bluuebunny/crossref_metadata_2025 huggingface dataset:
Executive Function Predicts Adaptive Behavior in Children with Histories of Heavy Prenatal Alcohol Exposure and Attention‐Deficit/Hyperactivity Disorder
Authors: Ware Ashley L. , Crocker Nicole , O'Brien Jessica W. , Deweese Benjamin N. , Roesch Scott C. , Coles Claire D. , Kable Julie A. , May Philip A. , Kalberg Wendy O. , Sowell Elizabeth R. , Jones Kenneth Lyons , Riley Edward P. , Mattson Sarah N. ,   the CIFASD
Published: May 2012

Background

Prenatal exposure to alcohol often results in disruption to discrete cognitive and behavioral domains, including executive function (EF) and adaptive functioning. In the current study, the relation between these 2 domains was examined in children with histories of heavy prenatal alcohol exposure, nonexposed children with a diagnosis of attention‐deficit/hyperactivity disorder (ADHD), and typically developing controls.

Methods

As part of a multisite study, 3 groups of children (8 to 18 years, M = 12.10) were tested: children with histories of heavy prenatal alcohol exposure (ALC, n = 142), nonexposed children with ADHD (ADHD, n = 82), and typically developing controls (CON, n = 133) who did not have ADHD or a history of prenatal alcohol exposure. Children completed subtests of the Delis–Kaplan Executive Function System (D‐KEFS), and their primary caregivers completed the Vineland Adaptive Behavior Scales‐II. Data were analyzed using regression analyses.

Results

Analyses showed that EF measures were predictive of adaptive abilities, and significant interactions between D‐KEFS measures and group were present. For the ADHD group, the relation between adaptive abilities and EF was more general, with 3 of the 4 EF measures showing a significant relation with adaptive score. In contrast, for the ALC group, this relation was specific to the nonverbal EF measures. In the CON group, performance on EF tasks did not predict adaptive scores over the influence of age.

Conclusions

These results support prior research in ADHD, suggesting that EF deficits are predictive of poorer adaptive behavior and extend this finding to include children with heavy prenatal exposure to alcohol. However, the relation between EF and adaptive ability differed by group, suggesting unique patterns of abilities in these children. These results provide enhanced understanding of adaptive deficits in these populations, as well as demonstrate the ecological validity of laboratory measures of EF.
Frailty and Disability in Older Adults with Intellectual Disabilities: Results from the Healthy Ageing and Intellectual Disability Study
Authors: Evenhuis Heleen M. , Hermans Heidi , Hilgenkamp Thessa I. M. , Bastiaanse Luc P. , Echteld Michael A.
Published: May 2012

Objectives

To obtain first insight into prevalence and correlates of frailty in older people with intellectual disability (ID).

Design

Population‐based cross‐sectional study in persons using formal ID services.

Setting

Three Dutch care provider services.

Participants

Eight hundred forty‐eight individuals with borderline to profound ID aged 50 and older participating in the Healthy Ageing and Intellectual Disability (HA‐ID) Study.

Measurements

All participants underwent an extensive health examination. Frailty was diagnosed according to Cardiovascular Health Study criteria. Associations between frailty and participant characteristics were investigated using multivariate logistic regression analysis.

Results

Prevalence of frailty was 11% at age 50 to 64 and 18% at age 65 and older. Age, Down syndrome, dementia, motor disability, and severe ID were significantly associated with frailty, but only motor disability had a unique association with frailty. In a regression model with these variables, 25% of the variance of frailty was explained.

Conclusion

At age 50 to 64, prevalence of frailty is as high as in the general population aged 65 and older (7–9%), with a further increase after the age of 65. Motor disability only partially explains frailty. Future studies should address health outcomes, causes, and prevention of frailty in this population.
Underuse of Diagnostic Codes for Specific Dementias in the Veterans Affairs New England Healthcare System
Authors: Butler Daniel , Kowall Neil W. , Lawler Elizabeth , Michael Gaziano J. , Driver Jane A.
Published: May 2012

Objectives

To examine the specificity of dementia coding in large populations.

Design

Retrospective cohort and chart review study of dementia diagnosis.

Setting

U.S. Department of Veterans Affairs (VA) New England healthcare system.

Participants

Veterans aged 50 and older given outpatient visit codes for dementia between January 1, 2000, and December 31, 2009.

Measurements

The frequency of the code “dementia not otherwise specified (DNOS)” as a first and final diagnosis was determined. DNOS use was examined according to provider type and geographic location. The medical records of 100 individuals with unspecified dementia were reviewed to determine their underlying diagnoses and describe their examination.

Results

Twenty‐two thousand fifty veterans diagnosed with dementia were identified over 10 years of follow‐up. One‐third of all cases had no specific dementia code (n = 6,659). DNOS was the most commonly used code as a first dementia diagnosis (42.5%) and was second only to Alzheimer's type dementia (35.8%) as a final diagnosis. Individuals who saw geriatricians and neurologists were most likely to have a specific dementia diagnosis, and DNOS use was lowest in centers with the most dementia specialists. Only 12% of primary care physicians performed cognitive testing the first time they used the DNOS code, compared with 98% of specialists. Nearly half of individuals with a persistent diagnosis of DNOS met criteria for a specific dementia.

