Recursos de Sanidad, Biomedicina y Salud

Noticias Externas del Friday 16 de December de 2011


by Greg W. Mitchell, Christopher G. Guglielmo, Nathaniel T. Wheelwright, Corey R. Freeman-Gallant, D. Ryan Norris

Conditions experienced during development can have long-term consequences for individual success. In migratory songbirds, the proximate mechanisms linking early life events and survival are not well understood because tracking individuals across stages of the annual cycle can be extremely challenging. In this paper, we first use a 13 year dataset to demonstrate a positive relationship between 1st year survival and nestling mass in migratory Savannah sparrows (Passerculus sandwichensis). We also use a brood manipulation experiment to show that nestlings from smaller broods have higher mass in the nest relative to individuals from larger broods. Having established these relationships, we then use three years of field data involving multiple captures of individuals throughout the pre-migratory period and a multi-level path model to examine the hypothesis that conditions during development limit survival during migration by affecting an individual's ability to accumulate sufficient lean tissue and fat mass prior to migration. We found a positive relationship between fat mass during the pre-migratory period (Sept–Oct) and nestling mass and a negative indirect relationship between pre-migratory fat mass and fledging date. Our results provide the first evidence that conditions during development limit survival during migration through their effect on fat stores. These results are particularly important given recent evidence showing that body condition of songbirds at fledging is affected by climate change and anthropogenic changes to landscape structure.

by Maria V. Turkina, Hanna Klang Årstrand, Alexander V. Vener

Protein synthesis in plants is characterized by increase in the translation rates for numerous proteins and central metabolic enzymes during the day phase of the photoperiod. The detailed molecular mechanisms of this diurnal regulation are unknown, while eukaryotic protein translation is mainly controlled at the level of ribosomal initiation complexes, which also involves multiple events of protein phosphorylation. We characterized the extent of protein phosphorylation in cytosolic ribosomes isolated from leaves of the model plant Arabidopsis thaliana harvested during day or night. Proteomic analyses of preparations corresponding to both phases of the photoperiod detected phosphorylation at eight serine residues in the C-termini of six ribosomal proteins: S2-3, S6-1, S6-2, P0-2, P1 and L29-1. This included previously unknown phosphorylation of the 40S ribosomal protein S6 at Ser-231. Relative quantification of the phosphorylated peptides using stable isotope labeling and mass spectrometry revealed a 2.2 times increase in the day/night phosphorylation ratio at this site. Phosphorylation of the S6-1 and S6-2 variants of the same protein at Ser-240 increased by the factors of 4.2 and 1.8, respectively. The 1.6 increase in phosphorylation during the day was also found at Ser-58 of the 60S ribosomal protein L29-1. It is suggested that differential phosphorylation of the ribosomal proteins S6-1, S6-2 and L29-1 may contribute to modulation of the diurnal protein synthesis in plants.

by Lili Xu, Linlin Bao, Fengdi Li, Qi Lv, Yila Ma, Jiangfang Zhou, Yanfeng Xu, Wei Deng, Lingjun Zhan, Hua Zhu, Chunmei Ma, Yuelong Shu, Chuan Qin

The experimental infection of a mouse lung with influenza A virus has proven to be an invaluable model for studying the mechanisms of viral adaptation and virulence. The mouse adaption of human influenza A virus can result in mutations in the HA and other proteins, which is associated with increased virulence in mouse lungs. In this study, a mouse-adapted seasonal H1N1 virus was obtained through serial lung-to-lung passages and had significantly increased virulence and pathogenicity in mice. Genetic analysis indicated that the increased virulence of the mouse-adapted virus was attributed to incremental acquisition of three mutations in the HA protein (T89I, N125T, and D221G). However, the mouse adaption of influenza A virus did not change the specificity and affinity of receptor binding and the pH-dependent membrane fusion of HA, as well as the in vitro replication in MDCK cells. Notably, infection with the mouse adapted virus induced severe lymphopenia and modulated cytokine and chemokine responses in mice. Apparently, mouse adaption of human influenza A virus may change the ability to replicate in mouse lungs, which induces strong immune responses and inflammation in mice. Therefore, our findings may provide new insights into understanding the mechanisms underlying the mouse adaption and pathogenicity of highly virulent influenza viruses.

by Zhen Wang, Hong Zhang, Xu-Hui Shen, Kui-Li Jin, Guo-fen Ye, Li Qian, Bo Li, Yong-Hong Zhang, Guo-Ping Shi


Recent studies have suggested that mast-cell activation and inflammation are important in obesity and diabetes. Plasma levels of mast cell proteases and the mast cell activator immunoglobulin E (IgE) may serve as novel inflammatory markers that associate with the risk of pre-diabetes and diabetes mellitus.

Methods and Results

A total of 340 subjects 55 to 75 years of age were grouped according to the American Diabetes Association 2003 criteria of normal glucose tolerance, pre-diabetes, and diabetes mellitus. The Kruskal-Wallis test demonstrated significant differences in plasma IgE levels (P = 0.008) among groups with different glucose tolerance status. Linear regression analysis revealed significant correlations between plasma levels of chymase (P = 0.030) or IgE (P = 0.022) and diabetes mellitus. Ordinal logistic regression analysis showed that IgE was a significant risk factor of pre-diabetes and diabetes mellitus (odds ratio [OR]: 1.674, P = 0.034). After adjustment for common diabetes risk factors, including age, sex, hypertension, body-mass index, cholesterol, homeostatic model assessment (HOMA) index, high-sensitivity C-reactive protein (hs-CRP), and mast cell chymase and tryptase, IgE remained a significant risk factor (OR: 1.866, P = 0.015). Two-variable ordinal logistic analysis indicated that interactions between hs-CRP and IgE, or between IgE and chymase, increased further the risks of developing pre-diabetes and diabetes mellitus before (OR: 2.204, P = 0.044; OR: 2.479, P = 0.033) and after (OR: 2.251, P = 0.040; OR: 2.594, P = 0.026) adjustment for common diabetes risk factors.


Both IgE and chymase associate with diabetes status. While IgE and hs-CRP are individual risk factors of pre-diabetes and diabetes mellitus, interactions of IgE with hs-CRP or with chymase further increased the risk of pre-diabetes and diabetes mellitus.


by Joanne D. Stekler, Giovanina M. Ellis, Jacquelyn Carlsson, Braiden Eilers, Sarah Holte, Janine Maenza, Claire E. Stevens, Ann C. Collier, Lisa M. Frenkel


To evaluate minority variant drug resistance mutations detected by the oligonucleotide ligation assay (OLA) but not consensus sequencing among subjects with primary HIV-1 infection.


Observational, longitudinal cohort study. Consensus sequencing and OLA were performed on the first available specimens from 99 subjects enrolled after 1996. Survival analyses, adjusted for HIV-1 RNA levels at the start of antiretroviral (ARV) therapy, evaluated the time to virologic suppression (HIV-1 RNA


by Velibor Tasic, Ann Marie Hynes, Kenichiro Kitamura, Hae Il Cheong, Vladimir J. Lozanovski, Zoran Gucev, Promsuk Jutabha, Naohiko Anzai, John A. Sayer

Idiopathic renal hypouricaemia is an inherited form of hypouricaemia, associated with abnormal renal handling of uric acid. There is excessive urinary wasting of uric acid resulting in hypouricaemia. Patients may be asymptomatic, but the persistent urinary abnormalities may manifest as renal stone disease, and hypouricaemia may manifest as exercise induced acute kidney injury. Here we have identified Macedonian and British patients with hypouricaemia, who presented with a variety of renal symptoms and signs including renal stone disease, hematuria, pyelonephritis and nephrocalcinosis. We have identified heterozygous missense mutations in SLC22A12 encoding the urate transporter protein URAT1 and correlate these genetic findings with functional characterization. Urate handling was determined using uptake experiments in HEK293 cells. This data highlights the importance of the URAT1 renal urate transporter in determining serum urate concentrations and the clinical phenotypes, including nephrolithiasis, that should prompt the clinician to suspect an inherited form of renal hypouricaemia.

by Eva A. V. Moelants, Jo Van Damme, Paul Proost


Posttranslational deimination or citrullination by peptidylarginine deiminases (PAD) regulates the biological function of proteins and may be involved in the development of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. This posttranslational modification of arginine was recently discovered on inflammatory chemokines including CXCL8 and CXCL10, and significantly reduced their biological activity. To evaluate the importance of these modified chemokines in patients, methods for the detection and quantification of citrullinated chemokines are needed. Since citrullination only results in an increase of the protein mass with one mass unit and the loss of one positive charge, selective biochemical detection is difficult. Therefore, we developed an antibody-based method to specifically detect and quantify citrullination on a protein of interest.

Methodology/Principal Findings

First, the citrullinated proteins were chemically modified with antipyrine and 2,3-butanedione at low pH. Such selectively modified citrullines were subsequently detected and quantified by specific antibodies raised against a modified citrulline-containing peptide. The specificity of this two-step procedure was validated for citrullinated CXCL8 ([Cit5]CXCL8). Specific detection of [Cit5]CXCL8 concentrations between 1 and 50 ng/ml was possible, also in complex samples containing an excess of contaminating proteins. This novel detection method was used to evaluate the effect of lipopolysaccharide (LPS) on the citrullination of inflammatory chemokines induced in peripheral blood mononuclear cells (PBMCs) and granulocytes. LPS had no significant effect on the induction of CXCL8 citrullination in human PBMCs and granulocytes. However, granulocytes, known to contain PAD, were essential for the production of significant amounts of [Cit5]CXCL8.


