain. However, the mechanisms by which specific purinergic receptors contribute to chronic pain states are still poorly characterized. Here, we demonstrate that in response to peripheral nerve injury, P2X4receptors (P2X4R) are expressedde novoby activated microglia in the spinal cord. Usingin vitroandin vivomodels, we provide direct evidence that P2X4R stimulation leads to the release of BDNF from activated microglia and, most likely phosphorylation of the NR1 subunit of NMDA receptors in dorsal horn neurons of the spinal cord. Consistent with these findings, P2X4-deficient mice lack mechanical hyperalgesia induced by peripheral nerve injury and display impaired BDNF signaling in the spinal cord. Furthermore, ATP stimulation is unable to stimulate BDNF release from P2X4-deficient mice microglia in primary cultures. These results indicate that P2X4R contribute to chronic pain through a central inflammatory pathway. P2X4R might thus represent a potential therapeutic target to limit microglia-mediated inflammatory responses associated with brain injury and neurodegenerative disorders.
On-Line Processing of Uncertain Information in Visuomotor Control
Authors: Izawa Jun , Shadmehr Reza
Published: October 2008

Our sensory observations represent a delayed, noisy estimate of the environment. Delay causes instability and noise causes uncertainty. To deal with these problems, theory suggests that the processing of sensory information by the brain should be probabilistic: to start a movement or to alter it midflight, our brain should make predictions about the near future of sensory states and then continuously integrate the delayed sensory measures with predictions to form an estimate of the current state. To test the predictions of this theory, we asked participants to reach to the center of a blurry target. With increased uncertainty about the target, reach reaction times increased. Occasionally, we changed the position of the target or its blurriness during the reach. We found that the motor response to a given second target was influenced by the uncertainty about the first target. The specific trajectories of motor responses were consistent with predictions of a “minimum variance” state estimator. That is, the motor output that the brain programmed to start a reaching movement or correct it midflight was a continuous combination of two streams of information: a stream that predicted the near future of the state of the environment and a stream that provided a delayed measurement of that state.
CNS Learns Stable, Accurate, and Efficient Movements Using a Simple Algorithm
Authors: Franklin David W. , Burdet Etienne , Peng Tee Keng , Osu Rieko , Chew Chee-Meng , Milner Theodore E. , Kawato Mitsuo
Published: October 2008

We propose a new model of motor learning to explain the exceptional dexterity and rapid adaptation to change, which characterize human motor control. It is based on the brain simultaneously optimizing stability, accuracy and efficiency. Formulated as a V-shaped learning function, it stipulates precisely how feedforward commands to individual muscles are adjusted based on error. Changes in muscle activation patterns recorded in experiments provide direct support for this control scheme. In simulated motor learning of novel environmental interactions, muscle activation, force and impedance evolved in a manner similar to humans, demonstrating its efficiency and plausibility. This model of motor learning offers new insights as to how the brain controls the complex musculoskeletal system and iteratively adjusts motor commands to improve motor skills with practice.
Pediatric Antiphospholipid Syndrome: Clinical and Immunologic Features of 121 Patients in an International Registry
Authors: Avčin Tadej , Cimaz Rolando , Silverman Earl D. , Cervera Ricard , Gattorno Marco , Garay Stella , Berkun Yackov , Sztajnbok Flavio R. , Silva Clovis A. , Campos Lucia M. , Saad-Magalhaes Claudia , Rigante Donato , Ravelli Angelo , Martini Alberto , Rozman Blaž , Meroni Pier Luigi
Published: October 2008

OBJECTIVES. The purpose of this study was to obtain data on the association of antiphospholipid antibodies with clinical manifestations in childhood and to enable future studies to determine the impact of treatment and long-term outcome of pediatric antiphospholipid syndrome.

PATIENTS AND METHODS. A European registry extended internationally of pediatric patients with antiphospholipid syndrome was established as a collaborative project of the European Antiphospholipid Antibodies Forum and Lupus Working Group of the Pediatric Rheumatology European Society. To be eligible for enrollment the patient must meet the preliminary criteria for the classification of pediatric antiphospholipid syndrome and the onset of antiphospholipid syndrome must have occurred before the patient's 18th birthday.