Conclusion

Substantial overuse was found of nonspecific dementia codes in the VA New England healthcare system, leading to an underestimation of the prevalence of Alzheimer's disease and other dementias. System‐based changes in dementia coding and greater access to dementia specialists may help improve diagnostic specificity.
Assimilating evidence quality at a glance using graphic display: research synthesis on labor induction
Authors: FOX CAROLINE E. , TIRLAPUR SEEMA A. , GÜLMEZOGLU AHMET METIN , SOUZA JOÃO PAULO , KHAN KHALID S. ,   WITH THE EBM‐CONNECT COLLABORATION
Published: May 2012

Evidence profiled in the World Health Organization induction of labor guideline extended to 84 tables and 116 pages, which is hard to assimilate. Summarizing this evidence graphically can present information on key outcomes succinctly, illustrating where the gaps, strengths and weaknesses lie. For induction of labor, graphic representation clearly showed that evidence was lacking on maternal complications when comparing oxytocin with other agents, evidence was strong on birth within 24 h when comparing vaginal prostaglandins with placebo or no treatment, but again it was weak on uterine hyperstimulation when comparing oxytocin with vaginal prostaglandins. These graphs/plots allow readers to capture the essence of the information gathered at a glance. The use of graphical displays when interpreting and publishing data on several comparisons and outcomes is encouraged.
Primary biliary cirrhosis: a multi‐faced interactive disease involving genetics, environment and the immune response
Authors: Uibo Raivo , Kisand Kai , Yang Chen‐Yen , Gershwin M. Eric
Published: May 2012

Primary biliary cirrhosis (PBC) is considered a model autoimmune disease based on several features, including the presence of a highly directed and very specific immune response to mitochondrial autoantigens, a female predominance, a targeted destruction of the biliary epithelium, and homogeneity between patients. It is essentially a chronic progressive cholestatic liver disease characterized by immune‐mediated destruction of small‐ and medium‐sized intrahepatic bile ducts. There is considerable variation in the incidence and prevalence of the disease between regions of the world, although such differences likely reflect not only a true disparity in disease but also differences in awareness; for example, in the United States, PBC is often detected in an asymptomatic stage based on multi‐phasic clinical testing. There has been considerable progress at defining the immune response in this disease, including quantitation of autoreactive T cells against PDC‐E2, the major mitochondrial autoantigen. The overwhelming data suggests that patients develop PBC based on a genetic predisposition and loss of tolerance to one or more environmental agents. In this review, we will present an updated overview of PBC and place it in the context of autoimmunity.
Periodontal regeneration employing gingival margin‐derived stem/progenitor cells: an animal study
Authors: Fawzy El‐Sayed Karim M. , Paris Sebastian , Becker Stephan T. , Neuschl Matthias , De Buhr Wiebke , Sälzer Sonja , Wulff Andreas , Elrefai Mahmoud , Darhous Mona S. , El‐Masry Manal , Wiltfang Jörg , Dörfer Christof E.
Published: May 2012

Aim

This study investigated the periodontal regenerative potential of gingival margin‐derived multipotent postnatal stem/progenitor cells.

Material and Methods

Periodontal defects were induced at six sites in eight miniature pigs in the premolar/molar area (−4 weeks). Autologous cells isolated from the gingival margin were magnetically sorted using STRO‐1 antibodies and characterized flow cytometrically for the expression of CD14, CD31, CD34, CD45, CD117 and STRO‐1 surface markers. Colony formation and multilineage differentiation potential were tested. The cells were expanded and loaded on deproteinized bovine cancellous bone (DBCB) and Collagen scaffolds. Within every miniature pig, six periodontal defects were randomly treated with loaded‐DBCB (test group 1), unloaded‐DBCB (control group 1), loaded‐Collagen scaffolds (test group 2), unloaded‐Collagen scaffolds (control group 1), scaling and root planing (negative control 1) or left untreated (negative control 2). Differences in clinical attachment level (ΔCAL), probing depth (ΔPD), gingival recession (ΔGR) and radiographic defect volume (ΔRDV) between baseline and 12 weeks, as well as histological attachment level (HAL), junctional epithelium length (JE) and connective tissue adhesion (CTA) after 12 weeks were evaluated.

Results

Isolated cells showed stem/progenitor cell characteristics. Cell‐loaded scaffolds showed higher ΔCAL, ΔPD, ΔGR, HAL and lower JE and CTA compared with unloaded scaffolds and negative controls. The sort of scaffold had no significant influence on the measured outcomes.

Conclusion

Gingival margin‐derived stem/progenitor cells show significant periodontal regenerative potential.
Early intervention for conversion disorder: neurologists and psychiatrists working together
Authors: Aybek Selma , Hubschmid Monica , Mossinger Corinna , Berney Alexandre , Vingerhoets François
Published: May 2012

Objective

To evaluate the efficacy of an early multidisciplinary (neurology and psychiatry) intervention for conversion disorder (CD).

Methods

Consecutive patients newly diagnosed with CD from 2005 to 2007 were compared to a control group of newly diagnosed CD patients receiving usual care. At 3 years, a questionnaire evaluated self‐rated subjective outcome, symptom severity, SF‐36 scores, employment status and medical care use.

Results

Data from 12 cases (mean age 25.5 ± 8.2; 9 females) and 11 controls (mean age 34.7 ± 13.5; 10 females) showed that 83% of cases had a good subjective outcome (symptom improved or cured) when only 36% of controls had a good outcome (p < 0.05). Cases significantly improved their SF‐36 scores on subscales involving physical complaints compared to controls. A minority (20%) of cases reduced or ceased professional activity when 70% of controls did (p < 0.001). Only 16% of cases sought further medical advice for the initial symptom when 73% of controls did. Both groups accepted psychiatric referrals (83% of cases and 73% of controls) and found it beneficial.