The newly developed antibody-based method to specifically detect and quantify chemically modified citrullinated proteins is proven to be effective. This study furthermore demonstrates that granulocytes were essential to obtain significant levels of [Cit5]CXCL8. For human PBMCs and granulocytes stimulation with LPS did not affect the citrullination of CXCL8.


by Phyllis Fung Yi Cheung, Christine Kei Chin Cheng, Nicholas Chun Lim Wong, Jenny Chung Yee Ho, Chi Wai Yip, Vincent Chi Hang Lui, Annie Nga Yin Cheung, Sheung Tat Fan, Siu Tim Cheung

Background and Aims

Increasing evidence has suggested that hepatocellular carcinoma (HCC) might originate from a distinct subpopulation called cancer stem cells (CSCs), which are responsible for the limited efficacy of conventional therapies. We have previously demonstrated that granulin-epithelin precursor (GEP), a pluripotent growth factor, is upregulated in HCC but not in the adjacent non-tumor, and that GEP is a potential therapeutic target for HCC. Here, we characterized its expression pattern and stem cell properties in fetal and cancerous livers.


Protein expression of GEP in fetal and adult livers was examined in human and mouse models by immunohistochemical staining and flow cytometry. Liver cancer cell lines, isolated based on their GEP and/or ATP-dependent binding cassette (ABC) drug transporter ABCB5 expression, were evaluated for hepatic CSC properties in terms of colony formation, chemoresistance and tumorigenicity.


We demonstrated that GEP was a hepatic oncofetal protein that expressed in the fetal livers, but not in the normal adult livers. Importantly, GEP+ fetal liver cells co-expressed the embryonic stem (ES) cell-related signaling molecules including β-catenin, Oct4, Nanog, Sox2 and DLK1, and also hepatic CSC-markers CD133, EpCAM and ABCB5. Phenotypic characterization in HCC clinical specimens and cell lines revealed that GEP+ cancer cells co-expressed these stem cell markers similarly as the GEP+ fetal liver cells. Furthermore, GEP was shown to regulate the expression of ES cell-related signaling molecules β-catenin, Oct4, Nanog, and Sox2. Isolated GEPhigh cancer cells showed enhanced colony formation ability and chemoresistance when compared with the GEPlow counterparts. Co-expression of GEP and ABCB5 better defined the CSC populations with enhanced tumorigenic ability in immunocompromised mice.


Our findings demonstrate that GEP is a hepatic oncofetal protein regulating ES cell-related signaling molecules. Co-expression of GEP and ABCB5 further enriches a subpopulation with enhanced CSC properties. The current data provide new insight into the therapeutic strategy.


by Ákos Boros, Péter Pankovics, Peter Simmonds, Gábor Reuter

A novel positive-sense, single-stranded RNA (+ssRNA) virus (Halastavi árva RNA virus, HalV; JN000306) with di-cistronic genome organization was serendipitously identified in intestinal contents of freshwater carps (Cyprinus carpio) fished by line-fishing from fishpond “Lőrinte halastó” located in Veszprém County, Hungary. The complete nucleotide (nt) sequence of the genomic RNA is 9565 nt in length and contains two long - non-in-frame - open reading frames (ORFs), which are separated by an intergenic region. The ORF1 (replicase) is preceded by an untranslated sequence of 827 nt, while an untranslated region of 139 nt follows the ORF2 (capsid proteins). The deduced amino acid (aa) sequences of the ORFs showed only low (less than 32%) and partial similarity to the non-structural (2C-like helicase, 3C-like cystein protease and 3D-like RNA dependent RNA polymerase) and structural proteins (VP2/VP4/VP3) of virus families in Picornavirales especially to members of the viruses with dicistronic genome. Halastavi árva RNA virus is present in intestinal contents of omnivorous freshwater carps but the origin and the host species of this virus remains unknown. The unique viral sequence and the actual position indicate that Halastavi árva RNA virus seems to be the first member of a new di-cistronic ssRNA virus. Further studies are required to investigate the specific host species (and spectrum), ecology and role of Halastavi árva RNA virus in the nature.

by Uta Faust, Nico Hampe, Wolfgang Rubner, Norbert Kirchgeßner, Sam Safran, Bernd Hoffmann, Rudolf Merkel

Recognition of external mechanical signals is vital for mammalian cells. Cyclic stretch, e.g. around blood vessels, is one such signal that induces cell reorientation from parallel to almost perpendicular to the direction of stretch. Here, we present quantitative analyses of both, cell and cytoskeletal reorientation of umbilical cord fibroblasts. Cyclic strain of preset amplitudes was applied at mHz frequencies. Elastomeric chambers were specifically designed and characterized to distinguish between zero strain and minimal stress directions and to allow accurate theoretical modeling. Reorientation was only induced when the applied stretch exceeded a specific amplitude, suggesting a non-linear response. However, on very soft substrates no mechanoresponse occurs even for high strain. For all stretch amplitudes, the angular distributions of reoriented cells are in very good agreement with a theory modeling stretched cells as active force dipoles. Cyclic stretch increases the number of stress fibers and the coupling to adhesions. We show that changes in cell shape follow cytoskeletal reorientation with a significant temporal delay. Our data identify the importance of environmental stiffness for cell reorientation, here in direction of zero strain. These in vitro experiments on cultured cells argue for the necessity of rather stiff environmental conditions to induce cellular reorientation in mammalian tissues.

by Luis G. Morello, Patricia P. Coltri, Alexandre J. C. Quaresma, Fernando M. Simabuco, Tereza C. L. Silva, Guramrit Singh, Jeffrey A. Nickerson, Carla C. Oliveira, Melissa J. Moore, Nilson I. T. Zanchin

NIP7 is one of the many trans-acting factors required for eukaryotic ribosome biogenesis, which interacts with nascent pre-ribosomal particles and dissociates as they complete maturation and are exported to the cytoplasm. By using conditional knockdown, we have shown previously that yeast Nip7p is required primarily for 60S subunit synthesis while human NIP7 is involved in the biogenesis of 40S subunit. This raised the possibility that human NIP7 interacts with a different set of proteins as compared to the yeast protein. By using the yeast two-hybrid system we identified FTSJ3, a putative ortholog of yeast Spb1p, as a human NIP7-interacting protein. A functional association between NIP7 and FTSJ3 is further supported by colocalization and coimmunoprecipitation analyses. Conditional knockdown revealed that depletion of FTSJ3 affects cell proliferation and causes pre-rRNA processing defects. The major pre-rRNA processing defect involves accumulation of the 34S pre-rRNA encompassing from site A′ to site 2b. Accumulation of this pre-rRNA indicates that processing of sites A0, 1 and 2 are slower in cells depleted of FTSJ3 and implicates FTSJ3 in the pathway leading to 18S rRNA maturation as observed previously for NIP7. The results presented in this work indicate a close functional interaction between NIP7 and FTSJ3 during pre-rRNA processing and show that FTSJ3 participates in ribosome synthesis in human cells.

by Eduard Gallardo, Noemi de Luna, Jordi Diaz-Manera, Ricardo Rojas-García, Lidia Gonzalez-Quereda, Bàrbara Flix, Antoine de Morrée, Silvère van der Maarel, Isabel Illa


Dysferlinopathies are caused by mutations in the dysferlin gene (DYSF). Diagnosis is complex due to the high clinical variability of the disease and because dysferlin expression in the muscle biopsy may be secondarily reduced due to a primary defect in some other gene. Dysferlin is also expressed in peripheral blood monocytes (PBM). Studying dysferlin in monocytes is used for the diagnosis of dysferlin myopathies. The aim of the study was to determine whether dysferlin expression in PBM correlates with that in skeletal muscle.

Methodology/Principal Findings

Using western-blot (WB) we quantified dysferlin expression in PBM from 21 pathological controls with other myopathies in whom mutations in DYSF were excluded and from 17 patients who had dysferlinopathy and two mutations in DYSF. Results were compared with protein expression in muscle by WB and immunohistochemistry (IH). We found a good correlation between skeletal muscle and monocytes using WB. However, IH results were misleading because abnormal expression of dysferlin was also observed in 13/21 pathological controls.


The analysis of dysferlin protein expression in PBM is helpful when: 1) the skeletal muscle IH pattern is abnormal or 2) when muscle WB can not be performed either because muscle sample is lacking or insufficient or because the muscle biopsy is taken from a muscle at an end-stage and it mainly consists of fat and fibrotic tissue.


by David Melcher, Manuela Piazza

Many common tasks require us to individuate in parallel two or more objects out of a complex scene. Although the mechanisms underlying our abilities to count the number of items, remember the visual properties of objects and to make saccadic eye movements towards targets have been studied separately, each of these tasks require selection of individual objects and shows a capacity limit. Here we show that a common factor—salience—determines the capacity limit in the various tasks. We manipulated bottom-up salience (visual contrast) and top-down salience (task relevance) in enumeration and visual memory tasks. As one item became increasingly salient, the subitizing range was reduced and memory performance for all other less-salient items was decreased. Overall, the pattern of results suggests that our abilities to enumerate and remember small groups of stimuli are grounded in an attentional priority or salience map which represents the location of important items.

by Clare Louise Protheroe, Anastasia Dikareva, Carlo Menon, Victoria Elizabeth Claydon


Syncope, or fainting, affects approximately 6.2% of the population, and is associated with significant comorbidity. Many syncopal events occur secondary to excessive venous pooling and capillary filtration in the lower limbs when upright. As such, a common approach to the management of syncope is the use of compression stockings. However, research confirming their efficacy is lacking. We aimed to investigate the effect of graded calf compression stockings on orthostatic tolerance.

