bluuebunny/crossref_metadata_2025 huggingface dataset:
Faster‐acting insulin aspart: earlier onset of appearance and greater early pharmacokinetic and pharmacodynamic effects than insulin aspart
Authors: Heise T. , Hövelmann U. , Brøndsted L. , Adrian C. L. , Nosek L. , Haahr H.
Published: April 2015

Aims

To evaluate the pharmacokinetics and pharmacodynamics of faster‐acting insulin aspart and insulin aspart in a randomized, single‐centre, double‐blind study.

Methods

Fifty‐two patients with type 1 diabetes (mean age 40.3 years) received faster‐acting insulin aspart, insulin aspart, or another faster aspart formulation (not selected for further development), each as a single 0.2 U/kg subcutaneous dose, under glucose‐clamp conditions, in a three‐way crossover design (3–12 days washout between dosing).

Results

Faster‐acting insulin aspart had a faster onset of exposure compared with insulin aspart, shown by a 57% earlier onset of appearance [4.9 vs 11.2 min; ratio 0.43, 95% confidence interval (CI) 0.36; 0.51], a 35% earlier time to reach 50% maximum concentration (20.7 vs 31.6 min; ratio 0.65, 95% CI 0.59; 0.72) and a greater early exposure within 90 min after dosing. The greatest difference occurred during the first 15 min, when area under the serum insulin aspart curve was 4.5‐fold greater with faster‐acting insulin aspart than with insulin aspart. Both treatments had a similar time to maximum concentration, total exposure and maximum concentration. Faster‐acting insulin aspart had a significantly greater glucose‐lowering effect within 90 min after dosing [largest difference: area under the curve for the glucose infusion rate (AUCGIR), 0–30 min ratio 1.48, 95% CI 1.13; 2.02] and 17% earlier time to reach 50% maximum glucose infusion rate (38.3 vs 46.1 min; ratio 0.83, 95% CI 0.73; 0.94). The primary endpoint (AUCGIR, 0–2 h) was 10% greater for faster‐acting insulin aspart, but did not reach statistical significance (ratio 1.10, 95% CI 1.00; 1.22). Both treatments had similar total and maximum glucose‐lowering effects, indicating similar overall potency.

Conclusions

Faster‐acting insulin aspart was found to have earlier onset and higher early exposure than insulin aspart, and a greater early glucose‐lowering effect, with similar potency.
The impact of governance and transparency on firm investment in Vietnam
Authors: Malesky Edmund , McCulloch Neil , Nhat Nguyen Duc
Published: April 2015

A large literature asserts a causal relationship between the quality of economic governance and economic performance. However, attempts to establish such a link at an aggregate level have met with considerable methodological criticism. This paper seeks to overcome this limitation. We match a panel of Vietnamese enterprises from 2006 to 2010 with a unique panel dataset measuring sub‐national economic governance to estimate a relationship between local governance and private investment. We do not find a significant relationship between investment and most traditional forms of governance. However, there is one important exception – transparency, especially the public posting of planning documents, is strongly associated with higher investment across a range of different specifications. Our results have significant implications for policy, given the prevailing theory that changes in the quality of local economic governance will spur improved economic performance.
Outcomes of light‐chain amyloidosis patients treated with first‐line bortezomib: a collaborative retrospective multicenter assessment
Authors: Gatt Moshe E. , Hardan Izhar , Chubar Evgeni , Suriu Celia , Tadmor Tamar , Shevetz Olga , Patachenco Paulina , Dally Najib , Yeganeh Shay , Ballan‐Haj Mouna , Cohen Yael , Trestman Svetlana , Muchtar Eli , Magen Hila , Jakubinsky Julia , Avivi Irit ,   the Israeli MM study group
Published: April 2015