Conclusions

Early intervention involving both neurologists and psychiatrists is effective for CD in alleviating physical complaints, reducing sick leave and health care use.
Interventions to improve patient participation in the treatment process for culturally and linguistically diverse people with cancer: A systematic review
Authors: Harun Aisha , Harrison James D. , Young Jane M.
Published: May 2012

Disparities in cancer outcomes for people from culturally and linguistically diverse (CALD) groups are well known. Improving CALD patients' active participation in treatment processes holds potential to improve outcomes, but little is known of effective strategies to facilitate this. This systematic review investigated interventions to improve three aspects of participation in cancer care among CALD groups, namely involvement in decision‐making, communication with health providers and treatment adherence. A comprehensive search of electronic bibliographic databases was conducted to identify intervention studies that reported outcomes relevant to patient participation for CALD groups. Two reviewers independently critically appraised the studies and abstracted data. Of 10 278 potential articles, seven met the inclusion criteria, including three randomized controlled, three non‐randomized and one mixed‐method experimental studies. Interventions included the use of patient navigators, videos and decision aids. The impact on patient participation was varied. The effect of a decision aid and patient navigator interventions on communication with health providers was positive. While the use of a decisions aid successfully facilitated shared decision‐making and patients' perception of treatment adherence, the use of patient navigators was ineffective. A computer support system was found to improve general patient participation; however little clarification of what this involved was provided. This systematic review identified few rigorous evaluations of interventions to improve treatment participation for CALD people with cancer, highlighting the lack of a robust evidence base to improve this crucial aspect of care. The development and evaluation of interventions for diverse populations remains a priority.
The Effect of Bottle Fill Rate and Pour Technique on the Recovery of Volatile Organics
Authors: Parker Louise , Britt Sanford
Published: May 2012

This field study was conducted to examine whether the method or the flow rate (fill rate) used to fill a sample vial affects recovery of volatile organics (VOCs). To our knowledge, there have not been any systematic studies that have examined this issue. For this field study, three fill rates (50 mL/min, 250 mL/min, and ~1 L/min) and three filling methods (top‐pour, side‐pour, and bottom‐fill) were used to fill sample vials. We found that the bottom‐fill method, with the tubing submerged in the sample as it fills, yielded the greatest recovery (i.e., highest concentrations) of VOCs. Little improvement was observed by pouring down the side of a vial vs. simply pouring straight down from the top. We also found that filling the vials at the fastest fill rate (~1 L/min) yielded higher recovery than the slowest fill rate (50 mL/min) using all three filling methods. These results are counter to prevailing guidance and conventional wisdom that slower filling is preferable to faster filling and that pouring down the side of a sample vial is the best practice for VOC sampling. However, because we were unable to randomize the order the samples were collected with respect to fill rate, we recommend a follow‐on study be conducted that will allow us to confirm our findings and better determine which fill rates minimize losses of VOCs
Augmenting Antidepressant Medication Treatment of Depressed Women With Emotionally Focused Therapy for Couples: A Randomized Pilot Study
Authors: Denton Wayne H. , Wittenborn Andrea K. , Golden Robert N.
Published: May 2012

This is the first study to evaluate adding emotionally focused therapy for couples (EFT) to antidepressant medication in the treatment of women with major depressive disorder and comorbid relationship discord. Twenty‐four women and their male partners were randomized to 6 months of medication management alone (MM) or MM augmented with EFT (MM + EFT). MM followed the Texas Medication Algorithm Project guidelines. Fifteen EFT sessions were delivered following the EFT treatment manual. The primary outcome was severity of depressive symptoms (assessed by the 30‐item Inventory of Depressive Symptomatology—Clinician Rated version [IDS‐C30] administrated by evaluators blinded to cell assignment). Secondary outcome was relationship quality as assessed by the Quality of Marriage Index. Results from assessments at intake, termination, and two posttreatment follow‐ups were analyzed using growth analysis techniques. IDS‐C30 scores improved over 6 months of treatment, regardless of the treatment assignment, and women receiving MM + EFT experienced significantly more improvement in relationship quality compared with women in MM. Because relationship discord after depression treatment predicts worse outcome, interventions improving relationship quality may reduce depression relapse and recurrence. Testing this hypothesis in larger samples with longer follow‐up could contribute to knowledge on the mechanisms involved in determining the course of depressive illness.
Establishment of reed canary grass with perennial legumes or barley and different fertilization treatments: effects on yield, botanical composition and nitrogen fixation
Authors: Lindvall Eva , Gustavsson Anne‐Maj , Palmborg Cecilia
Published: May 2012

In two field experiments in northern Sweden, we investigated if intercropping reed canary grass (RCG; Phalaris arundinacea L.) with nitrogen‐fixing perennial legumes could reduce N‐fertilizer requirements and also if RCG ash or sewage sludge could be used as a supplement for mineral P and K. We compared biomass production, N uptake and N‐fixation of RCG in monoculture and mixtures of RCG with alsike clover (Trifolium hybridum L.), red clover (Trifolium pratense L.), goat's rue (Galega orientalis Lam.) and kura clover (Trifolium ambiguum M. Bieb.). In one experiment, RCG was also undersown in barley (Hordeum vulgare L.). Three fertilization treatments were applied: 100 kg N ha−1, 50 kg N ha−1 and 50 kg N ha−1 + RCG ash/sewage sludge. We used a delayed harvest method: cutting the biomass in late autumn, leaving it on the field during the winter and harvesting in spring. The legume biomass of the mixtures at the inland experimental site was small and did not affect RCG growth negatively. At the coastal site, competition from higher amount of clover biomass affected RCG growth and spring yield negatively. N‐fixation in red clover and alsike clover mixtures in the first production year approximately covered half of recommended N‐fertilization rate. Goat's rue and kura clover did not establish well at the costal site, but at the inland site goat's rue formed a small but vital undergrowth. RCG undersown in barley gave lower yield, both in autumn and spring, than the other treatments. The high N treatment gave a higher spring yield at the inland site than the low N treatments, but there were no differences due to fertilization treatments at the coastal site. For spring harvest, there were no yield benefits of RCG/legume intercropping compared with RCG monoculture. However, intercropping might be more beneficial in a two‐harvest system.
Cohomological Hall algebra of a symmetric quiver
Authors: Efimov Alexander I.
Published: May 2012

