bluuebunny/crossref_metadata_2025 huggingface dataset:
Scaling up the diversity–resilience relationship with trait databases and remote sensing data: the recovery of productivity after wildfire
Authors: Spasojevic Marko J. , Bahlai Christie A. , Bradley Bethany A. , Butterfield Bradley J. , Tuanmu Mao‐Ning , Sistla Seeta , Wiederholt Ruscena , Suding Katharine N.
Published: November 2015

Understanding the mechanisms underlying ecosystem resilience – why some systems have an irreversible response to disturbances while others recover – is critical for conserving biodiversity and ecosystem function in the face of global change. Despite the widespread acceptance of a positive relationship between biodiversity and resilience, empirical evidence for this relationship remains fairly limited in scope and localized in scale. Assessing resilience at the large landscape and regional scales most relevant to land management and conservation practices has been limited by the ability to measure both diversity and resilience over large spatial scales. Here, we combined tools used in large‐scale studies of biodiversity (remote sensing and trait databases) with theoretical advances developed from small‐scale experiments to ask whether the functional diversity within a range of woodland and forest ecosystems influences the recovery of productivity after wildfires across the four‐corner region of the United States. We additionally asked how environmental variation (topography, macroclimate) across this geographic region influences such resilience, either directly or indirectly via changes in functional diversity. Using path analysis, we found that functional diversity in regeneration traits (fire tolerance, fire resistance, resprout ability) was a stronger predictor of the recovery of productivity after wildfire than the functional diversity of seed mass or species richness. Moreover, slope, elevation, and aspect either directly or indirectly influenced the recovery of productivity, likely via their effect on microclimate, while macroclimate had no direct or indirect effects. Our study provides some of the first direct empirical evidence for functional diversity increasing resilience at large spatial scales. Our approach highlights the power of combining theory based on local‐scale studies with tools used in studies at large spatial scales and trait databases to understand pressing environmental issues.
The effects of body image and self‐esteem on frequency of closet cleaning
Authors: Saiki Diana , Crecelius Kayla
Published: November 2015

The purpose of this study was to examine divestment of clothing and its relationship to psychological characteristics (body image and self‐esteem) and demographic characteristics (gender and age) of the consumer. The relationship between frequencies in closet cleaning to categories selected for body image (Appearance Orientation, Appearance Evaluation, Body Areas Satisfaction, Subjective Weight, and Weight Preoccupation) were calculated using Pearson's Correlation and Analysis of Variance. Frequencies in closet cleaning were also compared to the overall score from responses to the Rosenberg Self‐Esteem Scale. The relationship between disposal frequency and Appearance Orientation was statistically significant for both gender groups, particularly among groups 18–25 years. Individuals with a higher Appearance Orientation tended to dispose clothing more frequently than others. When comparing men to women, body image accounted for garment disposal more among men, suggesting women have more varied reasons to dispose of clothing. Self‐esteem measures were not related to disposal frequency among all groups. The findings contribute to knowledge and have implications related to self‐concept and consumption behavior post purchasing. For example, results were similar between young men and women suggesting men may have similar clothing and appearance oriented behavior to women. In another example, those with high appearance orientation could be targeted for campaigns related to sustainable disposal strategies.
Factors affecting non‐green consumer behaviour: an exploratory study among Chinese consumers
Authors: He Ai‐zhong , Cai Tom , Deng Tian‐xiang , Li Xue
Published: November 2015

The purpose of this study was to explore the factors that affect a typical non‐green consumption behaviour among Chinese consumers. A conceptual framework was developed and an empirical study was conducted using a geographically diverse sample of Chinese consumers. Based on the consumer choice theory, the conceptual framework in the current study included both economic and non‐economic factors. Ten research hypotheses were developed under the framework. A survey was conducted among 600 consumers in four cities in China in 2013. Confirmatory factor analysis and hierarchical regression analysis were used for hypothesis testing. The empirical results showed that consumer preference, reference groups, and face perception have a significantly positive effect on the consumers’ non‐green consumption behaviour; whereas budget constraints and social responsibility consciousness have a significantly negative effect on the consumers’ non‐green consumption behaviour. Furthermore, the current research demonstrated that the relationships between consumer non‐green behaviour and its four antecedents – budget constraint, reference groups, social responsibility consciousness and face perception – are significantly moderated by extravagant atmosphere; whereas the relationship between consumer non‐green behaviour and consumer preference is not moderated by extravagant atmosphere.
Bimodal Dynamics of Faces and Voices Influence Older Infants' Perception of Emotion
Authors: Heck Alison R. , Panneton Robin K. , Mills‐Smith Laura
Published: November 2015

Given the importance of infants' perception of bimodal speech for emerging language and emotion development, this study used eye‐tracking technology to examine infants' attention to face+voice displays differing by emotion (fear, sad, happy) and visual stimulus (dynamic versus static). Peripheral distracters were presented to measure attention disengagement. It was predicted that infants would look longer at and disengage more slowly from dynamic bimodal emotion displays, especially when viewing dynamic fear. However, the results from twenty‐two 10‐month‐olds found significantly greater attention on dynamic versus static trials, independent of emotion. Interestingly, infants looked equally to mouth and eye regions of speakers' faces except when viewing/hearing dynamic fear; in this case, they fixated more on the speakers' mouth region. Average latencies to distracters were longer on dynamic compared to static bimodal stimuli, but not differentiated by emotion. Thus, infants' attention was enhanced (in terms of both elicitation and maintenance) by dynamic, bimodal emotion displays. Results are compared to conflicting findings using static emotion displays, with suggestions for future research using more ecologically relevant dynamic, multimodal displays to gain a richer understanding of infants' processing of emotion.
Exploring the diary as a recovery‐oriented therapeutic tool
Authors: Alexander June , McAllister Margaret , Brien Donna Lee
Published: November 2015

