bluuebunny/crossref_metadata_2025 huggingface dataset:
Lineage diversification and historical demography of a montane bird Garrulax elliotii - implications for the Pleistocene evolutionary history of the eastern Himalayas
Authors: Qu Yanhua , Luo Xu , Zhang Ruiying , Song Gang , Zou Fasheng , Lei Fumin
Published: June 2011

Background

Pleistocene climate fluctuations have shaped the patterns of genetic diversity observed in many extant species. In montane habitats, species' ranges may have expanded and contracted along an altitudinal gradient in response to environmental fluctuations leading to alternating periods of genetic isolation and connectivity. Because species' responses to climate change are influenced by interactions between species-specific characteristics and local topography, diversification pattern differs between species and locations. The eastern Himalayas is one of the world's most prominent mountain ranges. Its complex topography and environmental heterogeneity present an ideal system in which to study how climatic changes during Pleistocene have influenced species distributions, genetic diversification, and demography. The Elliot's laughing thrush (Garrulax elliotii) is largely restricted to high-elevation shrublands in eastern Himalayas. We used mitochondrial DNA and microsatellites to investigate how genetic diversity in this species was affected by Pleistocene glaciations.

Results

Mitochondrial data detected two partially sympatric north-eastern and southern lineages. Microsatellite data, however, identified three distinct lineages congruent with the geographically separated southern, northern and eastern eco-subregions of the eastern Himalayas. Geographic breaks occur in steep mountains and deep valleys of the Kangding-Muli-Baoxin Divide. Divergence time estimates and coalescent simulations indicate that lineage diversification occurred on two different geographic and temporal scales; recent divergence, associated with geographic isolation into individual subregions, and historical divergence, associated with displacement into multiple refugia. Despite long-term isolation, genetic admixture among these subregional populations was observed, indicating historic periods of connectivity. The demographic history of Garrulax elliotii shows continuous population growth since late Pleistocene (about 0.125 mya).

Conclusion

While altitude-associated isolation is typical of many species in other montane regions, our results suggest that eco-subregions in the eastern Himalayas exhibiting island-like characteristics appear to have determined the diversification of Garrulax elliotii. During the Pleistocene, these populations became isolated on subregions during interglacial periods but were connected when these expanded to low altitude during cooler periods. The resultant genetic admixture of lineages might obscure pattern of genetic variation. Our results provide new insights into sky island diversification in a previously unstudied region, and further demonstrate that Pleistocene climatic changes can have profound effects on lineage diversification and demography in montane species.
Comparative genome analysis and genome-guided physiological analysis of Roseobacter litoralis
Authors: Kalhoefer Daniela , Thole Sebastian , Voget Sonja , Lehmann Rüdiger , Liesegang Heiko , Wollher Antje , Daniel Rolf , Simon Meinhard , Brinkhoff Thorsten
Published: June 2011

Background

Roseobacter litoralis OCh149, the type species of the genus, and Roseobacter denitrificans OCh114 were the first described organisms of the Roseobacter clade, an ecologically important group of marine bacteria. Both species were isolated from seaweed and are able to perform aerobic anoxygenic photosynthesis.

Results

The genome of R. litoralis OCh149 contains one circular chromosome of 4,505,211 bp and three plasmids of 93,578 bp (pRLO149_94), 83,129 bp (pRLO149_83) and 63,532 bp (pRLO149_63). Of the 4537 genes predicted for R. litoralis, 1122 (24.7%) are not present in the genome of R. denitrificans. Many of the unique genes of R. litoralis are located in genomic islands and on plasmids. On pRLO149_83 several potential heavy metal resistance genes are encoded which are not present in the genome of R. denitrificans. The comparison of the heavy metal tolerance of the two organisms showed an increased zinc tolerance of R. litoralis. In contrast to R. denitrificans, the photosynthesis genes of R. litoralis are plasmid encoded. The activity of the photosynthetic apparatus was confirmed by respiration rate measurements, indicating a growth-phase dependent response to light. Comparative genomics with other members of the Roseobacter clade revealed several genomic regions that were only conserved in the two Roseobacter species. One of those regions encodes a variety of genes that might play a role in host association of the organisms. The catabolism of different carbon and nitrogen sources was predicted from the genome and combined with experimental data. In several cases, e.g. the degradation of some algal osmolytes and sugars, the genome-derived predictions of the metabolic pathways in R. litoralis differed from the phenotype.

Conclusions

The genomic differences between the two Roseobacter species are mainly due to lateral gene transfer and genomic rearrangements. Plasmid pRLO149_83 contains predominantly recently acquired genetic material whereas pRLO149_94 was probably translocated from the chromosome. Plasmid pRLO149_63 and one plasmid of R. denitrifcans (pTB2) seem to have a common ancestor and are important for cell envelope biosynthesis. Several new mechanisms of substrate degradation were indicated from the combination of experimental and genomic data. The photosynthetic activity of R. litoralis is probably regulated by nutrient availability.
Suprasellar cysts: clinical presentation, surgical indications, and optimal surgical treatment
Authors: Gui Song-Bai , Wang Xin-Sheng , Zong Xu-Yi , Zhang Ya-Zhuo , Li Chu-Zhong
Published: June 2011

Background

To describe the clinical presentation of suprasellar cysts (SSCs) and surgical indications, and compare the treatment methods of endoscopic ventriculocystostomy (VC) and ventriculocystocisternotomy (VCC).