In [M. Kontsevich and Y. Soibelman,Cohomological Hall algebra, exponential Hodge structures and motivic Donaldson–Thomas invariants, Preprint (2011), arXiv:1006.2706v2[math.AG]], the authors, in particular, associate to each finite quiverQwith a set of verticesIthe so-called cohomological Hall algebra ℋ, which is ℤI≥0-graded. Its graded component ℋγis defined as cohomology of the Artin moduli stack of representations with dimension vectorγ. The product comes from natural correspondences which parameterize extensions of representations. In the case of a symmetric quiver, one can refine the grading to ℤI≥0×ℤ, and modify the product by a sign to get a super-commutative algebra (ℋ,⋆) (with parity induced by the ℤ-grading). It is conjectured in [M. Kontsevich and Y. Soibelman,Cohomological Hall algebra, exponential Hodge structures and motivic Donaldson–Thomas invariants, Preprint (2011), arXiv:1006.2706v2[math.AG]] that in this case the algebra (ℋ⊗ℚ,⋆) is free super-commutative generated by a ℤI≥0×ℤ-graded vector space of the formV=Vprim⊗ℚ[x] , wherexis a variable of bidegree (0,2)∈ℤI≥0×ℤ, and all the spaces ⨁k∈ℤVprimγ,k,γ∈ℤI≥0. are finite-dimensional. In this paper we prove this conjecture (Theorem 1.1). We also prove some explicit bounds on pairs (γ,k) for whichVprimγ,k≠0 (Theorem 1.2). Passing to generating functions, we obtain the positivity result for quantum Donaldson–Thomas invariants, which was used by Mozgovoy to prove Kac’s conjecture for quivers with sufficiently many loops [S. Mozgovoy,Motivic Donaldson–Thomas invariants and Kac conjecture, Preprint (2011), arXiv:1103.2100v2[math.AG]]. Finally, we mention a connection with the paper of Reineke [M. Reineke,Degenerate cohomological Hall algebra and quantized Donaldson–Thomas invariants form-loop quivers, Preprint (2011), arXiv:1102.3978v1[math.RT]].
A lower bound on the waist of unit spheres of uniformly convex normed spaces
Authors: Memarian Yashar
Published: May 2012

In this paper we give a lower bound on the waist of the unit sphere of a uniformly convex normed space by using the localization technique in codimension greater than one and a strong version of the Borsuk–Ulam theorem. The tools used in this paper follow ideas of Gromov in [Isoperimetry of waists and concentration of maps, Geom. Funct. Anal. 13 (2003), 178–215] and we also include an independent proof of our main theorem which does not rely on Gromov’s waist of the sphere. Our waist inequality in codimension one recovers a version of the Gromov–Milman inequality in [Generalisation of the spherical isoperimetric inequality to uniformly convex Banach spaces, Compositio Math. 62 (1987), 263–282].
Orai1, STIM1, and their associating partners
Authors: Srikanth Sonal , Gwack Yousang
Published: May 2012

Abstract  Store‐operated Ca2+ (SOC) entry is one of the major mechanisms to raise intracellular Ca2+ concentration in non‐excitable cells. Ca2+‐release‐activated Ca2+ (CRAC) channels are a subtype of SOC channels that are extensively characterized in immune cells. Identification of STIM1 as an endoplasmic reticulum Ca2+ sensor and Orai1 as the pore subunit has dramatically advanced the molecular understanding of CRAC channels. Recent efforts have focused on understanding the physiological aspects of CRAC channels at an organism level using transgenic animal models and at a molecular level using electrophysiological and biochemical tools. In this review, we summarize our current understanding of the interacting partners of Orai and STIM proteins in the regulation of CRAC channel activity and other non‐CRAC channel‐related functions.
Functional coupling of the metabotropic glutamate receptor, InsP3 receptor and L‐type Ca2+ channel in mouse CA1 pyramidal cells
Authors: Kato Hiroyuki K. , Kassai Hidetoshi , Watabe Ayako M. , Aiba Atsu , Manabe Toshiya
Published: May 2012

Key points

While the metabotropic glutamate receptor (mGluR) is supposed to modulate L‐type voltage‐dependent calcium channels (L‐VDCCs), its reported actions include both facilitation and suppression, and thus the modulation of L‐VDCCs by synaptic activity has still been under debate.

In this study, using acute hippocampal slices of subtype‐specific knockout mice, we have shown that mGluR5 induces facilitation of the depolarization‐evoked calcium current.

This facilitation was not accompanied by the change in single‐channel properties of the L‐VDCC itself, but required the activation of calcium‐induced calcium release that was triggered by L‐VDCC opening.

L‐VDCCs and mGluR5 were shown to form a complex by coimmunoprecipitation, suggesting that the specific functional coupling between mGluR5, InsP3 receptors and L‐VDCCs played a pivotal role in the calcium‐current facilitation.

Our study has identified a novel mechanism of the interaction between the mGluR and calcium signalling, and suggested a contribution of mGluR5 to synaptic plasticity.