Methodology/Principal Findings

We evaluated orthostatic tolerance (OT) and haemodynamic control in 15 healthy volunteers wearing graded calf compression stockings compared to two placebo stockings in a randomized, cross-over, double-blind fashion. OT (time to presyncope, min) was determined using combined head-upright tilting and lower body negative pressure applied until presyncope. Throughout testing we continuously monitored beat-to-beat blood pressures, heart rate, stroke volume and cardiac output (finger plethysmography), cerebral and forearm blood flow velocities (Doppler ultrasound) and breath-by-breath end tidal gases. There were no significant differences in OT between compression stocking (26.0±2.3 min) and calf (29.3±2.4 min) or ankle (27.6±3.1 min) placebo conditions. Cardiovascular, cerebral and respiratory responses were similar in all conditions. The efficacy of compression stockings was related to anthropometric parameters, and could be predicted by a model based on the subject's calf circumference and shoe size (r = 0.780, p = 0.004).


These data question the use of calf compression stockings for orthostatic intolerance and highlight the need for individualised therapy accounting for anthropometric variables when considering treatment with compression stockings.


by Yannick Béjot, Claude Mossiat, Maurice Giroud, Anne Prigent-Tessier, Christine Marie


Whereas brain-derived neurotrophic factor (BDNF) levels are measured in the brain in animal models of stroke, neurotrophin levels in stroke patients are measured in plasma or serum samples. The present study was designed to investigate the meaning of circulating BDNF levels in stroke patients.

Methods and Results

Unilateral ischemic stroke was induced in rats by the injection of various numbers of microspheres into the carotid circulation in order to mimic the different degrees of stroke severity observed in stroke patients. Blood was serially collected from the jugular vein before and after (4 h, 24 h and 8 d) embolization and the whole brains were collected at 4, 24 h and 8 d post-embolization. Rats were then selected from their degree of embolization, so that the distribution of stroke severity in the rats at the different time points was large but similar. Using ELISA tests, BDNF levels were measured in plasma, serum and brain of selected rats. Whereas plasma and serum BDNF levels were not changed by stroke, stroke induced an increase in brain BDNF levels at 4 h and 24 h post-embolization, which was not correlated with stroke severity. Individual plasma BDNF levels did not correlate with brain levels at any time point after stroke but a positive correlation (r = 0.67) was observed between individual plasma BDNF levels and stroke severity at 4 h post-embolization.


Circulating BDNF levels do not mirror brain BDNF levels after stroke, and severe stroke is associated with high plasma BDNF in the very acute stage.


by Cal F. Rabang, Edward L. Bartlett

Acoustic stimuli are often represented in the early auditory pathway as patterns of neural activity synchronized to time-varying features. This phase-locking predominates until the level of the medial geniculate body (MGB), where previous studies have identified two main, largely segregated response types: Stimulus-synchronized responses faithfully preserve the temporal coding from its afferent inputs, and Non-synchronized responses, which are not phase locked to the inputs, represent changes in temporal modulation by a rate code. The cellular mechanisms underlying this transformation from phase-locked to rate code are not well understood. We use a computational model of a MGB thalamocortical neuron to test the hypothesis that these response classes arise from inferior colliculus (IC) excitatory afferents with divergent properties similar to those observed in brain slice studies. Large-conductance inputs exhibiting synaptic depression preserved input synchrony as short as 12.5 ms interclick intervals, while maintaining low firing rates and low-pass filtering responses. By contrast, small-conductance inputs with Mixed plasticity (depression of AMPA-receptor component and facilitation of NMDA-receptor component) desynchronized afferent inputs, generated a click-rate dependent increase in firing rate, and high-pass filtered the inputs. Synaptic inputs with facilitation often permitted band-pass synchrony along with band-pass rate tuning. These responses could be tuned by changes in membrane potential, strength of the NMDA component, and characteristics of synaptic plasticity. These results demonstrate how the same synchronized input spike trains from the inferior colliculus can be transformed into different representations of temporal modulation by divergent synaptic properties.

by Kun Zhao, Márton Karsai, Ginestra Bianconi

Human dynamical social networks encode information and are highly adaptive. To characterize the information encoded in the fast dynamics of social interactions, here we introduce the entropy of dynamical social networks. By analysing a large dataset of phone-call interactions we show evidence that the dynamical social network has an entropy that depends on the time of the day in a typical week-day. Moreover we show evidence for adaptability of human social behavior showing data on duration of phone-call interactions that significantly deviates from the statistics of duration of face-to-face interactions. This adaptability of behavior corresponds to a different information content of the dynamics of social human interactions. We quantify this information by the use of the entropy of dynamical networks on realistic models of social interactions.

by Ineke van Dis, Daan Kromhout, Jolanda M. A. Boer, Johanna M. Geleijnse, W. M. Monique Verschuren


A positive parental history of myocardial infarction (MI) is an independent risk factor for cardiovascular diseases (CVD). However, different definitions of parental history have been used. We evaluated the impact of parental gender and age of onset of MI on CVD incidence.


Baseline data were collected between 1993 and 1997 in 10 524 respondents aged 40–65 years. CVD events were obtained from the National Hospital Discharge Register and Statistics Netherlands. We used proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (CI) for CVD incidence and adjusted for lifestyle and biological risk factors.


At baseline, 36% had a parental history of MI. During 10-year follow-up, 914 CVD events occurred. The age and gender adjusted HR was 1.3 (95% CI 1.1–1.5) for those with a paternal MI, 1.5 (1.2–1.8) for those with a maternal MI and 1.6 (1.2–2.2) for those with both parents with an MI. With decreasing parental age of MI, HR increased from 1.2 (1.0–1.6) for age ≥70 years to 1.5 (1.2–1.8) for age


by Cristina Zanini, Stefania Bruno, Giorgia Mandili, Denisa Baci, Francesco Cerutti, Giovanna Cenacchi, Leo Izzi, Giovanni Camussi, Marco Forni


Regarding regenerative medicine for diabetes, accessible sources of Mesenchymal Stem Cells (MSCs) for induction of insular beta cell differentiation may be as important as mastering the differentiation process itself.

Methodology/Principal Findings

In the present work, stem cells from pancreatic islets (human islet-mesenchymal stem cells, HI-MSCs) and from human bone marrow (bone marrow mesenchymal stem cells, BM-MSCs) were cultured in custom-made serum-free medium, using suitable conditions in order to induce differentiation into Islet-like Cells (ILCs). HI-MSCs and BM-MSCs were positive for the MSC markers CD105, CD73, CD90, CD29. Following this induction, HI-MSC and BM-MSC formed evident islet-like structures in the culture flasks. To investigate functional modifications after induction to ILCs, ultrastructural analysis and immunofluorescence were performed. PDX1 (pancreatic duodenal homeobox gene-1), insulin, C peptide and Glut-2 were detected in HI-ILCs whereas BM-ILCs only expressed Glut-2 and insulin. Insulin was also detected in the culture medium following glucose stimulation, confirming an initial differentiation that resulted in glucose-sensitive endocrine secretion. In order to identify proteins that were modified following differentiation from basal MSC (HI-MSCs and BM-MSCs) to their HI-ILCs and BM-ILCs counterparts, proteomic analysis was performed. Three new proteins (APOA1, ATL2 and SODM) were present in both ILC types, while other detected proteins were verified to be unique to the single individual differentiated cells lines. Hierarchical analysis underscored the limited similarities between HI-MSCs and BM-MSCs after induction of differentiation, and the persistence of relevant differences related to cells of different origin.