Methods

We retrospectively reviewed the records of 73 consecutive patients with SSC who were treated between June 2002 and September 2009. Twenty-two patients were treated with VC and 51 with VCC. Outcome was assessed by clinical examination and magnetic resonance imaging.

Results

The patients were divided into five groups based on age at presentation: age less than 1 year (n = 6), 1-5 years (n = 36), 6-10 years (n = 15), 11-20 years (n = 11), and 21-53 years (n = 5). The main clinical presentations were macrocrania (100%), motor deficits (50%), and gaze disturbance (33.3%) in the age less than 1 year group; macrocrania (75%), motor deficits (63.9%), and gaze disturbance (27.8%) in the 1-5 years group; macrocrania (46.7%), symptoms of raised intracranial pressure (ICP) (40.0%), endocrine dysfunction (40%), and seizures (33.3%) in the 6-10 years group; symptoms of raised ICP (54.5%), endocrine dysfunction (54.5%), and reduced visual field or acuity (36.4%) in the 11-20 years group; and symptoms of raised ICP (80.0%) and reduced visual field or acuity (40.0%) in the 21-53 years group. The overall success rate of endoscopic fenestration was 90.4%. A Kaplan-Meier curve for long-term efficacy of the two treatment modalities showed better results for VCC than for VC (p = 0.008).

Conclusions

Different age groups with SSCs have different main clinical presentations. VCC appears to be more efficacious than VC.
Platelet factor-4 and its p17-70 peptide inhibit myeloma proliferation and angiogenesis in vivo
Authors: Yang Longjiang , Du Juan , Hou Jian , Jiang Hua , Zou Jianfeng
Published: June 2011

Background

Angiogenesis plays an important role in the development of multiple myeloma (MM). The interaction between MM cells and the bone marrow microenvironment stimulates the proliferation and migration of endothelial progenitor cells (EPCs). Vascular endothelial growth factor (VEGF) contributes to the formation of new blood vessels by actively recruiting circulating EPCs. The production of proangiogenic and antiangiogenic factors is also dysregulated in MM. Platelet factor 4 (PF4) is a potent angiostatic cytokine that inhibits angiogenesis and tumor growth in several animal models.

Methods

In this study, we stably transfected human myeloma cell lines with the PF4 gene or the sequence encoding its more potent p17-70 peptide and investigated the effects of PF4 and p17-70 on angiogenesis and tumor growth in vitro and in a SCID-rab myeloma model.

Results

PF4 and p17-70 significantly attenuated VEGF production, both in vitro and in vivo. In a migration study using a Transwell system, PF4 or p17-70 markedly suppressed the migration of co-cultured human endothelial progenitor cells. PF4 or p17-70 also caused a significant reduction in microvessel densities in myeloma xenografts and markedly reduced the tumor volume in the SCID mice. Kaplan-Meier analysis demonstrated that PF4 and p17-70 significantly extended the overall survival of SCID mice bearing human myeloma xenografts.

Conclusions

Our findings indicate that PF4 or p17-70 could be valuable in combating multiple myeloma by disrupting tumor angiogenesis.
Synthetic fiber from a teddy bear causing keratitis and conjunctival granuloma: case report
Authors: Farooq Mohammed K , Prause Jan U , Heegaard Steffen
Published: June 2011

Background

To report a case of keratitis and a case of conjunctivitis caused by synthetic fibers from toy teddy bears.

Case presentation

Case stories with histopathological analysis. 1) A two-year-old girl developed a severe case of keratitis and corneal ulceration. The initial treatment with various antibiotics gave no improvement and eventually the patient developed spontaneous perforation of the cornea. The corneal swabs contained no bacteria or fungi. Corneal grafting was performed and the corneal button was sent for histopathological examination. 2) A five-year-old girl presented with ocular irritation in her left eye. Examination revealed a conjunctival granuloma in the inferior fornix. The lesion was excised and histopathologically examined.

Results

Microscopy revealed synthetic fibers embedded in the cornea and in the conjunctival granuloma. The diagnosis was confirmed by demonstration of marked birefringence of the synthetic fibers. Microscopical examination of synthetic fibers from two different types of fur (whiskers and face hairs) from the two-year-old girl's teddy bear was performed. Hairs from the face of the teddy bear were morphologically and microscopically identical with the fibers causing the severe corneal ulceration in the two-year-old girl.

Conclusions

Doctors should especially in small children be aware of the risk of ocular consequences of close exposure of synthetic fibers from stuffed toy animals. Corneal ulceration, clinically presenting as corneal infection with negative culturing and staining, should lead to a different clinical strategy and treatment. The treatment of conjunctival synthetic fiber granuloma is excision and antibiotic eye drops.
Alcohol and fatal life trajectories in Russia: understanding narrative accounts of premature male death in the family
Authors: Saburova Lyudmila , Keenan Katherine , Bobrova Natalia , Leon David A , Elbourne Diana
Published: June 2011

Background

In the post-Soviet period, Russian working-age men have suffered unusually high mortality rates. Earlier quantitative work found that part of this is attributable to hazardous and harmful patterns of alcohol consumption, which increased in the period of transition at a time of massive social and economic disruption and uncertainty. However, there has been very little work done to document and understand in detail the downward life trajectories of individual men who died prematurely from alcohol-related conditions. Building on an earlier case-control study, this unique qualitative study investigates the perceived interplay between men's drinking careers, their employment and family history, health and eventual death.