Abstract  Activity‐dependent regulation of calcium dynamics in neuronal cells can play significant roles in the modulation of many cellular processes such as intracellular signalling, neuronal activity and synaptic plasticity. Among many calcium influx pathways into neurons, the voltage‐dependent calcium channel (VDCC) is the major source of calcium influx, but its modulation by synaptic activity has still been under debate. While the metabotropic glutamate receptor (mGluR) is supposed to modulate L‐type VDCCs (L‐VDCCs), its reported actions include both facilitation and suppression, probably reflecting the uncertainty of both the molecular targets of the mGluR agonists and the source of the recorded calcium signal in previous reports. In this study, using subtype‐specific knockout mice, we have shown that mGluR5 induces facilitation of the depolarization‐evoked calcium current. This facilitation was not accompanied by the change in single‐channel properties of the VDCC itself; instead, it required the activation of calcium‐induced calcium release (CICR) that was triggered by VDCC opening, suggesting that the opening of CICR‐coupled cation channels was essential for the facilitation. This facilitation was blocked or reduced by the inhibitors of both L‐VDCCs and InsP3 receptors (InsP3Rs). Furthermore, L‐VDCCs and mGluR5 were shown to form a complex by coimmunoprecipitation, suggesting that the specific functional coupling between mGluR5, InsP3Rs and L‐VDCCs played a pivotal role in the calcium‐current facilitation. Finally, we showed that mGluR5 enhanced VDCC‐dependent long‐term potentiation (LTP) of synaptic transmission. Our study has identified a novel mechanism of the interaction between the mGluR and calcium signalling, and suggested a contribution of mGluR5 to synaptic plasticity.
Initiated-chemical vapor deposition of organosilicon layers: Monomer adsorption, bulk growth, and process window definition
Authors: Aresta Gianfranco , Palmans Jurgen , van de Sanden Mauritius C. M. , Creatore Mariadriana
Published: May 2012

Organosilicon layers have been deposited from 1,3,5-trivinyl-1,3,5-trimethylcyclotrisiloxane (V3D3) by means of the initiated-chemical vapor deposition (i-CVD) technique in a deposition setup, ad hoc designed for the engineering of multilayer moisture permeation barriers. The application of Fourier transform infrared (FTIR) spectroscopy shows that the polymerization proceeds through the scission of the vinyl bond and allows quantifying the degree of conversion of vinyl groups, which is found to be larger than 80% for all the deposited layers. In situ real-time spectroscopic ellipsometry (SE) allows following all the i-CVD growth stages, i.e., from the initial monomer adsorption to the layer bulk growth. Finally, the combination of SE and FTIR has allowed defining the process window for the deposition of stable and highly cross-linked poly(V3D3) layers by tuning a key process parameter, i.e. the surface monomer adsorption.
Automated treatment planning for a dedicated multi‐source intracranial radiosurgery treatment unit using projected gradient and grassfire algorithms
Authors: Ghobadi Kimia , Ghaffari Hamid R. , Aleman Dionne M. , Jaffray David A. , Ruschin Mark
Published: May 2012

Purpose:

The purpose of this work is to develop a framework to the inverse problem for radiosurgery treatment planning on the Gamma Knife® Perfexion™ (PFX) for intracranial targets.

Methods:

The approach taken in the present study consists of two parts. First, a hybrid grassfire and sphere‐packing algorithm is used to obtain shot positions (isocenters) based on the geometry of the target to be treated. For the selected isocenters, a sector duration optimization (SDO) model is used to optimize the duration of radiation delivery from each collimator size from each individual source bank. The SDO model is solved using a projected gradient algorithm. This approach has been retrospectively tested on seven manually planned clinical cases (comprising 11 lesions) including acoustic neuromas and brain metastases.

Results:

In terms of conformity and organ‐at‐risk (OAR) sparing, the quality of plans achieved with the inverse planning approach were, on average, improved compared to the manually generated plans. The mean difference in conformity index between inverse and forward plans was −0.12 (range: −0.27 to +0.03) and +0.08 (range: 0.00–0.17) for classic and Paddick definitions, respectively, favoring the inverse plans. The mean difference in volume receiving the prescribed dose () between forward and inverse plans was 0.2% (range: −2.4% to +2.0%). After plan renormalization for equivalent coverage (i.e., ), the mean difference in dose to 1 mm3 of brainstem between forward and inverse plans was −0.24 Gy (range: −2.40 to +2.02 Gy) favoring the inverse plans. Beam‐on time varied with the number of isocenters but for the most optimal plans was on average 33 min longer than manual plans (range: −17 to +91 min) when normalized to a calibration dose rate of 3.5 Gy/min. In terms of algorithm performance, the isocenter selection for all the presented plans was performed in less than 3 s, while the SDO was performed in an average of 215 min.

Conclusions:

PFX inverse planning can be performed using geometric isocenter selection and mathematical modeling and optimization techniques. The obtained treatment plans all meet or exceed clinical guidelines while displaying high conformity.
Silence Please
Authors: Ray L. Bryan
Published: May 2012

A Polycomb group protein regulates the cell cycle by promoting cyclin B ubiquitylation and degradation.
Efficacy of Rifaximin Vaginal Tablets in Treatment of Bacterial Vaginosis: a Molecular Characterization of the Vaginal Microbiota
Authors: Cruciani Federica , Brigidi Patrizia , Calanni Fiorella , Lauro Vittoria , Tacchi Raffaella , Donders Gilbert , Peters Klaus , Guaschino Secondo , Vitali Beatrice
Published: May 2012