Proteomic analysis highlighted differences in the MSCs according to site of origin, reflecting spontaneous differentiation and commitment. A more detailed understanding of protein assets may provide insights required to master the differentiation process of HI-MSCs to functional beta cells based only upon culture conditioning. These findings may open new strategies for the clinical use of BM-MSCs in diabetes.


by Yifang Fan, Yubo Fan, Zhiyu Li, Mushtaq Loan, Changsheng Lv, Zhang Bo

Bone modeling and remodeling is an optimization process where no agreement has been reached regarding a unified theory or model. We measured 384 pieces of bone in vivo by 64-slice CT and discovered that the bone's center of mass approximately superposes its centroid of shape. This phenomenon indicates that the optimization process of non-homogeneous materials such as bone follows the same law of superposition of center of mass and centroid of shape as that of homogeneous materials. Based upon this principle, an index revealing the relationship between the center of mass and centroid of shape of the compact bone is proposed. Another index revealing the relationship between tissue density and distribution radius is followed. Applying these indexes to evaluate the strength of bone, we have some new findings.

by Ping Yin, Danielle Bousquet-Moore, Suresh P. Annangudi, Bruce R. Southey, Richard E. Mains, Betty A. Eipper, Jonathan V. Sweedler

Amidated neuropeptides play essential roles throughout the nervous and endocrine systems. Mice lacking peptidylglycine α-amidating monooxygenase (PAM), the only enzyme capable of producing amidated peptides, are not viable. In the amidation reaction, the reactant (glycine-extended peptide) is converted into a reaction intermediate (hydroxyglycine-extended peptide) by the copper-dependent peptidylglycine-α-hydroxylating monooxygenase (PHM) domain of PAM. The hydroxyglycine-extended peptide is then converted into amidated product by the peptidyl-α-hydroxyglycine α-amidating lyase (PAL) domain of PAM. PHM and PAL are stitched together in vertebrates, but separated in some invertebrates such as Drosophila and Hydra. In addition to its luminal catalytic domains, PAM includes a cytosolic domain that can enter the nucleus following release from the membrane by γ-secretase. In this work, several glycine- and hydroxyglycine-extended peptides as well as amidated peptides were qualitatively and quantitatively assessed from pituitaries of wild-type mice and mice with a single copy of the Pam gene (PAM+/−) via liquid chromatography-mass spectrometry-based methods. We provide the first evidence for the presence of a peptidyl-α-hydroxyglycine in vivo, indicating that the reaction intermediate becomes free and is not handed directly from PHM to PAL in vertebrates. Wild-type mice fed a copper deficient diet and PAM+/− mice exhibit similar behavioral deficits. While glycine-extended reaction intermediates accumulated in the PAM+/− mice and reflected dietary copper availability, amidated products were far more prevalent under the conditions examined, suggesting that the behavioral deficits observed do not simply reflect a lack of amidated peptides.

by Wenyan Lu, Cuihong Lin, Michael J. Roberts, William R. Waud, Gary A. Piazza, Yonghe Li

The Wnt/β-catenin signaling pathway is important for tumor initiation and progression. The low density lipoprotein receptor-related protein-6 (LRP6) is an essential Wnt co-receptor for Wnt/β-catenin signaling and represents a promising anticancer target. Recently, the antihelminthic drug, niclosamide was found to inhibit Wnt/β-catenin signaling, although the mechanism was not well defined. We found that niclosamide was able to suppress LRP6 expression and phosphorylation, block Wnt3A-induced β-catenin accumulation, and inhibit Wnt/β-catenin signaling in HEK293 cells. Furthermore, the inhibitory effects of niclosamide on LRP6 expression/phosphorylation and Wnt/β-catenin signaling were conformed in human prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. Moreover, we showed that the mechanism by which niclosamide suppressed LRP6 resulted from increased degradation as evident by a shorter half-life. Finally, we demonstrated that niclosamide was able to induce cancer cell apoptosis, and displayed excellent anticancer activity with IC50 values less than 1 µM for prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. The IC50 values are comparable to those shown to suppress the activities of Wnt/β-catenin signaling in prostate and breast cancer cells. Our data indicate that niclosamide is a unique small molecule Wnt/β-catenin signaling inhibitor targeting the Wnt co-receptor LRP6 on the cell surface, and that niclosamide has a potential to be developed a novel chemopreventive or therapeutic agent for human prostate and breast cancer.

by AnnSofi Sandberg, C. Magnus Sköld, Johan Grunewald, Anders Eklund, Åsa M. Wheelock


Cigarette smoke causes both acute and chronic changes of the immune system. Excluding recent smoking is therefore important in clinical studies with chronic inflammation as primary focus. In this context, it is common to ask the study subjects to refrain from smoking within a certain time frame prior to sampling. The duration of the smoking cessation is typically from midnight the evening before, i.e. 8 hours from sampling. As it has been shown that a proportion of current smokers underestimates or denies smoking, objective assessment of recent smoking status is of great importance. Our aim was to extend the use of exhaled carbon monoxide (CObreath), a well-established method for separating smokers from non-smokers, to assessment of recent smoking status.

Methods and Findings

The time course of CObreath decline was investigated by hourly measurements during one day on non-symptomatic smokers and non-smokers (6+7), as well as by measurements on three separate occasions on non-smokers (n = 29), smokers with normal lung function (n = 38) and smokers with chronic obstructive pulmonary disease (n = 19) participating in a clinical study. We used regression analysis to model the decay, and receiver operator characteristics analysis for evaluation of model performance. The decline was described as a mono-exponential decay (r2 = 0.7) with a half-life of 4.5 hours. CO decline rate depends on initial CO levels, and by necessity a generic cut-off is therefore crude as initial CObreath varies a lot between individuals. However, a cut-off level of 12 ppm could classify recent smokers from smokers having refrained from smoking during the past 8 hours with a specificity of 94% and a sensitivity of 90%.


We hereby describe a method for classifying recent smokers from smokers having refrained from smoking for >8 hours that is easy to implement in a clinical setting.


by Tim Horstkotte, Jon Moen, Tomas Lämås, Timo Helle

In northern Sweden, the availability of arboreal lichens (Bryoria fuscescens, Alectoria sarmentosa) as winter grazing resources is an important element in reindeer husbandry. With the industrialization of forestry, forests rich in arboreal lichens have diminished considerably. Here, we analyze how forestry has impacted lichen availability from the 1920's to the present day and model its future development assuming different forest management scenarios. We recorded the current occurrence of B. fuscescens in 144 sampling plots, stratified by forest age class and dominant tree species in a 26,600 ha boreal forest landscape that is used for both reindeer herding and forestry. Lichen abundance was visually estimated in four classes: none, sparse, moderate and abundant. A binary logistic model using forest age as the independent variable was developed to predict the probability of lichens being present. Using this model, we found that lichens were present in stands that are at least 63 years old. Because of the relative paucity of stands rich in arboreal lichens, it was not possible to reliably determine how age affects the variation in abundance of older forest stands. The historical development of forests where arboreal lichens could potentially occur was studied using historic forestry records dating back 80 years. Between 1926 and the present day, forestry has reduced the cover of forests older than 60 years from 84% to 34%. The likely future spatial coverage of these stands over the next 120 years was estimated for two different management scenarios and an unmanaged reference scenario, using the Heureka strategic planning program. Under both the “business as usual” scenario and that involving more intensive forestry, continued decreases in lichen availability are projected. Our results emphasize the importance of alternative forestry practices, such as prolonged rotation periods, to increase the availability of arboreal lichens as a grazing resource for reindeer.

by Jana Schmitt, Andreas Keller, Nasenien Nourkami-Tutdibi, Sabrina Heisel, Nunja Habel, Petra Leidinger, Nicole Ludwig, Manfred Gessler, Norbert Graf, Frank Berthold, Hans-Peter Lenhof, Eckart Meese

Several studies report autoantibody signatures in cancer. The majority of these studies analyzed adult tumors and compared the seroreactivity pattern of tumor patients with the pattern in healthy controls. Here, we compared the autoimmune response in patients with neuroblastoma and patients with Wilms tumor representing two different childhood tumors. We were able to differentiate untreated neuroblastoma patients from untreated Wilms tumor patients with an accuracy of 86.8%, a sensitivity of 87.0% and a specificity of 86.7%. The separation of treated neuroblastoma patients from treated Wilms tumor patients' yielded comparable results with an accuracy of 83.8%. We furthermore identified the antigens that contribute most to the differentiation between both tumor types. The analysis of these antigens revealed that neuroblastoma was considerably more immunogenic than Wilms tumor. The reported antigens have not been found to be relevant for comparative analyses between other tumors and controls. In summary, neuroblastoma appears as a highly immunogenic tumor as demonstrated by the extended number of antigens that separate this tumor from Wilms tumor.

by Romana Limberger, Stephen A. Wickham

Linking local communities to a metacommunity can positively affect diversity by enabling immigration of dispersal-limited species and maintenance of sink populations. However, connectivity can also negatively affect diversity by allowing the spread of strong competitors or predators. In a microcosm experiment with five ciliate species as prey and a copepod as an efficient generalist predator, we analysed the effect of connectivity on prey species richness in metacommunities that were either unconnected, connected for the prey, or connected for both prey and predator. Presence and absence of predator dispersal was cross-classified with low and high connectivity. The effect of connectivity on local and regional richness strongly depended on whether corridors were open for the predator. Local richness was initially positively affected by connectivity through rescue of species from stochastic extinctions. With predator dispersal, however, this positive effect soon turned negative as the predator spread over the metacommunity. Regional richness was unaffected by connectivity when local communities were connected only for the prey, while predator dispersal resulted in a pronounced decrease of regional richness. The level of connectivity influenced the speed of richness decline, with regional species extinctions being delayed for one week in weakly connected metacommunities. While connectivity enabled rescue of prey species from stochastic extinctions, deterministic extinctions due to predation were not overcome through reimmigration from predator-free refuges. Prey reimmigrating into these sink habitats appeared to be directly converted into increased predator abundance. Connectivity thus had a positive effect on the predator, even when the predator was not dispersing itself. Our study illustrates that dispersal of a species with strong negative effects on other community members shapes the dispersal-diversity relationship. When connections enable the spread of a generalist predator, positive effects of connectivity on prey species richness are outweighed by regional extinctions through predation.

by Liangcai Lin, Weiguo Fang, Xinggang Liao, Fengqing Wang, Dongzhi Wei, Raymond J. St. Leger