Methods

In-depth interviews were conducted with close relatives (most often the widow) of 19 men who died between 2003 and 2005 aged 25-54 years whose close relatives reported that alcohol contributed to their death. The study was conducted in a typical medium-sized Russian city. The relative's accounts were analysed using thematic content analysis.

Results

The accounts describe how hazardous drinking both contributed to serious employment, family and health problems, and was simultaneously used as a coping mechanism to deal with life crises and a decline in social status. The interviews highlighted the importance of the workplace and employment status for shaping men's drinking patterns. Common themes emerged around a culture of drinking in the workplace, peer pressure from colleagues to drink, use of alcohol as remuneration, consuming non-beverage alcohols, Russian-specific drinking patterns, attitudes to treatment, and passive attitudes towards health and drinking.

Conclusions

The study provides a unique insight into the personal decline that lies behind the extremely high working-age mortality due to heavy drinking in Russia, and highlights how health status and hazardous drinking are often closely intertwined with economic and social functioning. Descriptions of the development of drinking careers, hazardous drinking patterns and treatment experiences can be used to plan effective interventions relevant in the Russian context.
A simple clinical model for planning transfusion quantities in heart surgery
Authors: Simeone Felicetta , Franchi Federico , Cevenini Gabriele , Marullo Antonino , Fossombroni Vittorio , Scolletta Sabino , Biagioli Bonizella , Giomarelli Pierpaolo , Barbini Paolo
Published: June 2011

Background

Patients undergoing heart surgery continue to be the largest demand on blood transfusions. The need for transfusion is based on the risk of complications due to poor cell oxygenation, however large transfusions are associated with increased morbidity and risk of mortality in heart surgery patients. The aim of this study was to identify preoperative and intraoperative risk factors for transfusion and create a reliable model for planning transfusion quantities in heart surgery procedures.

Methods

We performed an observational study on 3315 consecutive patients who underwent cardiac surgery between January 2000 and December 2007. To estimate the number of packs of red blood cells (PRBC) transfused during heart surgery, we developed a multivariate regression model with discrete coefficients by selecting dummy variables as regressors in a stepwise manner. Model performance was assessed statistically by splitting cases into training and testing sets of the same size, and clinically by investigating the clinical course details of about one quarter of the patients in whom the difference between model estimates and actual number of PRBC transfused was higher than the root mean squared error.

Results

Ten preoperative and intraoperative dichotomous variables were entered in the model. Approximating the regression coefficients to the nearest half unit, each dummy regressor equal to one gave a number of half PRBC. The model assigned 4 units for kidney failure requiring preoperative dialysis, 2.5 units for cardiogenic shock, 2 units for minimum hematocrit at cardiopulmonary bypass less than or equal to 20%, 1.5 units for emergency operation, 1 unit for preoperative hematocrit less than or equal to 40%, cardiopulmonary bypass time greater than 130 minutes and type of surgery different from isolated artery bypass grafting, and 0.5 units for urgent operation, age over 70 years and systemic arterial hypertension.

Conclusions

The regression model proved reliable for quantitative planning of number of PRBC in patients undergoing heart surgery. Besides enabling more rational resource allocation of costly blood-conservation strategies and blood bank resources, the results indicated a strong association between some essential postoperative variables and differences between the model estimate and the actual number of packs transfused.
Trends in malaria research in 11 Asian Pacific countries: an analysis of peer-reviewed publications over two decades
Authors: Andersen Finn , Douglas Nick M , Bustos Dorina , Galappaththy Gawrie , Qi Gao , Hsiang Michelle S , Kusriastuti Rita , Mendis Kamini , Taleo George , Whittaker Maxine , Price Ric N , von Seidlein Lorenz
Published: June 2011

Background

Quantitative data are lacking on published malaria research. The purpose of the study is to characterize trends in malaria-related literature from 1990 to 2009 in 11 Asian-Pacific countries that are committed to malaria elimination as a national goal.

Methods

A systematic search was conducted for articles published from January 1990 to December 2009 in PubMed/MEDLINE using terms for malaria and 11 target countries (Bhutan, China, North Korea, Indonesia, Malaysia, Philippines, Solomon Islands, South Korea, Sri Lanka, Thailand and Vanuatu). The references were collated and categorized according to subject, Plasmodium species, and whether they contained original or derivative data.

Results

2,700 articles published between 1990 and 2009 related to malaria in the target countries. The annual output of malaria-related papers increased linearly whereas the overall biomedical output from these countries grew exponentially. The percentage of malaria-related publications was nearly 3% (111/3741) of all biomedical publications in 1992 and decreased to less than 1% (118/12171; p < 0.001) in 2009. Thailand had the highest absolute output of malaria-related papers (n = 1211), followed by China (n = 609) and Indonesia (n = 346). Solomon Islands and Vanuatu had lower absolute numbers of publications, but both countries had the highest number of publications per capita (1.3 and 2.5 papers/1,000 population). The largest percentage of papers concerned the epidemiology and control of malaria (53%) followed by studies of drugs and drug resistance (47%). There was an increase in the proportion of articles relating to epidemiology, entomology, biology, molecular biology, pathophysiology and diagnostics from the first to the second decade, whereas the percentage of papers on drugs, clinical aspects of malaria, immunology, and social sciences decreased.