Bacterial vaginosis (BV) is a common vaginal disorder characterized by an alteration of the vaginal bacterial morphotypes, associated with sexually transmitted infections and adverse pregnancy outcomes. The purpose of the present study was to evaluate the impact of different doses of rifaximin vaginal tablets (100 mg/day for 5 days, 25 mg/day for 5 days, and 100 mg/day for 2 days) on the vaginal microbiota of 102 European patients with BV enrolled in a multicenter, double-blind, randomized, placebo-controlled study. An integrated molecular approach based on quantitative PCR (qPCR) and PCR-denaturing gradient gel electrophoresis (PCR-DGGE) was used to investigate the effects of vaginal tablets containing the antibiotic. An increase in members of the genus
Lactobacillus
and a decrease in the BV-related bacterial groups after the antibiotic treatment were demonstrated by qPCR. PCR-DGGE profiles confirmed the capability of rifaximin to modulate the composition of the vaginal microbial communities and to reduce their complexity. This molecular analysis supported the clinical observation that rifaximin at 25 mg/day for 5 days represents an effective treatment to be used in future pivotal studies for the treatment of BV.
Efficacy of Daptomycin-Cloxacillin Combination in Experimental Foreign-Body Infection Due to Methicillin-Resistant Staphylococcus aureus
Authors: Garrigós C. , Murillo O. , Lora-Tamayo J. , Verdaguer R. , Tubau F. , Cabellos C. , Cabo J. , Ariza J.
Published: May 2012

Despite the use of daptomycin alone at high doses (greater than 6 mg/kg of body weight/day) against difficult-to-treat infections, clinical failures and resistance appeared. Recently, the combination daptomycin-cloxacillin showed enhanced efficacy in clearing bacteremia caused by methicillin-resistant
Staphylococcus aureus
(MRSA). The aim of this study was to evaluate the efficacy of daptomycin at usual and high doses (equivalent to 6 and 10 mg/kg/day in humans, respectively) in combination with cloxacillin in a rat tissue cage infection model by MRSA and to compare its efficacy to that of daptomycin-rifampin. We used MRSA strain ATCC BAA-39. In the log- and stationary-phase kill curves, daptomycin-cloxacillin improved the bactericidal activity of daptomycin, especially in log phase. For
in vivo
studies, therapy was administered intraperitoneally for 7 days with daptomycin at 100 mg/kg/day and 45/mg/kg/day (daptomycin 100 and daptomycin 45), daptomycin 100-cloxacillin at 200 mg/kg/12 h, daptomycin 45-cloxacillin, and daptomycin 100-rifampin at 25 mg/kg/12 h. Daptomycin-rifampin was the best therapy (
P
< 0.05). Daptomycin 45 was the least effective treatment and did not protect against the emergence of resistant strains. There were no differences between the two dosages of daptomycin plus cloxacillin in any situation, and both protected against resistance. The overall effect of the addition of cloxacillin to daptomycin was a significantly greater cure rate (against adhered bacteria) than that for daptomycin alone. In conclusion, daptomycin-cloxacillin enhanced modestly the
in vivo
efficacy of daptomycin alone against foreign-body infection by MRSA and was less effective than daptomycin plus rifampin. The benefits of adding cloxacillin to daptomycin should be especially evaluated against infections by rifampin-resistant MRSA and for protection against the emergence of daptomycin nonsusceptibility.
Mechanistic Assessment of DNA Ligase as an Antibacterial Target in Staphylococcus aureus
Authors: Podos Steven D. , Thanassi Jane A. , Pucci Michael J.
Published: May 2012

We report the use of a known pyridochromanone inhibitor with antibacterial activity to assess the validity of NAD
+
-dependent DNA ligase (LigA) as an antibacterial target in
Staphylococcus aureus
. Potent inhibition of purified LigA was demonstrated in a DNA ligation assay (inhibition constant [

K
i

] = 4.0 nM) and in a DNA-independent enzyme adenylation assay using full-length LigA (50% inhibitory concentration [IC
50
] = 28 nM) or its isolated adenylation domain (IC
50
= 36 nM). Antistaphylococcal activity was confirmed against methicillin-susceptible and -resistant
S. aureus
(MSSA and MRSA) strains (MIC = 1.0 μg/ml). Analysis of spontaneous resistance potential revealed a high frequency of emergence (4 × 10
−7
) of high-level resistant mutants (MIC > 64) with associated
ligA
lesions. There were no observable effects on growth rate in these mutants. Of 22 sequenced clones, 3 encoded point substitutions within the catalytic adenylation domain and 19 in the downstream oligonucleotide-binding (OB) fold and helix-hairpin-helix (HhH) domains.
In vitro
characterization of the enzymatic properties of four selected mutants revealed distinct signatures underlying their resistance to inhibition. The infrequent adenylation domain mutations altered the kinetics of adenylation and probably elicited resistance directly. In contrast, the highly represented OB fold domain mutations demonstrated a generalized resistance mechanism in which covalent LigA activation proceeds normally and yet the parameters of downstream ligation steps are altered. A resulting decrease in substrate

K
m

and a consequent increase in substrate occupancy render LigA resistant to competitive inhibition. We conclude that the observed tolerance of staphylococcal cells to such hypomorphic mutations probably invalidates LigA as a viable target for antistaphylococcal chemotherapy.
Pseudomonas aeruginosa Exopolysaccharide Psl Promotes Resistance to the Biofilm Inhibitor Polysorbate 80
Authors: Zegans Michael E. , Wozniak Daniel , Griffin Edward , Toutain-Kidd Christine M. , Hammond John H. , Garfoot Andrew , Lam Joseph S.
Published: May 2012