RESULTS. As of December 1, 2007, there were 121 confirmed antiphospholipid syndrome cases registered from 14 countries. Fifty-six patients were male, and 65 were female, with a mean age at the onset of antiphospholipid syndrome of 10.7 years. Sixty (49.5%) patients had underlying autoimmune disease. Venous thrombosis occurred in 72 (60%), arterial thrombosis in 39 (32%), small-vessel thrombosis in 7 (6%), and mixed arterial and venous thrombosis in 3 (2%). Associated nonthrombotic clinical manifestations included hematologic manifestations (38%), skin disorders (18%), and nonthrombotic neurologic manifestations (16%). Laboratory investigations revealed positive anticardiolipin antibodies in 81% of the patients, anti-β2-glycoprotein I antibodies in 67%, and lupus anticoagulant in 72%. Comparisons between different subgroups revealed that patients with primary antiphospholipid syndrome were younger and had a higher frequency of arterial thrombotic events, whereas patients with antiphospholipid syndrome associated with underlying autoimmune disease were older and had a higher frequency of venous thrombotic events associated with hematologic and skin manifestations.

CONCLUSIONS. Clinical and laboratory characterization of patients with pediatric antiphospholipid syndrome implies some important differences between antiphospholipid syndrome in pediatric and adult populations. Comparisons between children with primary antiphospholipid syndrome and antiphospholipid syndrome associated with autoimmune disease have revealed certain differences that suggest 2 distinct subgroups.
Ecotones: Marginal or central areas of transition?
Authors: Kark Salit , van Rensburg Berndt J.
Published: October 2008

Areas of environmental transition, where ecological communities coincide, are sometimes termed ecotones. These regions often correspond with sharp environmental gradients. Ecotones occur at multiple spatial scales, ranging from transitions between biomes to local small-scale transitions. In recent years ecotones have received increasing scientific attention after being neglected for years, as studies historically often focused on distinct communities. However, it is still debatable whether these transitional regions are speciation and biodiversity hotspots that deserve special conservation interest or are actually areas that hold marginal populations that depend on other parts of the range for the maintenance of their biodiversity and therefore should not deserve primary investment. This paper discusses some of the recent advancements in our understanding of the role of ecotones in ecology, evolution, and conservation.
Invited Minireview: Restoring Demographic Processes in Translocated Populations: The Case of Collared Lizards in the Missouri Ozarks Using Prescribed Forest Fires
Authors: Templeton Alan R. , Neuwald Jennifer L. , Brazeal Hilary , Robertson R. James
Published: October 2008

Habitat fragmentation is one of the more important contributors to species endangerment, but one form of fragmentation, here called dispersal fragmentation, can often go unobserved for many years after it has occurred. Many species live in naturally fragmented habitats, but the local populations are interconnected genetically and demographically by dispersal through the environmental matrix in which the habitats are embedded. Because of dispersal, the local populations are not truly fragmented evolutionarily or ecologically. However, when human activities alter the environmental matrix such that dispersal is no longer possible, the population does indeed become fragmented even though they initially are present in the same habitats. An example of dispersal fragmentation via an altered environmental matrix is provided by the eastern collared lizard (Crotaphytus collaris collaris). This lizard lives on open, rocky habitats, called glades, that are embedded in the forests of the Ozarks, a highland region located primarily in Missouri and Arkansas in the USA. Forest fire suppression has reduced this habitat, resulting in severe habitat fragmentation, disruption of gene flow, loss of genetic variation within glade populations, and local extinction without recolonization. Beginning in 1982, glade habitats were restored by clearing and burning in the Peck Ranch area of the Missouri Ozarks, a region where the lizards had gone extinct. Starting in 1984, lizard populations were translocated from other Missouri glades onto restored glades at the Peck Ranch. Although these translocated populations survived well on the restored glades, no movement was detected between glades, some just 50 m apart, and no colonization of nearby restored glades, some just 60 m away, occurred between 1984 and 1993. Fragmentation, lack of colonization, no gene flow, and loss of genetic variation still persisted despite translocation reversing some of the local extinction. Fire scar data from trees and tree stumps indicated that forest fires were common in this area prior to European settlement, so in 1994 a new management policy of prescribed burning of both the glades and their forest matrix was initiated. Once the forest had been burned, the lizards could disperse kilometers through the forest, thereby reestablishing the processes of dispersal, gene flow, colonization, and local extinction followed by recolonization. This resulted in a dramatic increase in population size and inhabited area. By incorporating a landscape perspective into the management strategy, the eastern collared lizard has been successfully reestablished in a region of historic extirpation.
Revisiting Heritable Variation and Limits to Species Distribution: Recent Developments
Authors: Hoffmann Ary , Kellermann Vanessa
Published: October 2008