Diary writing is a centuries‐old method of recording events, experiences, thoughts, and feelings that might offer potential as a tool that consumers and nurses could utilize in recovery‐oriented practice. While the diary has been used within health disciplines to detail and communicate personal experiences to enable collaborative examination of progress, a diary can also provide a more complete picture of what life is like; not only within the confines of a health service environment, but also outside. In recent times, the diary appears to be experiencing a renewed interest in terms of health care. People experiencing a mental health challenge might use diary‐based forms of communication to promote understanding between themselves and mental health workers, and ultimately the use of this form of narrative therapy might facilitate person‐centred, recovery‐based actions. The present study paper, therefore, explores multiple perspectives on the use of diaries in the therapeutic context. Suggesting that diaries have not yet been utilized to their fullest potential by and with consumers and clinicians, this discussion raises issues and offers clarity about diary forms and their uses in the health context. It also discusses the barriers to their use and how to engage consumers and clinicians in recovery‐oriented work.
Prevalence and prognostic significance of hyperkalemia in hospitalized patients with cirrhosis
Authors: Maiwall Rakhi , Kumar Suman , Sharma Manoj Kumar , Wani Zeeshan , Ozukum Mulu , Sarin Shiv Kumar
Published: November 2015

Background

The prevalence and clinical significance of hyponatremia in cirrhotics have been well studied; however, there are limited data on hyperkalemia in cirrhotics.

Aim

We evaluated the prevalence and prognostic significance of hyperkalemia in hospitalized patients with cirrhosis and developed a prognostic model incorporating potassium for prediction of liver‐related death in these patients.

Methods

The training derivative cohort of patients was used for development of prognostic scores (Group A, n = 1160), which were validated in a large prospective cohort of cirrhotic patients. (Group B, n = 2681) of cirrhosis.

Results

Hyperkalemia was seen in 189 (14.1%) and 336 (12%) in Group A and Group B, respectively. Potassium showed a significant association that was direct with creatinine (P < 0.001) and urea (P < 0.001) and inverse with sodium (P < 0.001). Mortality was also significantly higher in patients with hyperkalemia (P = 0.0015, Hazard Ratio (HR) 1.3, 95% confidence interval 1.11–1.57). Combination of all these parameters into a single value predictor, that is, renal dysfunction index predicted mortality better than the individual components. Combining renal dysfunction index with other known prognostic markers (i.e. serum bilirubin, INR, albumin, hepatic encephalopathy, and ascites) in the “K” model predicted both short‐term and long‐term mortality with an excellent accuracy (Concordance‐index 0.78 and 0.80 in training and validation cohorts, respectively). This was also superior to Model for End‐stage Liver Disease, Model for End‐stage liver disease sodium (MELDNa), and Child‐Turcott‐Pugh scores.

Conclusions

Cirrhotics frequently have impaired potassium homeostasis, which has a prognostic significance. Serum potassium correlates directly with serum creatinine and urea and inversely with serum sodium. The model incorporating serum potassium developed from this study (“K”model) can predict death in advanced cirrhotics with an excellent accuracy.
Image contrast enhancement of Ni/YSZ anode during the slice‐and‐view process in FIB‐SEM
Authors: LIU SHU‐SHENG , TAKAYAMA AKIKO , MATSUMURA SYO , KOYAMA MICHIHISA
Published: November 2015

Focused ion beam‐scanning electron microscopy (FIB‐SEM) is a widely used and easily operational equipment for three‐dimensional reconstruction with flexible analysis volume. It has been using successfully and increasingly in the field of solid oxide fuel cell. However, the phase contrast of the SEM images is indistinct in many cases, which will bring difficulties to the image processing. Herein, the phase contrast of a conventional Ni/yttria stabilized zirconia anode is tuned in an FIB‐SEM with In‐Lens secondary electron (SE) and backscattered electron detectors. Two accessories, tungsten probe and carbon nozzle, are inserted during the observation. The former has no influence on the contrast. When the carbon nozzle is inserted, best and distinct contrast can be obtained by In‐Lens SE detector. This method is novel for contrast enhancement. Phase segmentation of the image can be automatically performed. The related mechanism for different images is discussed.
Unique expression of cytoskeletal proteins in human soft palate muscles
Authors: Shah Farhan , Berggren Diana , Holmlund Thorbjörn , Levring Jäghagen Eva , Stål Per
Published: November 2015

The human oropharyngeal muscles have a unique anatomy with diverse and intricate functions. To investigate if this specialization is also reflected in the cytoarchitecture of muscle fibers, intermediate filament proteins and the dystrophin‐associated protein complex have been analyzed in two human palate muscles, musculus uvula (UV) and musculus palatopharyngeus (PP), with immunohistochenmical and morphological techniques. Human limb muscles were used as reference. The findings show that the soft palate muscle fibers have a cytoskeletal architecture that differs from the limb muscles. While all limb muscles showed immunoreaction for a panel of antibodies directed against different domains of cytoskeletal proteins desmin and dystrophin, a subpopulation of palate muscle fibers lacked or had a faint immunoreaction for desmin (UV 11.7% and PP 9.8%) and the C‐terminal of the dystrophin molecule (UV 4.2% and PP 6.4%). The vast majority of these fibers expressed slow contractile protein myosin heavy chain I. Furthermore, an unusual staining pattern was also observed in these fibers for β‐dystroglycan, caveolin‐3 and neuronal nitric oxide synthase nNOS, which are all membrane‐linking proteins associated with the dystrophin C‐terminus. While the immunoreaction for nNOS was generally weak or absent, β‐dystroglycan and caveolin‐3 showed a stronger immunostaining. The absence or a low expression of cytoskeletal proteins otherwise considered ubiquitous and important for integration and contraction of muscle cells indicate a unique cytoarchitecture designed to meet the intricate demands of the upper airway muscles. It can be concluded that a subgroup of muscle fibers in the human soft palate appears to have special biomechanical properties, and their unique cytoarchitecture must be taken into account while assessing function and pathology in oropharyngeal muscles.
A pilot study investigating the efficacy of botanical anti‐inflammatory agents in an OTC eczema therapy
Authors: Draelos Zoe Diana
Published: November 2015