Conclusions

The proportion of malaria-related publications out of the overall biomedical output from the 11 target Asian-Pacific countries is decreasing. The discovery and evaluation of new, safe and effective drugs and vaccines is paramount. In addition the elimination of malaria will require operational research to implement and scale up interventions.
Measuring naturally acquired immune responses to candidate malaria vaccine antigens in Ghanaian adults
Authors: Dodoo Daniel , Hollingdale Michael R , Anum Dorothy , Koram Kwadwo A , Gyan Ben , Akanmori Bartholomew D , Ocran Josephine , Adu-Amankwah Susan , Geneshan Harini , Abot Esteban , Legano Jennylyn , Banania Glenna , Sayo Renato , Brambilla Donald , Kumar Sanjai , Doolan Denise L , Rogers William O , Epstein Judith , Richie Thomas L , Sedegah Martha
Published: June 2011

Background

To prepare field sites for malaria vaccine trials, it is important to determine baseline antibody and T cell responses to candidate malaria vaccine antigens. Assessing T cell responses is especially challenging, given genetic restriction, low responses observed in endemic areas, their variability over time, potential suppression by parasitaemia and the intrinsic variability of the assays.

Methods

In Part A of this study, antibody titres were measured in adults from urban and rural communities in Ghana to recombinantPlasmodium falciparumCSP, SSP2/TRAP, LSA1, EXP1, MSP1, MSP3 and EBA175 by ELISA, and to sporozoites and infected erythrocytes by IFA. Positive ELISA responses were determined using two methods. T cell responses to defined CD8 or CD4 T cell epitopes from CSP, SSP2/TRAP, LSA1 and EXP1 were measured byex vivoIFN-γ ELISpot assays using HLA-matched Class I- and DR-restricted synthetic peptides. In Part B, the reproducibility of the ELISpot assay to CSP and AMA1 was measured by repeating assays of individual samples using peptide pools and low, medium or high stringency criteria for defining positive responses, and by comparing samples collected two weeks apart.

Results

In Part A, positive antibody responses varied widely from 17%-100%, according to the antigen and statistical method, with blood stage antigens showing more frequent and higher magnitude responses. ELISA titres were higher in rural subjects, while IFA titres and the frequencies and magnitudes of ex vivoELISpot activities were similar in both communities. DR-restricted peptides showed stronger responses than Class I-restricted peptides. In Part B, the most stringent statistical criteria gave the fewest, and the least stringent the most positive responses, with reproducibility slightly higher using the least stringent method when assays were repeated. Results varied significantly between the two-week time-points for many participants.

Conclusions

All participants were positive for at least one malaria protein by ELISA, with results dependent on the criteria for positivity. Likewise, ELISpot responses varied among participants, but were relatively reproducible by the three methods tested, especially the least stringent, when assays were repeated. However, results often differed between samples taken two weeks apart, indicating significant biological variability over short intervals.
Hormonal, follicular and endometrial dynamics in letrozole-treated versus natural cycles in patients undergoing controlled ovarian stimulation
Authors: Bedaiwy Mohamed A , Abdelaleem Mahmoud A , Hussein Mostafa , Mousa Noha , Brunengraber Lisa N , Casper Robert F
Published: June 2011

The objective of this study was to compare letrozole-stimulated cycles to natural cycles in 208 patients undergoing intrauterine insemination (IUI) between July of 2004 and January of 2007. Group I (n = 47) received cycle monitoring only (natural group), Group II (n = 125) received letrozole 2.5 mg/day on cycle days three to seven, and Group III (n = 36) received letrozole 5 mg/day on cycle days three to seven. There were no differences between the groups in endometrial thickness or P4 on the day of hCG. Estradiol levels had higher variation in the second half of the follicular phase in both letrozole-treated groups compared to the control group. Estradiol per preovulatory follicle was similar in both letrozole cycles to that observed in the natural cycles. LH was lower on the day of hCG administration in the letrozole 2.5 mg/day group vs. the natural group. In summary, letrozole results in some minor changes in follicular, hormonal and endometrial dynamics compared to natural cycles. Increased folliculogenesis and pregnancy rates were observed in the letrozole-treated groups compared to the natural group. These findings need to be confirmed in larger, prospective studies.
Weakly contractive multivalued maps and w-distances on complete quasi-metric spaces
Authors: Marín Josefa , Romaguera Salvador , Tirado Pedro
Published: June 2011

We obtain versions of the Boyd and Wong fixed point theorem and of the Matkowski fixed point theorem for multivalued maps and w-distances on complete quasi-metric spaces. Our results generalize, in several directions, some well-known fixed point theorems.
Fixed point results for contractions involving generalized altering distances in ordered metric spaces
Authors: Nashine Hemant Kumar , Samet Bessem , Kim Jong Kyu
Published: June 2011

In this article, we establish coincidence point and common fixed point theorems for mappings satisfying a contractive inequality which involves two generalized altering distance functions in ordered complete metric spaces. As application, we study the existence of a common solution to a system of integral equations.