There are several evolutionary reasons why species distributions are locally and geographically limited, and these mostly revolve around gene flow and levels of genetic variation in populations. While there has been progress in developing models assessing the impact of gene flow, empirical data on hypotheses about factors limiting distributions remain rare. A few recent plant studies have highlighted that levels of additive genetic variance are not limiting, suggesting a role for gene flow. However, some animal studies, mostly onDrosophilaspecies, have refocused attention on heritable variation as an evolutionary reason for distribution limits. There is a need for comparative studies that examine levels of heritable variation across related species groups with broad and narrow distributions, and also across a range of traits including those likely to be under selection at borders. These studies will help to test specific predictions about the relative importance of genetic variance and gene flow in limiting current borders and also help in predicting the impact of future environmental changes on distribution shifts.
Regressive Evolution of Pigmentation in the Cavefish Astyanax
Authors: Jeffery William R.
Published: October 2008

Many cave animals are colorless due to loss of pigment cells. Here, we review recent progress on how and why pigmentation has disappeared inAstyanax mexicanus, a single teleost species with conspecific surface-dwelling (surface fish) and many different cave-dwelling (cavefish) forms. During surface fish development, migratory neural crest cells form three types of pigment cells: silver iridophores, orange xanthophores, and black melanophores. Cavefish have eliminated or substantially reduced their complement of melanophores and exhibit albinism, loss of the capacity to synthesize melanin. Cell tracing, immunolocalization, and neural tube explant cultures show that cavefish have retained a colorless pre-melanophore (melanoblast) lineage derived from the neural crest. Thus, the cavefish neural crest produces melanoblasts that migrate normally but are blocked in differentiation and show defective melanogenesis. Cavefish melanoblasts can convert exogenous L-DOPA into melanin and therefore have active tyrosinase, the key enzyme in melanogenesis. In contrast, cavefish melanoblasts are unable to convert L-tyrosine to L-DOPA (and melanin), although this reaction is also catalyzed by tyrosinase. Thus, cavefish are tyrosinase-positive albinos that have a deficiency in L-tyrosine transport or utilization within the melanosome, the organelle in which melanin is synthesized. At least five different types ofAstyanaxcavefish show the same defect in melanogenesis. Genetic analysis shows that cavefish albinism is caused by loss of function mutations in a single gene,p/oca2, which encodes a large protein that probably spans the melanosome membrane. Different deletions in thep/oca2 protein-coding region are responsible for loss of function in at least two different cavefish populations, suggesting that albinism evolved by convergence. Based on current understanding of the genetic basis of albinism, we discuss potential mechanisms for regressive evolution of cavefish pigmentation.
Identifying the Fundamental Units of Diversity Among Bacillus Isolates From "Evolution Canyon" III
Authors: Perry Elizabeth B. , Koeppel Alexander , Krizanc Danny , Rooney Alejandro P. , Sikorski Johannes , Nevo Eviatar , Cohan Frederick M.
Published: October 2008

Bacterial systematics currently lacks a theory-based approach to identify the fundamental units of ecology and evolution. Consequently, a single bacterial species typically contains multiple phylogenetically and ecologically distinct lineages. Thus, the species of bacterial systematics are too broadly conceived to help the microbial ecologist who seeks to behold the full ecological diversity within a community, and to determine the interactions and functions of its ecologically distinct populations. Here, we review some of our recent work aiming to discover the ecologically distinct populations of a clade through analysis of DNA sequence diversity. We have developed an algorithm to compare simulations of bacterial sequence evolution with observed sequence diversity patterns within a clade. By finding the set of parameters that give a maximum likelihood fit between evolutionary simulations and actual sequence data, we are able to estimate lineage-specific rates of evolution and to make predictions about sequence clusters that correspond to ecologically distinct populations (ecotypes). We applied this approach to bacterial isolates of "Evolution Canyon" III in the southern Negev Desert. Within theBacillus subtilis-B. licheniformisclade, our simulation identified numerous putative ecotypes, some of which were shown to be strongly associated with different microhabitats, confirming their ecological distinctness. Also, several confirmed ecotypes were found to be grouped within a single named species, demonstrating the power of the algorithm to discern ecologically significant variation that is beyond the current focus of bacterial systematics. These findings highlight the promise of a theory-driven approach to identify fundamental units of bacterial diversity.
Impact of participants' values on construction sustainability
Authors: Fellows R. , Liu A.
Published: October 2008

This paper examines the processes through which the values relating to construction projects, with particular reference to sustainability, are determined and operationalised. Those values are fundamental in governing the performance of both the project, as a product in occupation and use, and project management, as processes of realisation of the project involving design and construction. The values determine what performance variables are considered and their relative importance which, within the applicable parameters, controls and constraints, yield the performance targets for the project—against which realised performance will be evaluated. Those values are derived from the value structures of the project participants and so must be elicited and collated under the influence of the evolving membership and power structure of the project temporary multi-organisation (TMO). The TMO, as a shifting, multi-goal, power-based coalition, promotes fluctuations in the values employed to drive the project as it develops and so makes evaluation of performance highly problematic. Given that the values are human-determined, they are grounded in culture. Thus, understanding culture, as an operative construct in the project value system, enables the concepts and practices relating to the sustainability of construction projects to be understood and developed.
The effect of moisture content and alkalinity on the anaerobic biodegradation of pit latrine sludge
Authors: Couderc A. A.-L. , Foxon K. , Buckley C. A. , Nwaneri C. F. , Bakare B. F. , Gounden T. , Battimelli A.
Published: October 2008