Fungal pathogens of plants and insects infect their hosts by direct penetration of the cuticle. Plant and insect cuticles are covered by a hydrocarbon-rich waxy outer layer that represents the first barrier against infection. However, the fungal genes that underlie insect waxy layer degradation have received little attention. Here we characterize the single cytochrome P450 monoxygenase family 52 (MrCYP52) gene of the insect pathogen Metarhizium robertsii, and demonstrate that it encodes an enzyme required for efficient utilization of host hydrocarbons. Expressing a green florescent protein gene under control of the MrCYP52 promoter confirmed that MrCYP52 is up regulated on insect cuticle as well as by artificial media containing decane (C10), extracted cuticle hydrocarbons, and to a lesser extent long chain alkanes. Disrupting MrCYP52 resulted in reduced growth on epicuticular hydrocarbons and delayed developmental processes on insect cuticle, including germination and production of appressoria (infection structures). Extraction of alkanes from cuticle prevented induction of MrCYP52 and reduced growth. Insect bioassays against caterpillars (Galleria mellonella) confirmed that disruption of MrCYP52 significantly reduces virulence. However, MrCYP52 was dispensable for normal germination and appressorial formation in vitro when the fungus was supplied with nitrogenous nutrients. We conclude therefore that MrCYP52 mediates degradation of epicuticular hydrocarbons and these are an important nutrient source, but not a source of chemical signals that trigger infection processes.

by Chuanyin Dai, Na Zhao, Wenjuan Wang, Congtian Lin, Bin Gao, Xiaojun Yang, Zhengwang Zhang, Fumin Lei

Although a number of studies have assessed the effects of geological and climatic changes on species distributions in East Asian, we still have limited knowledge of how these changes have impacted avian species in south-western and southern China. Here, we aim to study paleo-climatic effects on an East Asian bird, two subspecies of black-throated tit (A. c. talifuensis–concinnus) with the combined analysis of phylogeography and Ecological Niche Models (ENMs). We sequenced three mitochondrial DNA markers from 32 populations (203 individuals) and used phylogenetic inferences to reconstruct the intra-specific relationships among haplotypes. Population genetic analyses were undertaken to gain insight into the demographic history of these populations. We used ENMs to predict the distribution of target species during three periods; last inter-glacial (LIG), last glacial maximum (LGM) and present. We found three highly supported, monophyletic MtDNA lineages and different historical demography among lineages in A. c. talifuensis–concinnus. These lineages formed a narrowly circumscribed intra-specific contact zone. The estimated times of lineage divergences were about 2.4 Ma and 0.32 Ma respectively. ENMs predictions were similar between present and LGM but substantially reduced during LIG. ENMs reconstructions and molecular dating suggest that Pleistocene climate changes had triggered and shaped the genetic structure of black-throated tit. Interestingly, in contrast to profound impacts of other glacial cycles, ENMs and phylogeographic analysis suggest that LGM had limited effect on these two subspecies. ENMs also suggest that Pleistocene climatic oscillations enabled the formation of the contact zone and thus support the refuge theory.

by Dong-Seol Lee, Won-Joon Yoon, Eui Sic Cho, Heung-Joong Kim, Richard M. Gronostajski, Moon-Il Cho, Joo-Cheol Park

Transforming growth factor-β1 (TGF-β1) signaling plays a key role in vertebrate development, homeostasis, and disease. Nuclear factor I-C (NFI-C) has been implicated in TGF-β1 signaling, extracellular matrix gene transcription, and tooth root development. However, the functional relationship between NFI-C and TGF-β1 signaling remains uncharacterized. The purpose of this study was to identify the molecular interactions between NFI-C and TGF-β1 signaling in mouse odontoblasts. Real-time polymerase chain reaction and western analysis demonstrated that NFI-C expression levels were inversely proportional to levels of TGF-β1 signaling molecules during in vitro odontoblast differentiation. Western blot and immunofluorescence results showed that NFI-C was significantly degraded after TGF-β1 addition in odontoblasts, and the formation of the Smad3 complex was essential for NFI-C degradation. Additionally, ubiquitination assay results showed that Smurf1 and Smurf2 induced NFI-C degradation and polyubiquitination in a TGF-β1-dependent manner. Both kinase and in vitro binding assays revealed that the interaction between NFI-C and Smurf1/Smurf2 requires the activation of the mitogen-activated protein kinase pathway by TGF-β1. Moreover, degradation of NFI-C induced by TGF-β1 occurred generally in cell types other than odontoblasts in normal human breast epithelial cells. In contrast, NFI-C induced dephosphorylation of p-Smad2/3. These results show that crosstalk between NFI-C and TGF-β1 signaling regulates cell differentiation and homeostatic processes in odontoblasts, which might constitute a common cellular mechanism.

by Ioannis Mitroulis, Konstantinos Kambas, Akrivi Chrysanthopoulou, Panagiotis Skendros, Eirini Apostolidou, Ioannis Kourtzelis, Georgios I. Drosos, Dimitrios T. Boumpas, Konstantinos Ritis


Gout is a prevalent inflammatory arthritis affecting 1–2% of adults characterized by activation of innate immune cells by monosodium urate (MSU) crystals resulting in the secretion of interleukin-1β (IL-1β). Since neutrophils play a major role in gout we sought to determine whether their activation may involve the formation of proinflammatory neutrophil extracellular traps (NETs) in relation to autophagy and IL-1β.

Methodology/Principal Findings

Synovial fluid neutrophils from six patients with gout crisis and peripheral blood neutrophils from six patients with acute gout and six control subjects were isolated. MSU crystals, as well as synovial fluid or serum obtained from patients with acute gout, were used for the treatment of control neutrophils. NET formation was assessed using immunofluorescence microscopy. MSU crystals or synovial fluid or serum from patients induced NET formation in control neutrophils. Importantly, NET production was observed in neutrophils isolated from synovial fluid or peripheral blood from patients with acute gout. NETs contained the alarmin high mobility group box 1 (HMGB1) supporting their pro-inflammatory potential. Inhibition of phosphatidylinositol 3-kinase signaling or phagolysosomal fusion prevented NET formation, implicating autophagy in this process. NET formation was driven at least in part by IL-1β as demonstrated by experiments involving IL-1β and its inhibitor anakinra.


These findings document for the first time that activation of neutrophils in gout is associated with the formation of proinflammatory NETs and links this process to both autophagy and IL-1β. Modulation of the autophagic machinery may represent an additional therapeutic study in crystalline arthritides.


by Robyn A. Tamboli, Tahar Hajri, Aixiang Jiang, Pamela A. Marks-Shulman, D. Brandon Williams, Ronald H. Clements, Willie Melvin, Benjamin P. Bowen, Yu Shyr, Naji N. Abumrad, Charles Robb Flynn


To examine the effects of Roux-en-Y gastric bypass (RYGB) surgery with and without laparoscopic removal of omental fat (omentectomy) on the temporal gene expression profiles of skeletal muscle.


Previously reported were the whole-body metabolic effects of a randomized, single-blinded study in patients receiving RYGB surgery stratified to receive or not receive omentectomy. In this follow up study we report on changes in skeletal muscle gene expression in a subset of 21 patients, for whom biopsies were collected preoperatively and at either 6 months or 12 months postoperatively.

Methodology/Principal Findings

RNA isolated from skeletal muscle biopsies of 21 subjects (8 without omentectomy and 13 with omentectomy) taken before RYGB or at 6 and 12 months postoperatively were subjected to gene expression profiling via Exon 1.0 S/T Array and Taqman Low Density Array. Robust Multichip Analysis and gene enrichment data analysis revealed 84 genes with at least a 4-fold expression difference after surgery. At 6 and 12 months the RYGB with omentectomy group displayed a greater reduction in the expression of genes associated with skeletal muscle inflammation (ANKRD1, CDR1, CH25H, CXCL2, CX3CR1, IL8, LBP, NFIL3, SELE, SOCS3, TNFAIP3, and ZFP36) relative to the RYGB non-omentectomy group. Expressions of IL6 and CCL2 were decreased at all postoperative time points. There was differential expression of genes driving protein turnover (IGFN1, FBXW10) in both groups over time and increased expression of PAAF1 in the non-omentectomy group at 12 months. Evidence for the activation of skeletal muscle satellite cells was inferred from the up-regulation of HOXC10. The elevated post-operative expression of 22 small nucleolar RNAs and the decreased expression of the transcription factors JUNB, FOS, FOSB, ATF3 MYC, EGR1 as well as the orphan nuclear receptors NR4A1, NR4A2, NR4A3 suggest dramatic reorganizations at both the cellular and genetic levels.


These data indicate that RYGB reduces skeletal muscle inflammation, and removal of omental fat further amplifies this response.