2000 Mathematics subject classification. Primary 47H10, Secondary 54H25
On ε-optimality conditions for multiobjective fractional optimization problems
Authors: Kim Moon Hee , Kim Gwi Soo , Lee Gue Myung
Published: June 2011

A multiobjective fractional optimization problem (MFP), which consists of more than two fractional objective functions with convex numerator functions and convex denominator functions, finitely many convex constraint functions, and a geometric constraint set, is considered. Using parametric approach, we transform the problem (MFP) into the non-fractional multiobjective convex optimization problem (NMCP)
v
with parametric v ∈ ℝ
p
, and then give the equivalent relation between (weakly) ε-efficient solution of (MFP) and (weakly) "Equation missing"-efficient solution of "Equation missing". Using the equivalent relations, we obtain ε- optimality conditions for (weakly) ε- efficient solution for (MFP). Furthermore, we present examples illustrating the main results of this study.

2000 Mathematics Subject Classification: 90C30, 90C46.
A stabilized HIV-1 envelope glycoprotein trimer fused to CD40 ligand targets and activates dendritic cells
Authors: Melchers Mark , Matthews Katie , de Vries Robert P , Eggink Dirk , van Montfort Thijs , Bontjer Ilja , van de Sandt Carolien , David Kathryn , Berkhout Ben , Moore John P , Sanders Rogier W
Published: June 2011

Background

One reason why subunit protein and DNA vaccines are often less immunogenic than live-attenuated and whole-inactivated virus vaccines is that they lack the co-stimulatory signals provided by various components of the more complex vaccines. The HIV-1 envelope glycoprotein complex (Env) is no exception to this rule. Other factors that limit the induction of neutralizing antibodies against HIV-1 lie in the structure and instability of Env. We have previously stabilized soluble trimeric mimics of Env by introducing a disulfide bond between gp120 and gp41 and adding a trimer stabilizing mutation in gp41 (SOSIP.R6 gp140).

Results

We further stabilized the SOSIP.R6 gp140 using a GCN4-based isoleucine zipper motif, creating SOSIP.R6-IZ gp140. In order to target SOSIP.R6-IZ to immune cells, including dendritic cells, while at the same time activating these cells, we fused SOSIP.R6-IZ to the active domain of CD40 ligand (CD40L), which may serve as a 'cis-adjuvant'. The Env component of the SOSIP.R6-IZ-CD40L fusion construct bound to CD4 and neutralizing antibodies, while the CD40L moiety interacted with CD40. Furthermore, the chimeric molecule was able to signal efficiently through CD40 and induce maturation of human dendritic cells. Dendritic cells secreted IL-6, IL-10 and IL-12 in response to stimulation by SOSIP.R6-IZ-CD40L and were able to activate naïve T cells.

Conclusions

Chimeric HIV-1 gp140 - CD40L trimers can target and activate dendritic cells. Targeting and activating immune cells using CD40L and other 'cis-adjuvants' may improve subunit protein vaccine immunogenicity for HIV-1 and other infectious diseases.
Changes in multi‐segment foot biomechanics with a heat‐mouldable semi‐custom foot orthotic device
Authors: Ferber Reed , Benson Brittany
Published: June 2011

Background

Semi‐custom foot orthoses (SCO) are thought to be a cost‐effective alternative to custom‐made devices. However, previous biomechanical research involving either custom or SCO has only focused on rearfoot biomechanics. The purpose of this study was therefore to determine changes in multi‐segment foot biomechanics during shod walking with and without an SCO. We chose to investigate an SCO device that incorporates a heat‐moulding process, to further understand if the moulding process would significantly alter rearfoot, midfoot, or shank kinematics as compared to a no‐orthotic condition. We hypothesized the SCO, whether moulded or non‐moulded, would reduce peak rearfoot eversion, tibial internal rotation, arch deformation, and plantar fascia strain as compared to the no‐orthoses condition.

Methods

Twenty participants had retroreflective markers placed on the right limb to represent forefoot, midfoot, rearfoot and shank segments. 3D kinematics were recorded using an 8‐camera motion capture system while participants walked on a treadmill.

Results

Plantar fascia strain was reduced by 34% when participants walked in either the moulded or non‐moulded SCO condition compared to no‐orthoses. However, there were no significant differences in peak rearfoot eversion, tibial internal rotation, or medial longitudinal arch angles between any conditions.

Conclusions

A semi‐custom moulded orthotic does not control rearfoot, shank, or arch deformation but does, however, reduce plantar fascia strain compared to walking without an orthoses. Heat‐moulding the orthotic device does not have a measurable effect on any biomechanical variables compared to the non‐moulded condition. These data may, in part, help explain the clinical efficacy of orthotic devices.
Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy
Authors: Lawlor Michael W , Ottenheijm Coen A , Lehtokari Vilma-Lotta , Cho Kiyomi , Pelin Katarina , Wallgren-Pettersson Carina , Granzier Henk , Beggs Alan H
Published: June 2011

Background

Nemaline myopathy (NM) is a congenital muscle disease associated with weakness and the presence of nemaline bodies (rods) in muscle fibers. Mutations in seven genes have been associated with NM, but the most commonly mutated gene is nebulin (NEB), which is thought to account for roughly 50% of cases.

Results

We describe two siblings with severe NM, arthrogryposis and neonatal death caused by two novel NEB mutations: a point mutation in intron 13 and a frameshift mutation in exon 81. Levels of detectable nebulin protein were significantly lower than those in normal control muscle biopsies or those from patients with less severe NM due to deletion of NEB exon 55. Mechanical studies of skinned myofibers revealed marked impairment of force development, with an increase in tension cost.