Light‐chain amyloidosis (AL) is associated with low survival rates, particularly in patients with cardiac involvement. We evaluated the outcome of 73 consecutive, non‐selected ‘real‐world’ AL patients, treated with first‐line bortezomib‐based induction, focusing on the benefit of concurrent administration of alkylating agents. Most patients had renal (77%), cardiac (66%), or multiorgan (74%) involvement. Sixty‐eight per cent (n = 50) received alkylating agent (mostly cyclophosphamide). Severe adverse events were seen in 45%, most evident in patients with cardiac involvement, with no increased toxicity in patients receiving an alkylator agent. Hematological response (HemR) was obtained in 77% of patients, including 33% very good partial responses and 19% complete responses. Age <70 yr, lack of cardiac and peripheral neurologic involvement, and co‐administration of an alkylating agent were associated with significantly improved HemR. NYHA cardiac failure staging was the only independent factor affecting overall survival. Administration of an alkylating agent and the achievement of both HemR and organ response were associated with a statistically significant improved survival in those surviving the first 6 months of induction. First‐line bortezomib‐based regimen resulted in favorable response and survival in newly diagnosed patients. Co‐administration of an alkylating agent improved outcome without increasing treatment‐related toxicity.
In vivo relative quantitative proteomics reveals HMGB1 as a downstream mediator of oestrogen‐stimulated keratinocyte migration
Authors: Shin Jung U , Noh Ji Yeon , Lee Ju Hee , Lee Won Jai , Yoo Jong Shin , Kim Jin Young , Kim Hyeran , Jung Inhee , Jin Shan , Lee Kwang Hoon
Published: April 2015

It is known that oestrogen influences skin wound healing by modulating the inflammatory response, cytokine expression and extracellular matrix deposition; accelerating re‐epithelialization; and stimulating angiogenesis. To identify novel proteins associated with effects of oestrogen on keratinocyte, stable isotope labelling by amino acids in cell culture (SILAC)‐based mass spectrometry was performed. Using SILAC, quantification of 1085 proteins was achieved. Among these proteins, 60 proteins were upregulated and 32 proteins were downregulated. Among significantly upregulated proteins, high‐mobility group protein B1 (HMGB1) has been further evaluated for its role in the effect of oestrogen on keratinocytes. HMGB1 expression was strongly induced in oestrogen‐treated keratinocytes in dose‐ and time‐dependent manner. Further, HMGB1 was able to significantly accelerate the rate of HaCaT cell migration. To determine whether HMGB1 is involved in E2‐induced HaCaT cell migration, cells were transfected with HMGB1 siRNA. Knockdown of HMGB1 blocked oestrogen‐induced keratinocyte migration. Collectively, these experiments demonstrate that HMGB1 is a novel downstream mediator of oestrogen‐stimulated keratinocyte migration.
Interaction of Mycobacterium leprae with the HaCaT human keratinocyte cell line: new frontiers in the cellular immunology of leprosy
Authors: Lyrio Eloah C.D. , Campos‐Souza Ivy C. , Corrêa Luiz C.D. , Lechuga Guilherme C. , Verícimo Maurício , Castro Helena C. , Bourguignon Saulo C. , Côrte‐Real Suzana , Ratcliffe Norman , Declercq Wim , Santos Dilvani O.
Published: April 2015

Leprosy is a chronic granulomatous disease caused by Mycobacterium leprae affecting the skin and peripheral nerves. Despite M. leprae invasion of the skin and keratinocytes importance in innate immunity, the interaction of these cells in vitro during M. leprae infection is poorly understood. Conventional and fluorescence optical microscopy, transmission electronic microscopy, flow cytometry and ELISA were used to study the in vitro interaction of M. leprae with the HaCaT human keratinocyte cell line. Keratinocytes uptake of M. leprae is described, and modulation of the surface expression of CD80 and CD209, cathelicidin expression and TNF‐α and IL‐1β production of human keratinocytes are compared with dendritic cells and macrophages during M. leprae interaction. This study demonstrated that M. leprae interaction with human keratinocytes enhanced expression of cathelicidin and greatly increased TNF‐α production. The highest spontaneous expression of cathelicidin was by dendritic cells which are less susceptible to M. leprae infection. In contrast, keratinocytes displayed low spontaneous cathelicidin expression and were more susceptible to M. leprae infection than dendritic cells. The results show, for the first time, an active role for keratinocytes during infection by irradiated whole cells of M. leprae and the effect of vitamin D on this process. They also suggest that therapies which target cathelicidin modulation may provide novel approaches for treatment of leprosy.
Remarriage Beliefs as Predictors of Marital Quality and Positive Interaction in Stepcouples: An Actor–Partner Interdependence Model
Authors: Garneau Chelsea L. , Higginbotham Brian , Adler‐Baeder Francesca
Published: April 2015