This study investigated the effect of additional moisture and/or alkalinity on the rate of anaerobic digestion in samples of material obtained from pit latrines. In modified serum bottle tests it was shown that poor gas production rates were observed from all experiments with material collected at the lower part of one pit. Using material from the top layer of a second pit it was shown that experimental bottles produced significant amounts of gas for all treatments. Analysis of data indicated that treatment with additional alkalinity had no discernible effect on anaerobic gas production rates, but that there was some correlation between moisture content and gas production rate. These results did not support the hypothesis that low pH buffering capacity was a limiting factor in the rate of digestion of pit latrine sludge, but confirmed that low moisture content could reduce the rate of stabilisation. This implies that increasing the moisture content in a pit latrine has the potential to increase biological stabilisation rates in the pit when the material is not already well-stabilised.
A pilot-scale comparison of mesophilic and thermophilic digestion of source segregated domestic food waste
Authors: Banks Charles J. , Chesshire Michael , Stringfellow Anne
Published: October 2008

Source segregated food waste was collected from domestic properties and its composition determined together with the average weight produced per household, which was 2.91 kg per week. The waste was fed over a trial period lasting 58 weeks to an identical pair of 1.5 m3 anaerobic digesters, one at a mesophilic (36.5°C) and the other at a thermophilic temperature (56°C). The digesters were monitored daily for gas production, solids destruction and regularly for digestate characteristics including alkalinity, pH, volatile fatty acid (VFA) and ammonia concentrations. Both digesters showed high VFA and ammonia concentrations but in the mesophilic digester the pH remained stable at around 7.4, buffered by a high alkalinity of 13,000 mg l−1; whereas in the thermophilic digester VFA levels reached 45,000 mg l−1 causing a drop in pH and digester instability. In the mesophilic digester volatile solids (VS) destruction and specific gas yield were favourable, with 67% of the organic solids being converted to biogas at a methane content of 58% giving a biogas yield of 0.63 m3 kg−1 VSadded. Digestion under thermophilic conditions showed potentially better VS destruction at 70% VS and a biogas yield of 0.67 m3 kg−1 VSadded, but the shifts in alkalinity and the high VFA concentrations required a reduced loading to be applied. The maximum beneficial loading that could be achieved in the mesophilic digester was 4.0 kg VS m−3 d−1.
Anaerobic digestion of maize in coupled leach-bed and anaerobic filter reactors
Authors: Cysneiros D. , Banks C. J. , Heaven S.
Published: October 2008

The methane potential of a leach bed reactor (LBR) coupled to an anaerobic filter (AF) was assessed using energy maize (Zea mays) as substrate. Four LBRs were used operated as pairs, with and without leachate recirculation, over two feed cycles with retention times of 14 and 28 days. Performance was estimated from the total solids destruction in the LBR, and the volatile fatty acid (VFA) and soluble chemical oxygen demand (SCOD) in the leachate. Overall conversion of fresh substrate added to the combined system was good although the organic loading rate (OLR) was limited. The coupled LBR demonstrated improved hydrolysis performance promoted by good buffering, and the AF showed rapid conversion of leachate SCOD into methane with possible further hydrolysis and acidification. Theoretical estimation of the methane potential showed that between 20–40% of the methane was formed in the LBR and was not captured in this trial.
Den‐Site Characteristics of Black Bears in Rocky Mountain National Park, Colorado
Authors: BALDWIN ROGER A. , BENDER LOUIS C.
Published: October 2008

Abstract: We compared historic (1985–1992) and contemporary (2003–2006) black bear (Ursus americanus) den locations in Rocky Mountain National Park (RMNP), Colorado, USA, for habitat and physiographic attributes of den sites and used maximum entropy modeling to determine which factors were most influential in predicting den‐site locations. We observed variability in the relationship between den locations and distance to trails and elevation over time. Locations of historic den sites were most associated with slope, elevation, and covertype, whereas contemporary sites were associated with slope, distance to roads, aspect, and canopy height. Although relationships to covariates differed between historic and contemporary periods, preferred den‐site characteristics consistently included steep slopes and factors associated with greater snow depth. Distribution of den locations shifted toward areas closer to human developments, indicating little negative influence of this factor on den‐site selection by black bears in RMNP.