Conclusions

Our findings demonstrate that the mechanical phenotype of severe NM is the consequence of mutations that severely reduce nebulin protein levels and suggest that the level of nebulin expression may correlate with the severity of disease.
Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: a prospective longitudinal observational cohort study
Authors: Arends Suzanne , Brouwer Elisabeth , van der Veer Eveline , Groen Henk , Leijsma Martha K , Houtman Pieternella M , Th A Jansen Tim L , Kallenberg Cees GM , Spoorenberg Anneke
Published: June 2011

Introduction

Identifying ankylosing spondylitis (AS) patients who are likely to benefit from tumor necrosis factor-alpha (TNF-α) blocking therapy is important, especially in view of the costs and potential side effects of these agents. Recently, the AS Disease Activity Score (ASDAS) has been developed to assess both subjective and objective aspects of AS disease activity. However, data about the predictive value of the ASDAS with respect to clinical response to TNF-α blocking therapy are lacking. The aim of the present study was to identify baseline predictors of response and discontinuation of TNF-α blocking therapy in AS patients in daily clinical practice.

Methods

AS outpatients who started TNF-α blocking therapy were included in the Groningen Leeuwarden Ankylosing Spondylitis (GLAS) study, an ongoing prospective longitudinal observational cohort study with follow-up visits according to a fixed protocol. For the present analysis, patients were excluded if they had previously received anti-TNF-α treatment. Predictor analyses of response and treatment discontinuation were performed using logistic and Cox regression models, respectively.

Results

Between November 2004 and April 2010, 220 patients started treatment with infliximab (n = 32), etanercept (n = 137), or adalimumab (n = 51). At three and six months, 68% and 63% of patients were Assessments in Ankylosing Spondylitis (ASAS)20 responders, 49% and 46% ASAS40 responders, and 49% and 50% Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)50 responders, respectively. Baseline predictors of response were younger age, male gender, higher ASDAS score, higher erythrocyte sedimentation rate (ESR) level, higher C-reactive protein (CRP) level, presence of peripheral arthritis, higher patient's global assessment of disease activity, and lower modified Schober test. In August 2010, 64% of patients were still using their TNF-α blocking agent with a median follow-up of 33.1 months (range 2.4 to 68.2). Baseline predictors of discontinuation of TNF-α blocking therapy were female gender, absence of peripheral arthritis, higher BASDAI, lower ESR level, and lower CRP level.

Conclusions

Besides younger age and male gender, objective variables such as higher inflammatory markers or ASDAS score were identified as independent baseline predictors of response and/or continuation of TNF-α blocking therapy. In contrast, higher baseline BASDAI score was independently associated with treatment discontinuation. Based on these results, it seems clinically relevant to include more objective variables in the evaluation of anti-TNF-α treatment.
Potent anti-inflammatory and antinociceptive activity of the endothelin receptor antagonist bosentan in monoarthritic mice
Authors: Imhof Anne-Katja , Glück Laura , Gajda Mieczyslaw , Bräuer Rolf , Schaible Hans-Georg , Schulz Stefan
Published: June 2011

Introduction

Endothelins are involved in tissue inflammation, pain, edema and cell migration. Our genome-wide microarray analysis revealed that endothelin-1 (ET-1) and endothelin-2 (ET-2) showed a marked up-regulation in dorsal root ganglia during the acute phase of arthritis. We therefore examined the effects of endothelin receptor antagonists on the development of arthritis and inflammatory pain in monoarthritic mice.

Methods

Gene expression was examined in lumbar dorsal root ganglia two days after induction of antigen-induced arthritis (AIA) using mRNA microarray analysis. Effects of drug treatment were determined by repeated assessment of joint swelling, pain-related behavior, and histopathological manifestations during AIA.

Results

Daily oral administration of the mixed ETA and ETB endothelin receptor antagonist bosentan significantly attenuated knee joint swelling and inflammation to an extent that was comparable to dexamethasone. In addition, bosentan reduced inflammatory mechanical hyperalgesia. Chronic bosentan administration also inhibited joint swelling and protected against inflammation and joint destruction during AIA flare-up reactions. In contrast, the ETA-selective antagonist ambrisentan failed to promote any detectable antiinflammatory or antinociceptive activity.

Conclusions

Thus, the present study reveals a pivotal role for the endothelin system in the development of arthritis and arthritic pain. We show that endothelin receptor antagonists can effectively control inflammation, pain and joint destruction during the course of arthritis. Our findings suggest that the antiinflammatory and antinociceptive effects of bosentan are predominantly mediated via the ETB receptor.
Short term Candida albicans colonization reduces Pseudomonas aeruginosa-related lung injury and bacterial burden in a murine model
Authors: Ader Florence , Jawhara Samir , Nseir Saad , Kipnis Eric , Faure Karine , Vuotto Fanny , Chemani Chanez , Sendid Boualem , Poulain Daniel , Guery Benoit
Published: June 2011

Introduction

Pseudomonas aeruginosa is a frequent cause of ventilator-acquired pneumonia (VAP). Candida tracheobronchial colonization is associated with higher rates of VAP related to P. aeruginosa. This study was designed to investigate whether prior short term Candida albicans airway colonization modulates the pathogenicity of P. aeruginosa in a murine model of pneumonia and to evaluate the effect of fungicidal drug caspofungin.