Trial Registration NCT00212160


by Mario Orsi, Jonathan W. Essex

A new coarse-grain model for molecular dynamics simulation of lipid membranes is presented. Following a simple and conventional approach, lipid molecules are modeled by spherical sites, each representing a group of several atoms. In contrast to common coarse-grain methods, two original (interdependent) features are here adopted. First, the main electrostatics are modeled explicitly by charges and dipoles, which interact realistically through a relative dielectric constant of unity (). Second, water molecules are represented individually through a new parametrization of the simple Stockmayer potential for polar fluids; each water molecule is therefore described by a single spherical site embedded with a point dipole. The force field is shown to accurately reproduce the main physical properties of single-species phospholipid bilayers comprising dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylethanolamine (DOPE) in the liquid crystal phase, as well as distearoylphosphatidylcholine (DSPC) in the liquid crystal and gel phases. Insights are presented into fundamental properties and phenomena that can be difficult or impossible to study with alternative computational or experimental methods. For example, we investigate the internal pressure distribution, dipole potential, lipid diffusion, and spontaneous self-assembly. Simulations lasting up to 1.5 microseconds were conducted for systems of different sizes (128, 512 and 1058 lipids); this also allowed us to identify size-dependent artifacts that are expected to affect membrane simulations in general. Future extensions and applications are discussed, particularly in relation to the methodology's inherent multiscale capabilities.

by Xiaotao Jiang, Mingxia Zhang, Qintao Lai, Xuan Huang, Yongyin Li, Jian Sun, William G.H. Abbott, Shiwu Ma, Jinlin Hou

Invariant NKT (iNKT) cells are involved in the pathogenesis of various infectious diseases. However, their role in hepatitis B virus (HBV) infection is not fully understood, especially in human species. In this study, 35 chronic hepatitis B (CHB) patients, 25 inactive carriers (IC) and 36 healthy controls (HC) were enrolled and the proportions of circulating iNKT cells in fresh isolated peripheral blood mononuclear cells (PBMC) were detected by flow cytometry. A longitudinal analysis was also conducted in 19 CHB patients who received antiviral therapy with telbivudine. Thereafter, the immune functions of iNKT cells were evaluated by cytokine secretion and a two-chamber technique. The median frequency of circulating iNKT cells in CHB patients (0.13%) was lower than that in HC (0.24%, P = 0.01) and IC (0.19%, P = 0.02), and increased significantly during antiviral therapy with telbivudine (P = 0.0176). The expressions of CC chemokine receptor 5 (CCR5) and CCR6 were dramatically higher on iNKT cells (82.83%±9.87%, 67.67%±16.83% respectively) than on conventional T cells (30.5%±5.65%, 14.02%±5.92%, both P

by Kurt Showmaker, Gary W. Lawrence, Shien Lu, Clarissa Balbalian, Vincent P. Klink

A quantitative PCR procedure targeting the β-tubulin gene determined the number of Rotylenchulus reniformis Linford & Oliveira 1940 in metagenomic DNA samples isolated from soil. Of note, this outcome was in the presence of other soil-dwelling plant parasitic nematodes including its sister genus Helicotylenchus Steiner, 1945. The methodology provides a framework for molecular diagnostics of nematodes from metagenomic DNA isolated directly from soil.

by Simone C. Cardoso, Mariana P. Stelling, Bruna S. Paulsen, Stevens K. Rehen

The mechanisms underlying pluripotency and differentiation in embryonic and reprogrammed stem cells are unclear. In this work, we characterized the pluripotent state towards neural differentiated state through analysis of trace elements distribution using the Synchrotron Radiation X-ray Fluorescence Spectroscopy. Naive and neural-stimulated embryoid bodies (EB) derived from embryonic and induced pluripotent stem (ES and iPS) cells were irradiated with a spatial resolution of 20 µm to make elemental maps and qualitative chemical analyses. Results show that these embryo-like aggregates exhibit self-organization at the atomic level. Metallic elements content rises and consistent elemental polarization pattern of P and S in both mouse and human pluripotent stem cells were observed, indicating that neural differentiation and elemental polarization are strongly correlated.

by Marjan Askari, Peter C. Wierenga, Saied Eslami, Stephanie Medlock, Sophia E. de Rooij, Ameen Abu-Hanna


Care of the elderly is recognized as an increasingly important segment of health care. The Assessing Care Of Vulnerable Elderly (ACOVE) quality indicators (QIs) were developed to assess and improve the care of elderly patients.


The purpose of this review is to summarize studies that assess the quality of care using QIs from or based on ACOVE, in order to evaluate the state of quality of care for the reported conditions.


We systematically searched MEDLINE, EMBASE and CINAHL for English-language studies indexed by February 2010. Articles were included if they used any ACOVE QIs, or adaptations thereof, for assessing the quality of care. Included studies were analyzed and relevant information was extracted. We summarized the results of these studies, and when possible generated an overall conclusion about the quality of care as measured by ACOVE for each condition, in various settings, and for each QI.


Seventeen studies were included with 278 QIs (original, adapted or newly developed). The quality scores showed large variation between and within conditions. Only a few conditions showed a stable pass rate range over multiple studies. Overall, pass rates for dementia (interquartile range (IQR): 11%–35%), depression (IQR: 27%–41%), osteoporosis (IQR: 34%–43%) and osteoarthritis (IQR: 29–41%) were notably low. Medication management and use (range: 81%–90%), hearing loss (77%–79%) and continuity of care (76%–80%) scored higher than other conditions. Out of the 278 QIs, 141 (50%) had mean pass rates below 50% and 121 QIs (44%) had pass rates above 50%. Twenty-three percent of the QIs scored above 75%, and 16% scored below 25%.


Quality of care per condition varies markedly across studies. Although there has been much effort in improving the care for elderly patients in the last years, the reported quality of care according to the ACOVE indicators is still relatively low.


by Malin Stoltz, Karin B. Sundström, Åsa Hidmark, Conny Tolf, Sirkka Vene, Clas Ahlm, A. Michael Lindberg, Åke Lundkvist, Jonas Klingström

The bank vole (Myodes glareolus) is a common small mammal in Europe and a natural host for several important emerging zoonotic viruses, e.g. Puumala hantavirus (PUUV) that causes hemorrhagic fever with renal syndrome (HFRS). Hantaviruses are known to interfere with several signaling pathways in infected human cells, and HFRS is considered an immune-mediated disease. There is no in vitro-model available for infectious experiments in bank vole cells, nor tools for analyses of bank vole immune activation and responses. Consequently, it is not known if there are any differences in the regulation of virus induced responses in humans compared to natural hosts during infection. We here present an in vitro-model for studies of bank vole borne viruses and their interactions with natural host cell innate immune responses. Bank vole embryonic fibroblasts (VEFs) were isolated and shown to be susceptible for PUUV-infection, including a wild-type PUUV strain (only passaged in bank voles). The significance of VEFs as a model system for bank vole associated viruses was further established by infection studies showing that these cells are also susceptible to tick borne encephalitis, cowpox and Ljungan virus. The genes encoding bank vole IFN-β and Mx2 were partially sequenced and protocols for semi-quantitative RT-PCR were developed. Interestingly, PUUV did not induce an increased IFN-β or Mx2 mRNA expression. Corresponding infections with CPXV and LV induced IFN-β but not Mx2, while TBEV induced both IFN-β and Mx2. In conclusion, VEFs together with protocols developed for detection of bank vole innate immune activation provide valuable tools for future studies of how PUUV and other zoonotic viruses affect cells derived from bank voles compared to human cells. Notably, wild-type PUUV which has been difficult to cultivate in vitro readily infected VEFs, suggesting that embryonic fibroblasts from natural hosts might be valuable for isolation of wild-type hantaviruses.

by Fuminori Ono, Shigeru Kitazawa

Our previous research demonstrated that repetitive tone stimulation shortened the perceived duration of the preceding auditory time interval. In this study, we examined whether repetitive visual stimulation influences the perception of preceding visual time intervals. Results showed that a time interval followed by a high-frequency visual flicker was perceived as shorter than that followed by a low-frequency visual flicker. The perceived duration decreased as the frequency of the visual flicker increased. The visual flicker presented in one hemifield shortened the apparent time interval in the other hemifield. A final experiment showed that repetitive tone stimulation also shortened the perceived duration of preceding visual time intervals. We concluded that visual flicker shortened the perceived duration of preceding visual time intervals in the same way as repetitive auditory stimulation shortened the subjective duration of preceding tones.

by Yong-Guang Zhang, Jing-Hui Huang, Xue-Yu Hu, Qing-Song Sheng, Wei Zhao, Zhuo-Jing Luo


Tissue-engineered nerve scaffolds hold great potential in bridging large peripheral nerve defects. However, insufficient vascularization of nerve scaffolds limited neural tissues survival and regeneration, which hampered the successful implantation and clinical application of nerve scaffolds. The omentum possesses a high vascularization capacity and enhances regeneration and maturation of tissues and constructs to which it is applied. However, combined application of nerve scaffolds and omentum on axonal regeneration and functional recovery in the treatment of large peripheral nerve defects has rarely been investigated thus far.


In the present study, an omentum-wrapped collagen-chitosan scaffold was used to bridge a 15-mm-long sciatic nerve defect in rats. Rats that received nerve autografts or scaffolds alone were served as positive control or negative control, respectively. The axonal regeneration and functional recovery were examined by a combination of walking track analysis, electrophysiological assessment, Fluoro-Gold (FG) retrograde tracing, as well as morphometric analyses to both regenerated nerves and target muscles.


The results demonstrated that axonal regeneration and functional recovery were in the similar range between the omentum-wrapping group and the autograft group, which were significantly better than those in the scaffold alone group. Further investigation showed that the protein levels of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were significantly higher in the omentum-wrapping group than those in the scaffold alone group in the early weeks after surgery.