Using an Actor–Partner Interdependence Model, we examined remarriage beliefs as predictors of marital quality and positive interaction in a sample of 179 stepcouples. Three beliefs were measured using subscales from the Remarriage Belief Inventory (RMBI) including success is slim, children are the priority, and finances should be pooled. Several significant actor and partner effects were found for both wives' and husbands' beliefs. Wives' marital quality was positively associated with their own beliefs that finances should be pooled and negatively associated with their own beliefs that success is slim. Wives' reports of their own and spouses' positive interaction were both positively associated with their beliefs that finances should be pooled. Their reports of spouses' positive interaction were also negatively associated with husbands' beliefs that success is slim. Husbands' marital quality was positively associated with wives' beliefs that children are the priority, positively associated with their own beliefs that finances should be pooled, and negatively with success is slim. Positive interaction for husbands was positively associated with wives' beliefs that finances should be pooled and negatively associated with their own beliefs that success is slim. Finally, husbands' reports of positive interaction for their spouses were positively associated with wives' beliefs that finances should be pooled. Implications for future research utilizing dyadic data analysis with stepcouples are addressed.
Molecular features of the sortase enzyme family
Authors: Bradshaw William J. , Davies Abigail H. , Chambers Christopher J. , Roberts April K. , Shone Clifford C. , Acharya K. Ravi
Published: April 2015

Bacteria possess complex and varying cell walls with many surface exposed proteins. Sortases are responsible for the covalent attachment of specific proteins to the peptidoglycan of the cell wall of Gram‐positive bacteria. Sortase A of Staphylococcus aureus, which is seen as the archetypal sortase, has been shown to be essential for pathogenesis and has therefore received much attention as a potential target for novel therapeutics. Being widely present in Gram‐positive bacteria, it is likely that other Gram‐positive pathogens also require sortases for their pathogenesis. Sortases have also been shown to be of significant use in a range of industrial applications. We review current knowledge of the sortase family in terms of their structures, functions and mechanisms and summarize work towards their use as antibacterial targets and microbiological tools.
Large carbon release legacy from bark beetle outbreaks across Western United States
Authors: Ghimire Bardan , Williams Christopher A. , Collatz G. James , Vanderhoof Melanie , Rogan John , Kulakowski Dominik , Masek Jeffrey G.
Published: April 2015

Warmer conditions over the past two decades have contributed to rapid expansion of bark beetle outbreaks killing millions of trees over a large fraction of western United States (US) forests. These outbreaks reduce plant productivity by killing trees and transfer carbon from live to dead pools where carbon is slowly emitted to the atmosphere via heterotrophic respiration which subsequently feeds back to climate change. Recent studies have begun to examine the local impacts of bark beetle outbreaks in individual stands, but the full regional carbon consequences remain undocumented for the westernUS. In this study, we quantify the regional carbon impacts of the bark beetle outbreaks taking place in westernUSforests. The work relies on a combination of postdisturbance forest regrowth trajectories derived from forest inventory data and a process‐based carbon cycle model tracking decomposition, as well as aerial detection survey (ADS) data documenting the regional extent and severity of recent outbreaks. We find that biomass killed by bark beetle attacks across beetle‐affected areas in westernUSforests from 2000 to 2009 ranges from 5 to 15 Tg C yr−1and caused a reduction of net ecosystem productivity (NEP) of about 6.1–9.3 Tg C y−1by 2009. Uncertainties result largely from a lack of detailed surveys of the extent and severity of outbreaks, calling out a need for improved characterization across westernUSforests. The carbon flux legacy of 2000–2009 outbreaks will continue decades into the future (e.g., 2040–2060) as committed emissions from heterotrophic respiration of beetle‐killed biomass are balanced by forest regrowth and accumulation.
Brain metabolism in minimal hepatic encephalopathy assessed by 3.0‐Tesla magnetic resonance spectroscopy
Authors: Kooka Yohei , Sawara Kei , Endo Ryujin , Kato Akinobu , Suzuki Kazuyuki , Takikawa Yasuhiro
Published: April 2015

Aim

To examine whether the brain exhibits metabolic disorder prior to overt hepatic encephalopathy in patients with liver cirrhosis (LC), the intracerebral glutamine and myo‐inositol levels were determined using 3.0‐Tesla (T)1H (proton) magnetic resonance spectroscopy (MRS).