Methods

BALB/c mice received a single or a combined intratracheal administration of C. albicans (1 × 105 CFU/mouse) and P. aeruginosa (1 × 107 CFU/mouse) at time 0 (T0) upon C. albicans colonization, and Day 2. To evaluate the effect of antifungal therapy, mice received caspofungin intraperitoneally daily, either from T0 or from Day 1 post-colonization. After sacrifice at Day 4, lungs were analyzed for histological scoring, measurement of endothelial injury, and quantification of live P. aeruginosa and C. albicans. Blood samples were cultured for dissemination.

Results

A significant decrease in lung endothelial permeability, the amount of P. aeruginosa, and bronchiole inflammation was observed in case of prior C. albicans colonization. Mortality rate and bacterial dissemination were unchanged by prior C. albicans colonization. Caspofungin treatment from T0 (not from Day 1) increased their levels of endothelial permeability and lung P. aeruginosa load similarly to mice receiving P. aeruginosa alone.

Conclusions

P. aeruginosa-induced lung injury is reduced when preceded by short term C. albicans airway colonization. Antifungal drug caspofungin reverses that effect when used from T0 and not from Day 1.
Sniper: improved SNP discovery by multiply mapping deep sequenced reads
Authors: Simola Daniel F , Kim Junhyong
Published: June 2011

SNP (single nucleotide polymorphism) discovery using next-generation sequencing data remains difficult primarily because of redundant genomic regions, such as interspersed repetitive elements and paralogous genes, present in all eukaryotic genomes. To address this problem, we developed Sniper, a novel multi-locus Bayesian probabilistic model and a computationally efficient algorithm that explicitly incorporates sequence reads that map to multiple genomic loci. Our model fully accounts for sequencing error, template bias, and multi-locus SNP combinations, maintaining high sensitivity and specificity under a broad range of conditions. An implementation of Sniper is freely available at http://kim.bio.upenn.edu/software/sniper.shtml.
A global transcriptional analysis of Plasmodium falciparum malaria reveals a novel family of telomere-associated lncRNAs
Authors: Broadbent Kate M , Park Daniel , Wolf Ashley R , Van Tyne Daria , Sims Jennifer S , Ribacke Ulf , Volkman Sarah , Duraisingh Manoj , Wirth Dyann , Sabeti Pardis C , Rinn John L
Published: June 2011

Background

Mounting evidence suggests a major role for epigenetic feedback in Plasmodium falciparum transcriptional regulation. Long non-coding RNAs (lncRNAs) have recently emerged as a new paradigm in epigenetic remodeling. We therefore set out to investigate putative roles for lncRNAs in P. falciparum transcriptional regulation.

Results

We used a high-resolution DNA tiling microarray to survey transcriptional activity across 22.6% of the P. falciparum strain 3D7 genome. We identified 872 protein-coding genes and 60 putative P. falciparum lncRNAs under developmental regulation during the parasite's pathogenic human blood stage. Further characterization of lncRNA candidates led to the discovery of an intriguing family of lncRNA telomere-associated repetitive element transcripts, termed lncRNA-TARE. We have quantified lncRNA-TARE expression at 15 distinct chromosome ends and mapped putative transcriptional start and termination sites of lncRNA-TARE loci. Remarkably, we observed coordinated and stage-specific expression of lncRNA-TARE on all chromosome ends tested, and two dominant transcripts of approximately 1.5 kb and 3.1 kb transcribed towards the telomere.

Conclusions

We have characterized a family of 22 telomere-associated lncRNAs in P. falciparum. Homologous lncRNA-TARE loci are coordinately expressed after parasite DNA replication, and are poised to play an important role in P. falciparum telomere maintenance, virulence gene regulation, and potentially other processes of parasite chromosome end biology. Further study of lncRNA-TARE and other promising lncRNA candidates may provide mechanistic insight into P. falciparum transcriptional regulation.
Association of Diagnostic Radiation Exposure and Second Abdominal-Pelvic Malignancies After Testicular Cancer
Authors: van Walraven Carl , Fergusson Dean , Earle Craig , Baxter Nancy , Alibhai Shabbir , MacDonald Blair , Forster Alan J. , Cagiannos Ilias
Published: June 2011

Purpose

The evidence associating cancer risk with diagnostic radiation exposure is unclear. Men recovering from low-grade testicular cancer frequently undergo serial abdominal-pelvic computerized tomography (CT) scanning to monitor for recurrent disease.

Methods

We used population-based administrative data sets to identify every incident case of testicular cancer between 1991 and 2004 in Ontario, Canada. We excluded those with previous cancer, concurrent radiation therapy, retroperitoneal lymph node dissection, or fewer than 5 years observation. Patients were observed until the occurrences of death or development of a second abdominal-pelvic malignancy or until December 31, 2009.

Results

A total of 2,569 men (mean age, 34.7 years; standard deviation, 10.2) were observed for a median of 11.2 years (interquartile range [IQR], 8.3 to 14.3). During the first 5 years after diagnosis, men underwent a median of 10 computed tomography (CT) scans (IQR, 4 to 18) of the abdominal-pelvic area, and they were exposed to a median of 110 mSv of radiation from radiologic investigations (IQR, 44 to 190). After this, 14 men were diagnosed with a second abdominal-pelvic malignancy (rate, five per 10,000 patient-years observation, 95% CI, three to eight); the most common diagnoses were colorectal and kidney malignancies. Radiation exposure was not associated with an excess risk of second cancers (hazard ratio per 10 mSv increase, 0.99; 95% CI, 0.95 to 1.04). This association did not change if men observed for fewer than 5 years were included in the analysis (hazard ratio, 1.00; 95% CI, 0.96 to 1.04).