These findings indicate that the omentum-wrapped scaffold is capable of enhancing axonal regeneration and functional recovery, which might be served as a potent alternative to nerve autografts. The beneficial effect of omentum-wrapping on nerve regeneration might be related with the proteins produced by omentum.

The New York Times
To keep you warm this winter, Martha Rose Shulman, the Recipes for Health columnist, suggests blending up creamy homemade soup.
The Wall Street Journal
Pharmasset discontinued use of an experimental hepatitis C drug in a clinical trial because of safety concerns, but said the setback wouldn't derail its planned sale to Gilead Sciences for nearly $11 billion.
The New York Times
A nurse takes on a neglected caregiving task.
The Obama administration has proposed regulations that would provide the nation's two million home care workers with minimum wage and overtime protections.
National Institutes of Health (NIH)
Funding Opportunity RFA-AI-12-017 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) issued by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), invites research applications for projects that support preclinical development of lead candidate therapeutics or diagnostics against NIAID Category A, B, or C priority agents. Applications must include a Product Development Strategy attachment and demonstrate substantive investment by at least one industrial participant.
Funding Opportunity PAR-12-063 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to support dissemination and implementation studies to 1) develop innovative approaches to translating efficacious treatments and effective prevention modalities for heart, lung, and blood diseases and sleep disorders to the clinic, community, and/or other real-world settings; 2) test the effectiveness, sustainability, determinants, and cost-effectiveness of these approaches in real-world settings; and 3) examine the effectiveness of interventions as they are disseminated and implemented in real-world settings to reduce risk factors for and enhance prevention and treatment of heart, lung, and blood diseases and sleep disorders.
Notice NOT-AA-11-010 from the NIH Guide for Grants and Contracts
Funding Opportunity PAR-12-062 from the NIH Guide for Grants and Contracts. The purpose of the National Cancer Institute (NCI) Career Transition Award (K22) is to help ensure that a diverse pool of highly trained scientists are available in adequate numbers and in appropriate research areas to address the nation's biomedical, behavioral, and clinical research needs. The Diversity Training Branch (DTB), the Center to Reduce Cancer Health Disparities (CRCHD) ( invites applications from recipients of the NCI Mentored Career Development Award to Promote Diversity, or from advanced postdoctoral and/or newly independent research scientists representative of groups that are underrepresented in biomedical, behavioral, clinical, and/or social sciences (see Section III, Eligible Individuals). This award will provide "protected time" for recipients to develop and receive support for their initial cancer research program. In addition, this award can provide a two-year mentored experience in NCI intramural programs for interested individuals.
Funding Opportunity RFA-NS-12-009 from the NIH Guide for Grants and Contracts. The National Institute of Neurological Disorders and Stroke (NINDS) invites new and renewal applications for the Morris K. Udall Centers of Excellence for Parkinsons Disease Research program. The overarching goal of the specialized Udall Centers program is to establish a network of Centers that work independently as well as collaboratively to define the causes of and discover improved treatments for Parkinsons disease (PD). A more immediate goal for each Center is to rapidly advance synergistic basic, translational and clinical research programs while serving as local resources and national leaders in PD research.
Funding Opportunity RFA-TW-12-001 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) is intended to support paired consortium exploratory awards led by one Low and Middle Income Country (LMIC) institution and one U.S. institution to plan research, research training, and curriculum development activities that address and inform priority national and regional environmental and occupational health policy issues. The ultimate goal of the FOA is to foster the planning for multidisciplinary Global Environmental and Occupational Health Hubs (GEOHealth Hubs), based in LMICs, that will lead collaborative research and training for focal environmental and occupational health issues in several core science areas, including fields such as epidemiology, biostatistics, genetics, environmental science, industrial hygiene, systems science, toxicology, behavioral science, and implementation science. Focal environmental and occupational health areas, as well as core science areas, for each consortium will be selected by the applicants, building upon preexisting strengths within the proposed consortium and addressing priority public health needs in the region.
News Summaries from Science
Eager to replace the current tuberculosis vaccine, scientists hope to push a slew of promising candidates through clinical trials—if the money can be found.<br><br>Author: Kai Kupferschmidt
Enthusiasts hope that clinical trials of Ayurvedic medicines will buff the ancient art's tarnished reputation.<br><br>Author: Pallava Bagla
The director of the National Science Foundation has hit the ground running with a flurry of new programs aimed at leveraging precious federal dollars.<br><br>Author: Jeffrey Mervis
A new British proposal to make health data more available to scientists may run smack into the European Union, which is exploring revisions to its data-protection guidelines.<br><br>Author: Gretchen Vogel
A committee commissioned by the U.S. National Institutes of Health has recommended that NIH should continue funding biomedical and behavioral research with chimpanzees, but with new stipulations.<br><br>Author: Jon Cohen
The medical community is recognizing evolutionary medicine's potential for providing a holistic framework for their increasingly specialized field, but proponents say there is still a long way to go.<br><br>Author: Elizabeth Pennisi
China is contributing 3 billion yuan ($470 million) to the Human Variome Project, an international effort to catalog gene variations affecting human health.<br><br>Author: Mara HVistendahl
In the December issue of Arctic, a photographer and an arctic biologist note that there have now been three documented sightings of adult male polar bears on sea ice feeding on younger bear kills. The waxy buildup in a whale's ears may contain interesting data about its exposure to contaminants. And this week's numbers quantify worldwide malaria deaths in 2010, budget cuts at Cancer Research UK, and the amount paid at auction for James Lovell's Apollo 13 checklist.
This week's Newsmaker is David E. Wright, a science historian at Michigan State University, who will soon lead U.S. government efforts to guard against misdeeds in biomedical research.
This week, two teams of physicists reported tantalizing signs that the Higgs boson has been spotted. But one team sees additional oddities, so the results haven't bowled everyone over.<br><br>Author: Adrian Cho
Science Express
Lack of the transporter critical for recycling of nucleosides after phagocytosis results in a fatal expansion of macrophages.<br><br>Authors: Chia-Lin Hsu, Weiyu Lin, Dhaya Seshasayee, Yung-Hsiang Chen, Xiao Ding, Zhonghua Lin, Eric Suto, Zhiyu Huang, Wyne P. Lee, Hyunjoo Park, Min Xu, Mei Sun, Linda Rangell, Jeff L. Lutman, Sheila Ulufatu, Eric Stefanich, Cecile Chalouni, Meredith Sagolla, Lauri Diehl, Paul Fielder, Brian Dean, Mercedesz Balazs, Flavius Martin
The growing pole of the tuberculosis-causing bacterium is inherited by only one offspring, which can then elongate faster.<br><br>Authors: Bree B. Aldridge, Marta Fernandez-Suarez, Danielle Heller, Vijay Ambravaneswaran, Daniel Irimia, Mehmet Toner, Sarah M. Fortune
<br><br>Authors: Bruce M. Altevogt, Diana E. Pankevich, Andrew M. Pope, Jeffrey P. Kahn
News Summaries from Science
In science news around the world this week, FDA's decision on an emergency contraceptive has been overruled, controversial changes to forest law have been passed in the Brazilian Senate, climate negotiators have agreed to pursue a new treaty, Merck has committed $1.5 billion to build in Beijing, the Royal Society says courtroom neuroscience is not ready for prime time, and what will be the largest optical-infrared telescope ever built has taken a big step forward.
Science Express
Stochastic variation in a cellular stress response pathway can predict the outcome of mutations in individuals.<br><br>Authors: M. Olivia Casanueva, Alejandro Burga, Ben Lehner
Germinal center B cells undergo asymmetric cell division.<br><br>Authors: Burton E. Barnett, Maria L. Ciocca, Radhika Goenka, Lisa G. Barnett, Junmin Wu, Terri M. Laufer, Janis K. Burkhardt, Michael P. Cancro, Steven L. Reiner
Radiocarbon measurements of deep-sea corals reveal the presence of old, carbon-rich water in the Southern Ocean.<br><br>Authors: Andrea Burke, Laura F. Robinson
The New York Times
The National Institutes of Health suspended new grants for biomedical and behavioral research on chimpanzees.
The Obama administration proposed regulations on Thursday to give two million home care workers minimum wage and overtime protection.
The specter of nursing strikes is looming on both coasts, with more than 6,000 nurses poised to walk out of three prestigious hospitals in New York City.
As a candidate for president, Newt Gingrich is criticizing some of the same health care programs that he supported as a consultant.
Children’s Hospital and Research Center Oakland ranked lowest on a study of what 14 California hospitals sold in their cafes.
St. Jude Medical told doctors in November that the wires in its Riata defibrillator leads had a higher failure rate than was previously known.
Kevin W. Sharer, the chief executive, and Dr. Roger M. Perlmutter, the head of research, will step down in 2012. The company’s growth has slowed in recent years.
Eureka Alert!
(McLaughlin-Rotman Centre for Global Health) Grand Challenges Canada and the Bill and Melinda Gates Foundation have teamed up on an unprecedented global effort to discover and develop affordable, easy-to-use tools to help developing country health workers rapidly diagnose diseases in rural communities. The expected result: more timely and appropriate treatment of illnesses in poor countries, potentially saving countless lives.
(American Thoracic Society) Inhaled glucocorticoids for the treatment of asthma during pregnancy are not associated with an increased risk of most diseases in offspring, but may be a risk factor for endocrine and metabolic disturbances, according to a new study.