Methods

We tested 21 LC patients, including seven patients with minimal hepatic encephalopathy (MHE).

Results

No significant differences were noted between the two patient groups in terms of the severity of LC, levels of blood ammonia or levels of blood or liver enzymes. In the MHE group, the levels of brain glutamine were significantly higher than those in the non‐MHE group, whereas the levels of brain myo‐inositol were significantly lower. This demonstrated that MHE patients were already exhibiting metabolic disorder in the brain, similar to those observed during overt hepatic encephalopathy.

Conclusion

A quantitative analysis of this phenomenon using MRS may contribute to an early and objective diagnosis of MHE.
Recent developments in the sensorial assessment of cosmetic products: a review
Authors: Pensé‐Lhéritier A.‐M.
Published: April 2015

Synopsis

Cosmetic development is not exclusively guided by notions of rational effectiveness but also by notions of sensoriality. Thus, the sensorial properties of a cosmetic product are studied using internationally recognized discriminating or descriptive methods. Descriptive sensory profiling is an essential tool in this process as it allows an experienced panel to assess the qualitative and quantitative characteristics of a product. The results obtained with this method enable to get a more accurate image of the product. However, given the new demands of the industrial world and the new innovation paths (shorter development times, complex products or willingness to include the consumers in the process) a need to access new methods has arisen. These ‘alternative’ methods that offer product positioning, ratings and attribute citation frequency, can be implemented with either a panel of experts or with consumers. The flash profile, the pivot® profile or the check all that apply (CATA) are just a few of the methods that the cosmetic professionals have started to test. This article reviews the methods used in the sensory assessment of cosmetic products. The analysis carried out shows that the complementarity application of sensory assessment is essential in the upstream innovation phase of a product.
Push‐out bond strength of root fillings made with C‐Point and BC sealer versus gutta‐percha and AH Plus after the instrumentation of oval canals with the Self‐Adjusting File versus WaveOne
Authors: Pawar A. M. , Pawar S. , Kfir A. , Pawar M. , Kokate S.
Published: April 2015

Aim

To compare the push‐out bond strength exhibited by root fillings performed with either C‐Point and Endosequence® BC sealer™ (BC Sealer) or gutta‐percha and AH Plus® after the instrumentation of oval canals with either the Self‐Adjusting File (SAF) System or WaveOne (WO) reciprocating file.

Methodology

Eighty extracted premolars were selected and divided randomly into the following four groups (n = 20): group 1, SAF instrumentation and filling using gutta‐percha and AH Plus sealer; group 2, SAF instrumentation and C‐Point and BC sealer filling; group 3, WO instrumentation and filling using gutta‐percha and AH Plus sealer; and group 4, WO instrumentation and filling with C‐Point and BC sealer. Sodium hypochlorite (5.25%) and EDTA (17%) were used as irrigants for all groups. After the sealer was set completely, the teeth were prepared for micro push‐out assessment using 1.0‐mm‐thick root slices. Loading was performed with a universal testing machine at a speed of 0.5 mm min−1. Two‐way anova and Student's t‐test for pairwise comparisons were used to compare groups.

Results

All specimens filled with C‐Point and BC sealer were associated with significantly higher push‐out bond strength compared with gutta‐percha and AH Plus sealer (P < 0.001). The bond strength was higher for the coronal and apical samples of the C‐Point/BC sealer/SAF group (6.6 ± 0.3 and 3.2 ± 0.3 MPa) versus those of the gutta‐percha/AH Plus/WO group (4.8 ± 0.3 and 1.8 ± 0.3 MPa), by 38% and by 80% in the coronal and apical parts, respectively (P < 0.001, P < 0.0001). Adhesive bond failure was more common in the WaveOne‐instrumented group in general and in the buccal and lingual recesses in this group in particular.