Background

Eczema is a frequently encountered dermatologic condition characterized by inflammation resulting in erythema, scaling, induration, and lichenification.

Aims

The objective of this research was to examine the roll of botanical anti‐inflammatories in alleviating the signs and symptoms of mild‐to‐moderate eczema.

Method

A total of 25 subjects 18+ years of age with mild‐to‐moderate eczema were asked to leave all oral medications and cleansers unchanged substituting the botanical study moisturizer for all topical treatment three times daily for 2 weeks. Investigator, subject, and noninvasive assessments were obtained at baseline and week 2.

Results

There was a highly statistically significant (P < 0.001) improvement in investigator‐assessed irritation, erythema, desquamation, roughness, dryness, lichenification, itching, and overall skin appearance after 2 weeks of botanical anti‐inflammatory moisturizer use. Overall, a 79% reduction in itching was noted. Skin hydration as measured by corneometry increased 44% increase (P < 0.001).

Conclusions

The study moisturizer containing the occlusive ingredients of dimethicone and shea butter oil; the humectant ingredients of glycerin, vitamin B, sodium PCA, and sodium hyaluronate; the barrier repair ingredients of ceramide 3, cholesterol, phytosphingosine, ceramide 6 II, and ceramide 1; and the botanical anti‐inflammatories allantoin and bisabolol were helpful in reducing the signs and symptoms of mild‐to‐moderate eczema.
Hemodynamic Impact of Systolic Blood Pressure and Hematocrit Calculated by Computational Fluid Dynamics in Patients with Intracranial Atherosclerosis
Authors: Nam Hyo Suk , Scalzo Fabien , Leng Xinyi , Ip Hing Lung , Lee Hye Sun , Fan Florence , Chen Xiangyan , Soo Yannie , Miao Zhongrong , Liu Liping , Feldmann Edward , Leung Thomas , Wong Ka Sing , Liebeskind David S.
Published: November 2015

OBJECTIVE

Success in clinical trials of intracranial atherosclerosis (ICAS) is related to accurate identification of high‐risk patients. Noninvasive computational fluid dynamics (CFD) of stenotic lesions may enhance therapeutic decision‐making. We determined whether physiologic parameters change downstream cerebral hemodynamics in patients with ICAS.

METHODS

Consecutive ICAS patients who underwent both CT angiography (CTA) and digital subtraction angiography were enrolled. CFD models were made using CTA source images. Inlet boundary conditions were defined using three ranges of systolic blood pressure (BP) (109.2, 158, and 225 mmHg) and hematocrit (27.3, 40.2, and 48.8). Ratios of pressure, shear strain rates (SSR), and flow velocity across the lesion were calculated using CFD simulations. A linear mixed model was used for the statistical analysis of repeated simulations.

RESULTS

Among the 56 patients, 32 had moderate stenosis (50‐69%) and 24 had severe stenosis (70‐99%). A linear mixed model revealed that the ratio of pressure was predicted by systolic BP and stenosis group interaction (P = .036). These pressure decreases were associated with systolic BP (P < .001) and stenosis group (P < .001), but not with hematocrit (P = .337). Post‐hoc analysis revealed that pressure decreases were more profound in the severe stenosis than the moderate stenosis group when comparing high and low systolic BP (P = .0108). Ratios of SSR and velocity were only associated in the stenosis group.

CONCLUSIONS

Our study showed that systolic BP along with the degree of stenosis was associated with pressure decreases across stenotic lesions. Physiologic conditions may superimpose further changes in post‐stenotic or downstream blood flow.
Association between tooth loss and hypertension among a primarily rural middle aged and older Indian adult population
Authors: Singh Ankur , Gupta Adyya , Peres Marco A. , Watt Richard G. , Tsakos Georgios , Mathur Manu R.
Published: November 2015

Background

Studies in high‐income countries have reported associations between tooth loss and hypertension. There is however a lack of evidence on this association from South Asian countries especially India. The current study aimed to assess the association between self‐reported tooth loss and hypertension in a primarily rural middle‐aged and older Indian population.

Methods

A secondary analysis of cross‐sectional data from the Longitudinal Ageing Study of India – pilot survey was conducted on 1,486 adults aged 45 years and above from four states of India. The primary outcome was self‐reported hypertension and the main explanatory variable was self‐reported tooth loss. Multivariable logistic regression models estimated the association between hypertension and tooth loss after controlling for confounders including age, sex, marital status, area of residence, educational attainment, tobacco use, alcohol use, physical activity, and self‐reported diabetes.