Polysorbate 80 (PS80) is a nonionic surfactant and detergent that inhibits biofilm formation by
Pseudomonas aeruginosa
at concentrations as low as 0.001% and is well tolerated in human tissues. However, certain clinical and laboratory strains (PAO1) of
P. aeruginosa
are able to form biofilms in the presence of PS80. To better understand this resistance, we performed transposon mutagenesis with a PS80-resistant clinical isolate, PA738. This revealed that mutation of
algC
rendered PA738 sensitive to PS80 biofilm inhibition. AlgC contributes to the biosynthesis of the exopolysaccharides Psl and alginate, as well as lipopolysaccharide and rhamnolipid. Analysis of mutations downstream of AlgC in these biosynthetic pathways established that disruption of the
psl
operon was sufficient to render the PA738 and PAO1 strains sensitive to PS80-mediated biofilm inhibition. Increased levels of Psl production in the presence of arabinose in a strain with an arabinose-inducible
psl
promoter were correlated with increased biofilm formation in PS80. In
P. aeruginosa
strains MJK8 and ZK2870, known to produce both Pel and Psl, disruption of genes in the
psl
but not the
pel
operon conferred susceptibility to PS80-mediated biofilm inhibition. The laboratory strain PA14 does not produce Psl and does not form biofilms in PS80. However, when PA14 was transformed with a cosmid containing the
psl
operon, it formed biofilms in the presence of PS80. Taken together, these data suggest that production of the exopolysaccharide Psl by
P. aeruginosa
promotes resistance to the biofilm inhibitor PS80.
Population Pharmacokinetics of Extended-Infusion Piperacillin-Tazobactam in Hospitalized Patients with Nosocomial Infections
Authors: Felton T. W. , Hope W. W. , Lomaestro B. M. , Butterfield J. M. , Kwa A. L. , Drusano G. L. , Lodise T. P.
Published: May 2012

While extended infusions of piperacillin-tazobactam (TZP) are increasingly used in practice, the effect of infusion on the pharmacokinetic (PK) profile of TZP has not been widely assessed. To assess its effect on the pharmacokinetic profile of TZP, seven serum samples were collected from 11 hospitalized patients who received 3.375 g TZP intravenously for 4 h every 8 h. Population pharmacokinetic models were fit to the PK data utilizing first-order, Michaelis-Menten (MM), and parallel first-order/MM clearance. A population PK model with first-order clearance was fit to the tazobactam PK data. Monte Carlo simulations (MCSs) were used to determine the most effective administration schedule to ensure that free piperacillin concentrations were above the MIC for at least 50% of the dosing interval (50%
f
T>MIC) and to quantify the extent of the nonlinear clearance. The model incorporating parallel linear/MM clearance best fit the piperacillin PK data. The MCSs demonstrated that approximately 50% of the administered piperacillin is cleared by the nonlinear clearance mechanism. The results of the MCSs also revealed that more intensive TZP extended infusion dosing schemes (3.375 to 4.5 g intravenously [3-h infusion] every 6 h) than those commonly used in clinical practice were needed to maximize the 50%
f
T>MIC for MICs of ≥8 mg/liter. This study suggests that extended infusion of TZP is the most effective method of administration for patients with nosocomial infections. Due to the hyperclearance nature of the hospitalized patient populations studied, more intensive TZP dosing regimens may be needed to maximize
f
T>MIC in certain hospitalized populations.
In Vitro
Activity of TP-271 against Mycobacterium abscessus, Mycobacterium fortuitum, and Nocardia Species
Authors: Cynamon Michael , Jureller Jeff , Desai Balaji , Ramachandran Krithika , Sklaney Mary , Grossman Trudy H.
Published: May 2012

The
in vitro
activities of TP-271, a novel fluorocycline antimicrobial, against 22 isolates of
Mycobacterium abscessus
, 22 isolates of
Mycobacterium fortuitum
, and 19 isolates of
Nocardia
spp. were studied by a microtiter broth dilution method. The MIC
90
s for
M. abscessus
,
M. fortuitum
, and
Nocardia
spp. were 0.5 μg/ml, 0.03 μg/ml, and 8 μg/ml, respectively. TP-271 was significantly more active than the respective control drug in virtually all tests.
Evaluation of the Immunogenicity and Vaccine Potential of Recombinant Plasmodium falciparum Merozoite Surface Protein 8
Authors: Alaro James R. , Angov Evelina , Lopez Ana M. , Zhou Hong , Long Carole A. , Burns James M.
Published: May 2012

The C-terminal 19-kDa domain of merozoite surface protein 1 (MSP119) is the target of protective antibodies but alone is poorly immunogenic. Previously, using thePlasmodium yoeliimurine model, we fusedP. yoeliiMSP119(PyMSP119) with full-lengthP. yoeliimerozoite surface protein 8 (MSP8). Upon immunization, the MSP8-restricted T cell response provided help for the production of high and sustained levels of protectivePyMSP119- andPyMSP8-specific antibodies. Here, we assessed the vaccine potential of MSP8 of the human malaria parasite,Plasmodium falciparum. Distinct fromPyMSP8,P. falciparumMSP8 (PfMSP8) contains an N-terminal asparagine and aspartic acid (Asn/Asp)-rich domain whose function is unknown. Comparative analysis of recombinant full-lengthPfMSP8 and a truncated version devoid of the Asn/Asp-rich domain,PfMSP8(ΔAsn/Asp), showed that both proteins were immunogenic for T cells and B cells. All T cell epitopes utilized mapped within rPfMSP8(ΔAsn/Asp). The dominant B cell epitopes were conformational and common to both rPfMSP8 and rPfMSP8(ΔAsn/Asp). Analysis of nativePfMSP8 expression revealed thatPfMSP8 is present intracellularly in late schizonts and merozoites. Following invasion,PfMSP8 is found distributed on the surface of ring- and trophozoite-stage parasites. Consistent with a low and/or transient expression ofPfMSP8 on the surface of merozoites,PfMSP8-specific rabbit IgG did not inhibit thein vitrogrowth ofP. falciparumblood-stage parasites. These studies suggest that the further development ofPfMSP8 as a malaria vaccine component should focus on the use ofPfMSP8(ΔAsn/Asp) and its conserved, immunogenic T cell epitopes as a fusion partner for protective domains of poor immunogens, includingPfMSP119.
Differential Contribution of Bacillus anthracis Toxins to Pathogenicity in Two Animal Models
Authors: Levy Haim , Weiss Shay , Altboum Zeev , Schlomovitz Josef , Glinert Itai , Sittner Assa , Shafferman Avigdor , Kobiler David
Published: May 2012