Conclusions

In oval canals, the instrument used and the root filling material significantly affected the push‐out values of root fillings. The highest value was recorded in oval root canals instrumented with the SAF System and filled with C‐Point and BC sealer, whereas the lowest strength was noted in oval canals instrumented with WaveOne and filled with gutta‐percha and AH Plus sealer.
Exploring Auditors' Perceptions of the Usage and Importance of Audit Information Technology
Authors: Abou‐El‐Sood Heba , Kotb Amr , Allam Amir
Published: April 2015

This study provides novel evidence on the extent to which auditors perceive the usage and importance of audit technology in an emerging market. It explores the types of audit technology tools used and factors influencing the use of these; it tests the association between the perceived use and importance of the tools and firm‐specific/auditor‐specific characteristics. Using interviews and questionnaires from auditors at Big 4 and international non‐Big 4 audit firms, the findings reflect the highly perceived importance of using audit technology in technical and administrative procedures, specifically to assess risk. We find that the perceived use and importance of audit technology is relatively higher for those in Big 4 firms, with less years of auditor experience and higher auditor technology expertise, and those in management positions. The results provide policy makers with guidance on the opportunities and challenges of using information technology in the audit process.
Human spleen microanatomy: why mice do not suffice
Authors: Steiniger Birte S.
Published: April 2015

The microanatomical structure of the spleen has been primarily described in mice and rats. This leads to terminological problems with respect to humans and their species‐specific splenic microstructure. In mice, rats and humans the spleen consists of the white pulp embedded in the red pulp. In the white pulp, T and B lymphocytes form accumulations, the periarteriolar lymphatic sheaths and the follicles, located around intermediate‐sized arterial vessels, the central arteries. The red pulp is a reticular connective tissue containing all types of blood cells. The spleen of mice and rats exhibits an additional well‐delineated B‐cell compartment, the marginal zone, between white and red pulp. This area is, however, absent in human spleen. Human splenic secondary follicles comprise three zones: a germinal centre, a mantle zone and a superficial zone. In humans, arterioles and sheathed capillaries in the red pulp are surrounded by lymphocytes, especially by B cells. Human sheathed capillaries are related to the splenic ellipsoids of most other vertebrates. Such vessels are lacking in rats or mice, which form an evolutionary exception. Capillary sheaths are composed of endothelial cells, pericytes, special stromal sheath cells, macrophages and B lymphocytes. Human spleens most probably host a totally open circulation system, as connections from capillaries to sinuses were not found in the red pulp. Three stromal cell types of different phenotype and location occur in the human white pulp. Splenic white and red pulp structure is reviewed in rats, mice and humans to encourage further investigations on lymphocyte recirculation through the spleen.
Association of PPAR‐γ2 and β3‐AR Polymorphisms With Postmenopausal Hypertension
Authors: Grygiel‐Górniak Bogna , Kaczmarek Elżbieta , Mosor Maria , Przysławski Juliusz , Nowak Jerzy
Published: April 2015

The aim of this study was to test the association of peroxisome proliferator‐activated receptor (PPAR‐γ2) (Pro12Ala, C1431T) and β3‐AR (Trp64Arg) polymorphisms with metabolic, nutritional, and blood pressure parameters in 271 postmenopausal women (151 hypertensive and 120 normotensive controls). The TaqMan genotyping assay and restriction fragment length polymorphism methods were used to determine the distributions of selected alleles and genotype frequencies. Nutritional status was determined by a bioimpedance method and dietary habits were assessed via 7‐day dietary recall. The distribution of selected genotypes and allele frequencies did not differ between hypertensive women and normal controls after analysis by chi‐square test. The postmenopausal hypertensive women were older and had higher body fat mass, serum glucose, and triglyceride levels. The cluster analysis showed that the hypertensive group with Pro12Pro genotype had highest pulse pressure and mean arterial pressure values when compared with Pro12Ala patients. In the logistic regression analysis, blood glucose (Pro12Ala polymorphism) and energy intake (C1431Tand T1431T polymorphisms) determined hypertension.
Values‐based practice and phenomenological psychopathology: implications of existential changes in depression
Authors: Fernandez Anthony Vincent , Wieten Sarah
Published: April 2015