Results

Compared to those without any tooth loss, individuals with partial tooth loss had 1.62 times (95% CI: 1.12‐2.35) higher odds of being hypertensive after adjustment of confounders including age, sex, marital status, area of residence, educational attainment, tobacco use, alcohol use, physical activity, and self‐reported diabetes. The crude significant association (OR: 2.54; 95% CI: 1.50‐4.29) between edentulousness and hypertension became nonsignificant and attenuated after adjustment of potential confounders (fully adjusted model OR: 1.33; 95% CI: 0.72‐2.44).

Conclusion

Partial tooth loss was associated with a higher probability of hypertension among dentate middle‐aged and older adults in four states of India.
Clearance of HBV DNA in immunized children born to HBsAg‐positive mothers, years after being diagnosed with occult HBV infection
Authors: Sadeghi A. , Yahyapour Y. , Poortahmasebi V. , Shahmoradi S. , Roggendorf M. , Karimzadeh H. , Alavian S. M. , Jazayeri S. M.
Published: November 2015

In a previous study, we observed immunoprophylaxis failure due to occult hepatitis B virus (HBV) infection (OBI) despite the presence of adequate levels of anti‐HBs in 21 (28%) of 75 children born to HBsAg‐positive mothers. The aim of the study was to explore the maintenance of this cryptic condition in this population. Of 21 OBI‐positive children, 17 were enrolled. HBV serological profiles were determined by enzyme‐linked immunosorbent assay. Highly sensitive real‐time and standard PCR followed by direct sequencing were applied in positive cases. The mean age (±SD) of studied patients was 6.57 ± 2.75 years. All children still were negative for HBsAg. All but one (94%) were negative for HBV DNA. Only two children were positive for anti‐HBc. The results of the most recent anti‐HBs titration showed that 4 (23.5%) and 13 (76.5%) had low (<10 IU/mL) and adequate (>10 IU/mL) levels of anti‐HBs, respectively. The only still OBI‐positive patient had an HBV DNA level of 50 copy/mL, carried the G145R mutation when tested in 2009 and again in 2013 in the ‘a’ determinant region of the surface protein. Further follow‐up showed that after 18 months, he was negative for HBV DNA. In high‐risk children, the initial HBV DNA positivity early in the life (vertical infection) does not necessarily indicate a prolonged persistence of HBV DNA (occult infection). Adequate levels of anti‐HBs after vaccine and hepatitis B immune globulin immunoprophylaxis following birth could eventually clear the virus as time goes by. Periodic monitoring of these children at certain time intervals is highly recommended.
Selection for population‐specific adaptation shaped patterns of variation in the photoperiod pathway genes in Arabidopsis lyrata during post‐glacial colonization
Authors: Mattila Tiina M. , Aalto Esa A. , Toivainen Tuomas , Niittyvuopio Anne , Piltonen Susanna , Kuittinen Helmi , Savolainen Outi
Published: November 2015

Spatially varying selection can lead to population‐specific adaptation, which is often recognized at the phenotypic level; however, the genetic evidence is weaker in many groups of organisms. In plants, environmental shifts that occur due to colonization of a novel environment may require adaptive changes in the timing of growth and flowering, which are often governed by location‐specific environmental cues such as day length. We studied locally varying selection in 19 flowering time loci in nine populations of the perennial herb Arabidopsis lyrata, which has a wide but patchy distribution in temperate and boreal regions of the northern hemisphere. The populations differ in their recent population demographic and colonization histories and current environmental conditions, especially in the growing season length. We searched for population‐specific molecular signatures of directional selection by comparing a set of candidate flowering time loci with a genomic reference set within each population using multiple approaches and contrasted the patterns of different populations. The candidate loci possessed approximately 20% of the diversity of the reference loci. On average the flowering time loci had more rare alleles (a smaller Tajima's D) and an excess of highly differentiated sites relative to the reference, suggesting positive selection. The strongest signal of selection was detected in photoperiodic pathway loci in the colonizing populations of Northwestern Europe, whereas no evidence of positive selection was detected in the Central European populations. These findings emphasized the population‐specific nature of selection and suggested that photoperiodic adaptation was important during postglacial colonization of the species.
Sexually antagonistic epigenetic marks that canalize sexually dimorphic development
Authors: Rice William R. , Friberg Urban , Gavrilets Sergey
Published: November 2015

The sexes share the same autosomal genomes, yet sexual dimorphism is common due to sex‐specific gene expression. When present, XX and XY karyotypes trigger alternate regulatory cascades that determine sex‐specific gene expression profiles. In mammals, secretion of testosterone (T) by the testes during foetal development is the master switch influencing the gene expression pathways (male vs. female) that will be followed, but many genes have sex‐specific expression prior to T secretion. Environmental factors, like endocrine disruptors and mimics, can interfere with sexual development. However, sex‐specific ontogeny can be canalized by the production of epigenetic marks (epimarks) generated during early ontogeny that increase sensitivity of XY embryos to T and decrease sensitivity of XX embryos. Here, we integrate and synthesize the evidence indicating that canalizing epimarks are produced during early ontogeny. We will also describe the evidence that such epimarks sometimes carry over across generations and produce mosaicism in which some traits are discordant with the gonad. Such carryover epimarks are sexually antagonistic because they benefit the individual in which they were formed (via canalization) but harm opposite‐sex offspring when they fail to erase across generations and produce gonad‐trait discordances. SA‐epimarks have the potential to: i) magnify phenotypic variation for many sexually selected traits, ii) generate overlap along many dimensions of the masculinity/femininity spectrum, and iii) influence medically important gonad‐trait discordances like cryptorchidism, hypospadias and idiopathic hirsutism.
Obesity and discrimination – a systematic review and meta‐analysis of observational studies
Authors: Spahlholz J. , Baer N. , König H.‐H. , Riedel‐Heller S. G , Luck‐Sikorski C.
Published: November 2015

Background

Research on obesity has shown that stigma often accompanies obesity and impacts many life domains. No previous research has systematically reviewed published literature about the prevalence and the nature of perceived weight discrimination in individuals with obesity. This systematic review and meta‐analysis aims to fill that gap.