(American Thoracic Society) Adding inhaled dry powder mannitol to standard therapy for cystic fibrosis produced sustained improvement in lung function for up to 52 weeks, according to a new study. Along with the treatment's efficacy and good safety profile, the convenience and ease of administration of mannitol treatment may improve adherence with therapy in these patients.
(Science in China Press) The study of endophenotype is of particular useful for us to understand the underlying mechanism of the illness process of neuropsychiatric disorders, aiding the clinicians to make accurate diagnosis and for early detection purposes. In the special issue of Chinese Science Bulletin, 2011, Vol. 56(32), a forum is specifically aimed to address the cutting-edge research in endophenotype for neuropsychiatric disorders. It provides theoretical and clinical strategies for neuropsychiatric disorders research.
(Infectious Diseases Society of America) Among people recently infected with HIV, immediate antiretroviral therapy appears preferable to deferring treatment, according to a new study published in the Journal of Infectious Diseases and now available online. Although the benefits of ART during early HIV-1 infection remain unproven, the findings support growing evidence favoring earlier ART initiation.
(Helmholtz Association of German Research Centres) Scientists of the German Cancer Research Center have discovered a tiny RNA molecule, called miR-520, which at once blocks two important pathways in the development of cancer in cells. In estrogen receptor-negative breast cancer, the production of this microRNA is often reduced and this is correlated with malignant behavior of tumor cells. The DKFZ team has found out that tumors with low levels of miR-520 have a particularly strong tendency to metastasize.
(University of California - Irvine) While Road Rippers Lightning Rods, Let's Rock Elmo and the I Am T-Pain musical microphone might be sought-after gifts this holiday season, parents should ensure that their children don't risk permanent hearing damage by misusing them.
(Journal of the National Cancer Institute) Accelerated partial breast irradiation using brachytherapy for the treatment of breast cancer has been rapidly increasing over the last several years in the US as an alternative to standard whole-breast irradiation, according to a study published Dec. 16 in the Journal of the National Cancer Institute.
(Gladstone Institutes) The American Association for the Advancement of Science (AAAS) has named Gladstone Senior Investigator Deepak Srivastava, M.D., a fellow for his efforts to advance science and its applications.
(University at Buffalo) Will a drug used to treat childhood acute lymphoblastic leukemia and other pediatric cancers cause heart problems later in life? UB associate professor of pharmaceutical sciences, Javier G. Blanco, Ph.D., who sees his work as a bridge between research and clinical practice, has focused recent efforts on trying to answer this question.
(Georgia Health Sciences University) Scientists may have a way to double the efficacy and reduce the side effects of radiation therapy.
(University of Notre Dame) A team of researchers from the University of Notre Dame have demonstrated a novel DNA detection method that could prove suitable for many real-world applications.
(University of California - San Francisco) A large, international team of researchers led by scientists at the University of California, San Francisco has identified the gene that causes a rare childhood neurological disorder called PKD/IC, or "paroxysmal kinesigenic dyskinesia with infantile convulsions," a cause of epilepsy in babies and movement disorders in older children.
(Brown University) Engineers at Brown University have developed a system that cleanly and efficiently removes trace heavy metals from water. In experiments, the researchers showed the system reduced cadmium, copper, and nickel concentrations, returning contaminated water to near or below federally acceptable standards. The technique is scalable and has viable commercial applications, especially in the environmental remediation and metal recovery fields. Results appear in the Chemical Engineering Journal.
(Northwestern University) A Northwestern program that mentors urban minority high-school girls for college and careers in science and health received a mentoring award from President Obama. The program has expanded to other states.
(Oregon State University) In reaction to what midwives view as the overly medicalized way hospitals deliver babies, they have created birthing rituals to send the message that women's bodies know best.
(Boston University Medical Center) One in 13 teenage girls, aged 14 to 20, reported having a group-sex experience, with those young women more likely to have been exposed to pornography and childhood sexual abuse than their peers, according to a new study led by a Boston University School of Public Health researcher.
(American College of Radiology) The trial conducted by the Radiation Therapy Oncology Group (RTOG) shows the feasibility to deliver bevacizumab to the current chemoradiation standard without any apparent increased adverse side effects.
(University of Veterinary Medicine -- Vienna) It is well known that large mammals living in temperate climates lower their metabolism in winter. But does this represent a mechanism for coping with less food or is it merely a consequence of having less to eat? For the red deer, the puzzle has been solved by the group of Walter Arnold at the Research Institute of Wildlife Ecology, University of Veterinary Medicine, Vienna. The results are published in the Journal of Experimental Biology.
(Emory University) Emory University's Global Health Institute has received a three-year, $6 million grant from the Bill & Melinda Gates Foundation to further develop a model for strengthening national public health institutes (NPHIs) globally. The grant will build upon a previous foundation grant to the International Association of National Public Health Institutes (IANPHI), which since 2006 has created or increased capacity at NPHIs in 10 low-resource countries.
(Wyss Institute for Biologically Inspired Engineering at Harvard) Donald Ingber, M.D., Ph.D., founding director of Harvard's Wyss Institute, is awarded the 2011 Holst Medal in recognition of his pioneering work in mechanobiology and his groundbreaking development of bioinspired technologies, such as Organ-on-Chip microsystems that recapitulate human organ functions
(Vanderbilt University Medical Center) Statins, traditionally known as cholesterol-lowering drugs, may reduce mortality among patients hospitalized with influenza, according to a new study released online by the Journal of Infectious Diseases.
(Cold Spring Harbor Laboratory) Cancer researchers at Cold Spring Harbor Laboratory have carried out the first comprehensive study of the changes seen in the DNA of a patient with mast cell leukemia, an extremely aggressive subtype of acute myeloid leukemia with a very poor prognosis. Their genomic survey has helped identify two previously unknown mutations that could directly influence patient response to currently available therapeutic drugs.
The Wall Street Journal
Republican Rep. Ryan unveiled a new Medicare proposal giving seniors the choice of buying private insurance or staying in the federal plan.
The New York Times
The decline, though slight, offers hope that the tide may be turning on one of the nation’s most stubborn health issues.
La comunidad médica advierte de que la obesidad aumenta el riesgo de padecer enfermedades crónicas como la diabetes, las cardiopatías y ciertos tipos de cáncer. Además, debido a que la incidencia de la obesidad está aumentando tanto en Europa como en el resto del mundo, es importante poder realizar estimaciones precisas de la prevalencia que tendrá esta afección en un futuro. Dichas cifras pueden obtenerse mediante la recopilación y el análisis de datos extraídos de estudios longitudinales. Quality validation date: 2011-12-16
Un equipo de investigadores ha descubierto cómo funciona uno de los analgésicos más comunes en los hogares, gracias a lo cual pronto podría disponerse de analgésicos con menos efectos secundarios perjudiciales. En un artículo publicado en la revista Nature Communications, el equipo de científicos de Francia, Reino Unido y Suecia explicó cómo funciona realmente el paracetamol, uno de los fármacos más utilizados en el mundo. Aunque fue descubierto en la última década del siglo XIX y se lleva comercializando como analgésico de venta sin receta desde mediados del siglo XX, hasta ahora se desconocía el mecanismo por el que el paracetamol alivia el dolor. Quality validation date: 2011-12-16
Un equipo de científicos financiado por la Unión Europea ha descubierto que los lóbulos temporales humanos, que desempeñan un papel importante en el sentido del olfato, la memoria, el lenguaje y las funciones sociales, son relativamente mayores en el Homo sapiens de lo que eran en los neandertales. Los hallazgos, presentados en la revista Nature Communications, indican que el sistema olfativo del hombre moderno es mejor que el que tenían los neandertales. El estudio fue financiado parcialmente por el proyecto EVAN («Red virtual europea de antropología»), que recibió 3,3 millones de euros en forma de una subvención perteneciente a las Redes de formación mediante la investigación (RTN) Marie Curie del Sexto Programa Marco (6PM) de la Unión Europea. Quality validation date: 2011-12-16
Annals of Clinical Microbiology and Antimicrobials
Background: Training of infectious disease (ID) specialists is structured on classical clinical microbiology training in Turkey and ID specialists work as clinical microbiologists at the same time. Hence, this study aimed to determine the clinical skills and knowledge required by clinical microbiologists. Methods: A cross-sectional study was carried out between June 1, 2010 and September 15, 2010 in 32 ID departments in Turkey. Only patients hospitalized and followed up in the ID departments between January-June 2010 who required consultation with other disciplines were included. Results: A total of 605 patients undergoing 1343 consultations were included, with pulmonology, neurology, cardiology, gastroenterology, nephrology, dermatology, haematology, and endocrinology being the most frequent consultation specialties. The consultation patterns were quite similar and were not affected by either the nature of infections or the critical clinical status of ID patients. Conclusions: The results of our study show that certain internal medicine subdisciplines such as pulmonology, neurology and dermatology appear to be the principal clinical requisites in the training of ID specialists, rather than internal medicine as a whole.

Particle physics is at a turning point

Nature 480, 7378 (2011).

Author: Gordon Kane

The discovery of the Higgs boson will complete the standard model — but it could also point the way to a deeper understanding, says Gordon Kane.