The virulence of
Bacillus anthraci
s, the causative agent of anthrax, stems from its antiphagocytic capsule, encoded by pXO2, and the tripartite toxins encoded by pXO1. The accepted paradigm states that anthrax is both an invasive and toxinogenic disease and that the toxins play major roles in pathogenicity. We tested this assumption by a systematic study of mutants with combined deletions of the
pag
,
lef
, and
cya
genes, encoding protective antigen (PA), lethal factor (LF), and edema factor (EF), respectively. The resulting seven mutants (single, double, and triple) were evaluated following subcutaneous (s.c.) and intranasal (i.n.) inoculation in rabbits and guinea pigs. In the rabbit model, virulence is completely dependent on the presence of PA. Any mutant bearing a
pag
deletion behaved like a pXO1-cured mutant, exhibiting complete loss of virulence with attenuation indices of over 2,500,000 or 1,250 in the s.c. or i.n. route of infection, respectively. In marked contrast, in guinea pigs, deletion of
pag
or even of all three toxin components resulted in relatively moderate attenuation, whereas the pXO1-cured bacteria showed complete attenuation. The results indicate that a pXO1-encoded factor(s), other than the toxins, has a major contribution to the virulence mechanism of
B. anthracis
in the guinea pig model. These unexpected toxin-dependent and toxin-independent manifestations of pathogenicity in different animal models emphasize the importance and need for a comprehensive evaluation of
B. anthracis
virulence in general and in particular for the design of relevant next-generation anthrax vaccines.
The Hydrophilic Translocator for Vibrio parahaemolyticus, T3SS2, Is Also Translocated
Authors: Zhou Xiaohui , Ritchie Jennifer M. , Hiyoshi Hirotaka , Iida Tetsuya , Davis Brigid M. , Waldor Matthew K. , Kodama Toshio
Published: May 2012

The pathogenesis of the diarrheal disease caused by
Vibrio parahaemolyticus
, a leading cause of seafood-associated enteritis worldwide, is dependent upon a type III secretion system, T3SS2. This apparatus enables the pathogen to inject bacterial proteins (effectors) into the cytosol of host cells and thereby modulate host processes. T3SS effector proteins transit into the host cell via a membrane pore (translocon) typically formed by 3 bacterial proteins. We have identified the third translocon protein for T3SS2: VopW, which was previously classified as an effector protein for a homologous T3SS in
V. cholerae
. VopW is a hydrophilic translocon protein; like other such proteins, it is not inserted into the host cell membrane but is required for insertion of the two hydrophobic translocators, VopB2 and VopD2, that constitute the membrane channel. VopW is not required for secretion of T3SS2 effectors into the bacterial culture medium; however, it is essential for transfer of these proteins into the host cell cytoplasm. Consequently, deletion of
vopW
abrogates the virulence of
V. parahaemolyticus
in several animal models of diarrheal disease. Unlike previously described hydrophilic translocators, VopW is itself translocated into the host cell cytoplasm, raising the possibility that it functions as both a translocator and an effector.
Observational study on factors related to health-promoting community activity development in primary care (frAC Project): a study protocol
Authors: March Sebastià , Ripoll Joana , Ruiz-Giménez Juan Luís , Montaner Gomis Isabel , Benedé Azagra Carmen Belén , Elizalde Soto Lázaro , Vidal Mª Clara , Bauzà Amengual M de Lluc , Planas Juan Trinidad , Maria Pérez Mariano Damiana , Llull Sarralde Micaela , Bajo Viñas Rosa , Jordan Martin Matilde , Solano Villarubia Carmen , Rodriguez Bajo Maria , Cordoba Victoria Manuela , Badia Capdevila Marta , Serrano Ferrandez Elena , Bosom Diumenjo Maria , Zabaleta del Olmo Nieves , Bolívar-Ribas Bonaventura , Antoñanzas Lombarte Angel , Bregel Cotaina Samantha , Calvo Tocado Ana , Olivan Blázquez Barbara , Magallón Botaya Rosa , Marín Palacios Pilar , Echauri Ozcoidi Margarita , Perez-Jarauta Mª Jose , Ramos Maria
Published: May 2012

Introduction

According to Spanish health regulations, primary care professionals have the responsibility to carry out health-promoting community activities (CAs). However, in practice, their implementation is not as widespread as it should be. The aims of this study were to identify factors within the team, the community and the professionals that influence the development of these activities and to describe the community interventions in progress.

Methods and analysis

This study is an observational analytical retrospective study. The information will be collected from five Spanish regions: Catalonia, Madrid, the Balearic Islands, Navarra and Aragón. The authors will contact primary care teams (PCTs) and identify the CAs from the previous year. The research team will conduct a peer review whether the inclusion criteria are met. In the health centres where CAs are implemented, the authors will select professionals carrying them out and randomly select an identical number of professionals not doing these activities. In the centres where no CA is implemented, three professionals will be randomly selected. The selected professionals will complete the questionnaires for individual-level variables. Information about the registered population and the PCTs will be collected through questionnaires and secondary sources.

Outcomes

Variables will be collected from the community, the PCTs, the individual professionals and CAs.

Analysis

A descriptive analysis of all the variables will be carried out, along with a bivariate and a logistic regression analysis, with CAs being the primary outcome.

Ethics and dissemination

This study has been approved by the Research Ethics Committee of the Jordi Gol y Gurina Foundation in Barcelona and area 11 in Madrid. The questionnaire distributed to the professionals will be anonymous.