Methods

A systematic literature search was conducted without time limits using the databases Medline, ISI Web of Knowledge and the Cochrane Library. Meta‐analyses were performed using random effect models. Observational studies pertaining to (i) prevalence estimates and (ii) forms of perceived weight discrimination among individuals with obesity were included.

Results

Of 4393 citations retrieved, nine citations retrieved, nine studies met inclusion criteria. Pooled prevalence was 19.2% (95% confidence interval (CI) 11.7 to 29.8%) for individuals with class I obesity (Body mass index [BMI] = 30–35 kg m−2) and 41.8% (95% CI 36.9 to 46.9%) for individuals with more extreme obesity (BMI > 35 kg m−2). Findings from nationally representative US samples revealed higher prevalence estimates in individuals with higher BMI values (BMI > 35 kg m−2) and in women.

Conclusions

The results provide evidence that perceptions of weight discrimination by individuals with obesity were common, and its negative consequences are highly relevant issues within society and need to be the focus of potential interventions. © 2015 World Obesity
Resting state connectivity of the medial prefrontal cortex covaries with individual differences in high‐frequency heart rate variability
Authors: Jennings J. Richard , Sheu Lei K. , Kuan Dora C‐H. , Manuck Stephen B. , Gianaros Peter J.
Published: November 2015

Resting high‐frequency heart rate variability (HF‐HRV) relates to cardiac vagal control and predicts individual differences in health and longevity, but its functional neural correlates are not well defined. The medial prefrontal cortex (mPFC) encompasses visceral control regions that are components of intrinsic networks of the brain, particularly the default mode network (DMN) and the salience network (SN). Might individual differences in resting HF‐HRV covary with resting state neural activity in the DMN and SN, particularly within the mPFC? This question was addressed using fMRI data from an eyes‐open, 5‐min rest period during which echoplanar brain imaging yielded BOLD time series. Independent component analysis yielded functional connectivity estimates defining the DMN and SN. HF‐HRV was measured in a rest period outside of the scanner. Midlife (52% female) adults were assessed in two studies (Study 1, N = 107; Study 2, N = 112). Neither overall DMN nor SN connectivity strength was related to HF‐HRV. However, HF‐HRV related to connectivity of one region within mPFC shared by the DMN and SN, namely, the perigenual anterior cingulate cortex, an area with connectivity to other regions involved in autonomic control. In sum, HF‐HRV does not seem directly related to global resting state activity of intrinsic brain networks, but rather to more localized connectivity. A mPFC region was of particular interest as connectivity related to HF‐HRV was shared by the DMN and SN. These findings may indicate a functional basis for the coordination of autonomic cardiac control with engagement and disengagement from the environment.
Breathing pattern and breathlessness in idiopathic pulmonary fibrosis: An observational study
Authors: Olukogbon Kasope L. , Thomas Paul , Colasanti Ricardo , Hope‐Gill Ben , Williams Edgar Mark
Published: November 2015

Background and objective

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive decline in lung function and increasing dyspnoea. The aim of this study was to investigate the relationship among IPF, pulmonary function, resting tidal breathing patterns and level of breathlessness.

Methods

Thirty‐one participants with IPF and 17 matched healthy controls underwent lung function testing, followed by a 2‐min period of resting tidal breathing. The IPF cohort was stratified according to disease severity, based on their forced vital capacity and diffusion capacity for carbon monoxide.

Results

In comparison to the healthy controls, the IPF cohort showed a higher tidal volume, VT, of 0.22 L (P = 0.026) and a raised minute ventilation in the severest IPF group, while no differences in the timing of inspiration or expiration were observed. In the IPF cohort, the ratio of VT to forced vital capacity was around 15% higher. These changes corresponded with an increase in the self‐reported sensation of breathlessness.

Conclusion

Those with IPF increased their depth of breathing with worsening disease severity, with IPF‐induced changes in pulmonary function and breathlessness associated with an altered tidal breathing pattern.
Bisphosphonate‐related osteonecrosis of the jaws: Report of a case using conservative protocol
Authors: Heggendorn Fabiano Luiz , Leite Taiana Campos , Cunha Karin Soares Gonçalves , Junior Arley Silva , Gonçalves Lucio Souza , da Costa Karla Bianca Fernandes Fontes , Dias Eliane Pedra
Published: November 2015

Bisphosphonates have been the first‐line treatment option for osteometabolic diseases, such as osteoporosis, hypercalcaemia in malignant bone diseases, and in bone metastasis. It is possible to observe a growing number of cases of osteonecrosis of the jaws in patients using this medication, called bisphosphonate‐related osteonecrosis of the jaws. The purpose of this study was to report a conservative treatment for bisphosphonate‐related osteonecrosis of the jaws—Stage 2, using antibacterial solution and low‐level laser therapy. At the end of the treatment, the patient presented improvement of the lesion with the healing of the mucosa. The literature still lacks successful definite protocols, thus the present case may contribute with another option for conservative management for bisphosphonate‐related osteonecrosis of the jaws. More research is necessary in order to develop a good protocol management for bisphosphonate‐related osteonecrosis of the jaws.
Diagnosis of HIV infection on the basis of histoplasmosis‐related oral ulceration
Authors: Klein Isadora Peres , Martins Marco Antonio Trevizani , Martins Manoela Domingues , Carrard Vinicius Coelho
Published: November 2015