Conclusion

Second malignancies of the abdomen-pelvis are uncommon in men with low-grade testicular cancer. In this study, the risk of second cancer was not associated with the amount of diagnostic radiation exposure.
Quasistationary Distributions and Fleming-Viot Processes in Finite Spaces
Authors: Asselah Amine , Ferrari Pablo A. , Groisman Pablo
Published: June 2011

Consider a continuous-time Markov process with transition rates matrix Q in the state space Λ ⋃ {0}. In the associated Fleming-Viot process N particles evolve independently in Λ with transition rates matrix Q until one of them attempts to jump to state 0. At this moment the particle jumps to one of the positions of the other particles, chosen uniformly at random. When Λ is finite, we show that the empirical distribution of the particles at a fixed time converges as N → ∞ to the distribution of a single particle at the same time conditioned on not touching {0}. Furthermore, the empirical profile of the unique invariant measure for the Fleming-Viot process with N particles converges as N → ∞ to the unique quasistationary distribution of the one-particle motion. A key element of the approach is to show that the two-particle correlations are of order 1 / N.
A Lower Bound for the First Passage Time Density of the Suprathreshold Ornstein-Uhlenbeck Process
Authors: Thomas Peter J.
Published: June 2011

We prove that the first passage time density ρ(t) for an Ornstein-Uhlenbeck process X(t) obeying dX = -β Xdt + σdW to reach a fixed threshold θ from a suprathreshold initial condition x0 > θ > 0 has a lower bound of the form ρ(t) > kexp[-pe6βt] for positive constants k and p for times t exceeding some positive value u. We obtain explicit expressions for k, p, and u in terms of β, σ, x0, and θ, and discuss the application of the results to the synchronization of periodically forced stochastic leaky integrate-and-fire model neurons.
Efficient Simulation for the Maximum of Infinite Horizon Discrete-Time Gaussian Processes
Authors: Blanchet Jose , Li Chenxin
Published: June 2011

We consider the problem of estimating the probability that the maximum of a Gaussian process with negative mean and indexed by positive integers reaches a high level, sayb. In great generality such a probability converges to 0 exponentially fast in a power ofb. Under mild assumptions on the marginal distributions of the process and no assumption on the correlation structure, we develop an importance sampling procedure, called the target bridge sampler (TBS), which takes a polynomial (inb) number of function evaluations to achieve a small relative error. The procedure also yields samples of the underlying process conditioned on hittingbin finite time. In addition, we apply our method to the problem of estimating the tail of the maximum of a superposition of a large number,n, of independent Gaussian sources. In this situation TBS achieves a prescribed relative error with a bounded number of function evaluations asn↗ ∞. A remarkable feature of TBS is that it isnotbased on exponential changes of measure. Our numerical experiments validate the performance indicated by our theoretical findings.
Processes with Block-Associated Increments
Authors: Jakubowski Adam , Karłowska-Pik Joanna
Published: June 2011

This paper is motivated by relations between association and independence of random variables. It is well known that, for real random variables, independence implies association in the sense of Esary, Proschan and Walkup (1967), while, for random vectors, this simple relationship breaks. We modify the notion of association in such a way that any vector-valued process with independent increments also has associated increments in the new sense - association between blocks. The new notion is quite natural and admits nice characterization for some classes of processes. In particular, using the covariance interpolation formula due to Houdré, Pérez-Abreu and Surgailis (1998), we show that within the class of multidimensional Gaussian processes, block association of increments is equivalent to supermodularity (in time) of the covariance functions. We also define corresponding versions of weak association, positive association, and negative association. It turns out that the central limit theorem for weakly associated random vectors due to Burton, Dabrowski and Dehling (1986) remains valid, if the weak association is relaxed to the weak association between blocks.
A Central Limit Theorem and its Applications to Multicolor Randomly Reinforced Urns
Authors: Berti Patrizia , Crimaldi Irene , Pratelli Luca , Rigo Pietro
Published: June 2011

Let Xn be a sequence of integrable real random variables, adapted to a filtration (Gn). Define Cn = √{(1 / n)∑k=1nXk − E(Xn+1 | Gn)} and Dn = √n{E(Xn+1 | Gn) − Z}, where Z is the almost-sure limit of E(Xn+1 | Gn) (assumed to exist). Conditions for (Cn, Dn) → N(0, U) x N(0, V) stably are given, where U and V are certain random variables. In particular, under such conditions, we obtain √n{(1 / n)∑k=1nX_k - Z} = Cn + Dn → N(0, U + V) stably. This central limit theorem has natural applications to Bayesian statistics and urn problems. The latter are investigated, by paying special attention to multicolor randomly reinforced urns.
On the Maximal Offspring in a Critical Branching Process with Infinite Variance
Authors: Bertoin Jean
Published: June 2011

We investigate the maximal number Mk of offspring amongst all individuals in a critical Galton-Watson process started with k ancestors. We show that when the reproduction law has a regularly varying tail with index -α for 1 < α < 2, then k-1Mk converges in distribution to a Frechet law with shape parameter 1 and scale parameter depending only on α.