Histoplasmosis is an endemic systemic mycosis caused by the dimorphic fungus Histoplasma capsulatum. In immunocompromised patients, histoplasmosis generally occurs as an opportunistic disease, with dissemination to various organs. Cutaneous involvement is observed in 38% to 85% of cases, with oral mucosal involvement in 30% to 60% of cases. This article describes the case study of a 32‐year‐old woman who presented an extensive tongue ulcer due to histoplasmosis and had the HIV infection diagnosis based on laboratory tests requested by the dentist.
Genetic factors influencing ferritin levels in 14,126 blood donors: results from the Danish Blood Donor Study
Authors: Sørensen Erik , Rigas Andreas S. , Thørner Lise W. , Burgdorf Kristoffer S. , Pedersen Ole B. , Petersen Mikkel S. , Hjalgrim Henrik , Erikstrup Christian , Ullum Henrik
Published: November 2015

BACKGROUND

Many biologic functions depend on sufficient iron levels, and iron deficiency is especially common among blood donors. Genetic variants associated with iron levels have been identified, but the impact of genetic variation on iron levels among blood donors remains unclear.

STUDY DESIGN AND METHODS

The effect of six single‐nucleotide polymorphisms (SNPs) on ferritin levels in 14,126 blood donors were investigated in four genes: in Human Hemochromatosis Protein gene (HFE; rs1800562 and rs179945); in Transmembrane Protease gene, Serine 6 (TMPRSS6‐regulating hepcidin; rs855791); in BTB domain containing protein gene (BTBD9—associated with restless legs syndrome; rs9357271); and in the Transferrin gene (TF; rs2280673 and rs1830084). Multiple linear and logistic regression analyses were used to evaluate the effect of each SNP on ferritin levels and the risk of iron deficiency (ferritin < 15 ng/mL).

RESULTS

In HFE, the G‐allele of rs1800562 was associated with lower iron stores in both sexes. This was also true for the C‐allele of rs179945, but in men only. Also, the T‐allele of TMPRSS6 rs855791 was negatively associated with iron stores in men. Homozygocity for C in rs1799945 was associated with iron deficiency in women. Results for all other genetic variants were insignificant.

CONCLUSION

Genetic variants associated with hemochromatosis may protect donors against depleted iron stores. In addition, we showed that presence of the T‐allele at rs855791 in TMPRSS6 was associated with lower iron stores in men.
The costs of producing a unit of blood in Zimbabwe
Authors: Mafirakureva Nyashadzaishe , Nyoni Herbert , Nkomo Sisodwa Z. , Jacob Jeffery S. , Chikwereti Radhi , Musekiwa Zamile , Khoza Star , Mvere David A. , Emmanuel Jean C. , Postma Maarten J. , van Hulst Marinus
Published: November 2015

BACKGROUND

There is lack of published data on the costs of blood and blood transfusion in sub‐Saharan Africa. This study aimed to assess the unit costs of producing blood in Zimbabwe using an activity‐based costing (ABC) method.

STUDY DESIGN AND METHODS

A management accounting approach, based on the ABC method, was used to develop a cost model for blood. The production of blood was broken down into recruitment, collection, testing, processing, and storage plus distribution. Data for the year 2013 were collected retrospectively from budgets, financial and expenditure reports, databases, and interviews with transfusion personnel and managers. All direct and indirect costs, in 2013 US$, were allocated, accordingly, to the activities of blood acquisition.

RESULTS

The total cost of producing safe blood in Zimbabwe for the year 2013 was US$8.6 million. Variable costs accounted for 51.2% of the total cost of production. The unit production costs for red blood cells (RBCs) were US$15.94 for recruitment, US$34.62 for collection, US$17.88 for testing, US$11.49 for processing, and US$3.06 for storage plus distribution. The overall cost of production of one unit of whole blood was US$118.42 and RBCs was US$130.94 constituting 12.4 and 13.7% of the country's annual GDP per capita.

CONCLUSIONS

The high unit cost of producing blood relative to the annual GDP per capita demonstrates that acquiring safe blood is a burden on the health care sector in Zimbabwe. Introducing additional safety measures, such as nucleic acid amplification testing and pathogen reduction technology, although desirable, will further increase this burden.
Development of a New Antileishmanial Aziridine-2,3-Dicarboxylate-Based Inhibitor with High Selectivity for Parasite Cysteine Proteases
Authors: Schad Caroline , Baum Ulrike , Frank Benjamin , Dietzel Uwe , Mattern Felix , Gomes Carlos , Ponte-Sucre Alicia , Moll Heidrun , Schurigt Uta , Schirmeister Tanja
Published: November 2015

Leishmaniasis is one of the major neglected tropical diseases of the world. Druggable targets are the parasite cysteine proteases (CPs) of clan CA, family C1 (CAC1). In previous studies, we identified two peptidomimetic compounds, the aziridine-2,3-dicarboxylate compounds 13b and 13e, in a series of inhibitors of the cathepsin L (CL) subfamily of the papain clan CAC1. Both displayed antileishmanial activityin vitrowhile not showing cytotoxicity against host cells. In further investigations, the mode of action was characterized inLeishmania major. It was demonstrated that aziridines 13b and 13e mainly inhibited the parasitic cathepsin B (CB)-like CPC enzyme and, additionally, mammalian CL. Although these compounds induced cell death ofLeishmaniapromastigotes and amastigotesin vitro, the induction of a proleishmanial T helper type 2 (Th2) response caused by host CL inhibition was observedin vivo. Therefore, we describe here the synthesis of a new library of more selective peptidomimetic aziridine-2,3-dicarboxylates discriminating between host and parasite CPs. The new compounds are based on 13b and 13e as lead structures. One of the most promising compounds of this series is compound s9, showing selective inhibition of the parasite CPsLmaCatB (a CB-like enzyme ofL. major; also namedL. majorCPC) andLmCPB2.8 (a CL-like enzyme ofLeishmania mexicana) while not affecting mammalian CL and CB. It displayed excellent leishmanicidal activities againstL. majorpromastigotes (50% inhibitory concentration [IC50] = 37.4 μM) and amastigotes (IC50= 2.3 μM). In summary, we demonstrate a new selective aziridine-2,3-dicarboxylate, compound s9, which might be a good candidate for futurein vivostudies.
New Scheme of Intermittent Benznidazole Administration in Patients Chronically Infected with Trypanosoma cruzi: a Pilot Short-Term Follow-Up Study with Adult Patients
Authors: Álvarez María Gabriela , Hernández Yolanda , Bertocchi Graciela , Fernández Marisa , Lococo Bruno , Ramírez Juan Carlos , Cura Carolina , Albizu Constanza Lopez , Schijman Alejandro , Abril Marcelo , Sosa-Estani Sergio , Viotti Rodolfo
Published: November 2015

There is a clinical need to test new schemes of benznidazole administration that are expected to be at least as effective as the current therapeutic scheme but safer. This study assessed a new scheme of benznidazole administration in chronic Chagas disease patients. A pilot study with intermittent doses of benznidazole at 5 mg/kg/day in two daily doses every 5 days for a total of 60 days was designed. The main criterion of response was the comparison of quantitative PCR (qPCR) findings prior to and 1 week after the end of treatment. The safety profile was assessed by the rate of suspensions and severity of adverse effects. Twenty patients were analyzed for safety, while qPCR was tested for 17 of them. The average age was 43 ± 7.9 years; 55% were female. Sixty-five percent of treated subjects showed detectable qPCR results prior to treatment of 1.45 (0.63 to 2.81) and 2.1 (1.18 to 2.78) parasitic equivalents per milliliter of blood (par.eq/ml) for kinetoplastic DNA (kDNA) qPCR and nuclear repetitive sequence satellite DNA (SatDNA) qPCR, respectively. One patient showed detectable PCR at the end of treatment (1/17), corresponding to 6% treatment failure, compared with 11/17 (65%) patients pretreatment (
P
= 0.01). Adverse effects were present in 10/20 (50%) patients, but in only one case was treatment suspended. Eight patients showed mild adverse effects, whereas moderate reactions with increased liver enzymes were observed in two patients. The main accomplishment of this pilot study is the promising low rate of treatment suspension. Intermittent administration of benznidazole emerges a new potential therapeutic scheme, the efficacy of which should be confirmed by long-term assessment posttreatment.
Role of Mitochondrial RNA Polymerase in the Toxicity of Nucleotide Inhibitors of Hepatitis C Virus
Authors: Feng Joy Y. , Xu Yili , Barauskas Ona , Perry Jason K. , Ahmadyar Shekeba , Stepan George , Yu Helen , Babusis Darius , Park Yeojin , McCutcheon Krista , Perron Michel , Schultz Brian E. , Sakowicz Roman , Ray Adrian S.
Published: November 2015

Toxicity has emerged during the clinical development of many but not all nucleotide inhibitors (NI) of hepatitis C virus (HCV). To better understand the mechanism for adverse events, clinically relevant HCV NI were characterized in biochemical and cellular assays, including assays of decreased viability in multiple cell lines and primary cells, interaction with human DNA and RNA polymerases, and inhibition of mitochondrial protein synthesis and respiration. NI that were incorporated by the mitochondrial RNA polymerase (PolRMT) inhibited mitochondrial protein synthesis and showed a corresponding decrease in mitochondrial oxygen consumption in cells. The nucleoside released by the prodrug balapiravir (R1626), 4′-azido cytidine, was a highly selective inhibitor of mitochondrial RNA transcription. The nucleotide prodrug of 2′-C-methyl guanosine, BMS-986094, showed a primary effect on mitochondrial function at submicromolar concentrations, followed by general cytotoxicity. In contrast, NI containing multiple ribose modifications, including the active forms of mericitabine and sofosbuvir, were poor substrates for PolRMT and did not show mitochondrial toxicity in cells. In general, these studies identified the prostate cell line PC-3 as more than an order of magnitude more sensitive to mitochondrial toxicity than the commonly used HepG2 cells. In conclusion, analogous to the role of mitochondrial DNA polymerase gamma in toxicity caused by some 2′-deoxynucleotide analogs, there is an association between HCV NI that interact with PolRMT and the observation of adverse events. More broadly applied, the sensitive methods for detecting mitochondrial toxicity described here may help in the identification of mitochondrial toxicity prior to clinical testing.
In Vivo
Microdialysis To Determine Subcutaneous Interstitial Fluid Penetration and Pharmacokinetics of Fluconazole in Intensive Care Unit Patients with Sepsis
Authors: Sinnollareddy Mahipal G. , Roberts Michael S. , Lipman Jeffrey , Lassig-Smith Melissa , Starr Therese , Robertson Thomas , Peake Sandra L. , Roberts Jason A.
Published: November 2015

The objective of the study was to describe the subcutaneous interstitial fluid (ISF) pharmacokinetics of fluconazole in critically ill patients with sepsis. This prospective observational study was conducted at two tertiary intensive care units in Australia. Serial fluconazole concentrations were measured over 24 h in plasma and subcutaneous ISF using microdialysis. The concentrations in plasma and microdialysate were measured using a validated high-performance liquid chromatography system with electrospray mass spectrometer detector method. Noncompartmental pharmacokinetic analysis was performed. Twelve critically ill patients with sepsis were enrolled. The mean
in vivo
fluconazole recovery rates ± standard deviation (SD) for microdialysis were 51.4% ± 16.1% with a mean (±SD) fluconazole ISF penetration ratio of 0.52 ± 0.30 (coefficient of variation, 58%). The median free plasma area under the concentration-time curve from 0 to 24 h (AUC
0–24
) was significantly higher than the median ISF AUC
0–24
(340.4 versus 141.1 mg · h/liter;
P
= 0.004). There was no statistical difference in median fluconazole ISF penetration between patients receiving and not receiving vasopressors (median, 0.28 versus 0.78;
P
= 0.106). Both minimum and the maximum concentrations of drug in serum (
C
max
and
C
min
) showed a significant correlation with the fluconazole plasma exposure (
C
max
,
R
2
=
0.86,
P
< 0.0001;
C
min
,
R
2
= 0.75,
P
< 0.001). Our data suggest that fluconazole was distributed variably, but incompletely, from plasma into subcutaneous interstitial fluid in this cohort of critically ill patients with sepsis. Given the variability of fluconazole interstitial fluid exposures and lack of clinically identifiable factors by which to recognize patients with reduced distribution/exposure, we suggest higher than standard doses to ensure that drug exposure is adequate at the site of infection.
The GraS Sensor in Staphylococcus aureus Mediates Resistance to Host Defense Peptides Differing in Mechanisms of Action
Authors: Chaili Siyang , Cheung Ambrose L. , Bayer Arnold S. , Xiong Yan Q. , Waring Alan J. , Memmi Guido , Donegan Niles , Yang Soo-Jin , Yeaman Michael R.
Published: November 2015

Staphylococcus aureus
uses the two-component regulatory system GraRS to sense and respond to host defense peptides (HDPs). However, the mechanistic impact of GraS or its extracellular sensing loop (EL) on HDP resistance is essentially unexplored. Strains with null mutations in the GraS holoprotein (Δ
graS
) or its EL (ΔEL) were compared for mechanisms of resistance to HDPs of relevant immune sources: neutrophil α-defensin (human neutrophil peptide 1 [hNP-1]), cutaneous β-defensin (human β-defensin 2 [hBD-2]), or the platelet kinocidin congener RP-1. Actions studied by flow cytometry included energetics (ENR); membrane permeabilization (PRM); annexin V binding (ANX), and cell death protease activation (CDP). Assay conditions simulated bloodstream (pH 7.5) or phagolysosomal (pH 5.5) pH contexts.
S. aureus
strains were more susceptible to HDPs at pH 7.5 than at pH 5.5, and each HDP exerted a distinct effect signature. The impacts of Δ
graS
and ΔΕL on HDP resistance were peptide and pH dependent. Both mutants exhibited defects in ANX response to hNP-1 or hBD-2 at pH 7.5, but only hNP-1 did so at pH 5.5. Both mutants exhibited hyper-PRM, -ANX, and -CDP responses to RP-1 at both pHs and hypo-ENR at pH 5.5. The actions correlated with Δ
graS
or ΔΕL hypersusceptibility to hNP-1 or RP-1 (but not hBD-2) at pH 7.5 and to all study HDPs at pH 5.5. An exogenous EL mimic protected mutant strains from hNP-1 and hBD-2 but not RP-1, indicating that GraS and its EL play nonredundant roles in
S. aureus
survival responses to specific HDPs. These findings suggest that GraS mediates specific resistance countermeasures to HDPs in immune contexts that are highly relevant to
S. aureus
pathogenesis in humans.
Impaired Immunogenicity of Meningococcal Neisserial Surface Protein A in Human Complement Factor H Transgenic Mice
Authors: Lujan Eduardo , Pajon Rolando , Granoff Dan M.
Published: November 2015

Neisserial surface protein A (NspA) is a highly conserved outer membrane protein previously investigated as a meningococcal vaccine candidate. Despite eliciting serum bactericidal activity in mice, a recombinant NspA vaccine failed to elicit serum bactericidal antibodies in a phase 1 clinical trial in humans. The discordant results may be explained by the recent discovery that NspA is a human-specific ligand of the complement inhibitor factor H (FH). Therefore, in humans but not mice, NspA would be expected to form a complex with FH, which could impair human anti-NspA protective antibody responses. To investigate this question, we immunized human FH transgenic BALB/c mice with three doses of recombinant NspA expressed in
Escherichia coli
microvesicles, with each dose being separated by 3 weeks. Three of 12 (25%) transgenic mice and 13 of 14 wild-type mice responded with bactericidal titers of ≥1:10 in postimmunization sera (
P
= 0.0008, Fisher's exact test). In contrast, human FH transgenic and wild-type mice immunized with a control meningococcal native outer membrane vesicle vaccine had similar serum bactericidal antibody responses directed at PorA, which is not known to bind human FH, and a mutant factor H binding protein (FHbp) antigen with a >50-fold lower level of FH binding than wild-type FHbp antigen binding.Thus, human FH can impair anti-NspA serum bactericidal antibody responses, which may explain the poor immunogenicity of the NspA vaccine previously tested in humans. A mutant NspA vaccine engineered to have decreased binding to human FH may increase protective antibody responses in humans.