Values‐based practice (VBP), developed as a partner theory to evidence‐based medicine (EBM), takes into explicit consideration patients' and clinicians' values, preferences, concerns and expectations during the clinical encounter in order to make decisions about proper interventions.VBPtakes seriously the importance of life narratives, as well as how such narratives fundamentally shape patients' and clinicians' values. It also helps to explain difficulties in the clinical encounter as conflicts of values. While we believe thatVBPadds an important dimension to the clinician's reasoning and decision‐making procedures, we argue that it ignores the degree to which values can shift and change, especially in the case of psychiatric disorders.VBPdoes this in three respects. First, it does not appropriately engage with the fact that a person's values can change dramatically in light of major life events. Second, it does not acknowledge certain changes in the way people value, or in their modes of valuing, that occur in cases of severe psychiatric disorder. And third, it does not acknowledge the fact that certain disorders can even alter the degree to which one is capable of valuing anything at all. We believe that ignoring such changes limits the degree to whichVBPcan be effectively applied to clinical treatment and care. We conclude by considering a number of possible remedies to this issue, including the use of proxies and written statements of value generated through interviews and discussions between patient and clinician.
Development of mature BDNF‐specific sandwich ELISA
Authors: Lim Yoon , Zhong Jin‐Hua , Zhou Xin‐Fu
Published: April 2015

Mature brain‐derived neurotrophic factor (mBDNF) plays a vital role in the nervous system, whereas proBDNF elicits neurodegeneration and neuronal apoptosis. Although current enzyme‐linked immunosorbent assay (ELISA) has been widely used to measure BDNF levels, it cannot differentiate mBDNF from proBDNF. As the function of proBDNF differs from mBDNF, it is necessary to establish an ELISA assay specific for the detection of mBDNF. Therefore, we aimed to establish a new mBDNF‐specific sandwich ELISA. In this study, we have screened and found a combination of antibodies for a sandwich ELISA. A monoclonal antibody and sheep anti‐BDNF were chosen as capture and detection antibody for sandwich ELISA respectively. The new ELISA showed no cross‐reactivity to human recombinant NT‐3, NT‐4, nerve growth factor and negligible cross‐reactivity (0.99–4.99%) for proBDNF compared to commercial ELISA kits (33.18–91.09%). The application of the new mBDNF ELISA was shown through the measurement of mBDNF levels in different brain regions of rats and in the brain of β‐site amyloid precursor protein cleaving enzyme 1 (BACE1)−/− and WT mice and compared to western blot. Overall, this new ELISA will be useful for the measurement of mBDNF levels with high specificity.

image

As the function of proBDNF differs from mBDNF (mature BDNF), it is necessary to establish an ELISA specific for the detection of mBDNF. Here, we present a novel sandwich ELISA which detects mBDNF with high specificity. This new ELISA will be useful for the measurement of mBDNF levels with high specificity in various human and animal tissues. proBDNF, precursor of BDNF; BDNF, brain‐derived neurotrophic factor; NT‐3, neurotrophin‐3; NT‐4, neurotrophin‐4; NGF, nerve growth factor.
Intraoral diode laser epiglottectomy for treatment of epiglottis chondrosarcoma in a dog
Authors: De Lorenzi D. , Bertoncello D. , Dentini A.
Published: April 2015

Laryngeal tumours are rare in dogs. Surgery is the treatment of choice, but it is usually palliative in malignant conditions, due to advanced stage of the tumour at the time of diagnosis. In veterinary medicine, little information is available about the use of diode laser in laryngeal oncological surgery. In the case reported here, a dog with an epiglottic chondrosarcoma was successfully treated with diode laser epiglottectomy. The surgical technique and follow up are described.
Social support moderates the effects of stress on sleep in adolescents
Authors: van Schalkwijk Frank J. , Blessinga Agaath N. , Willemen Agnes M. , Van Der Werf Ysbrand D. , Schuengel Carlo
Published: April 2015

Academic expectations and demands become primary sources of stress during adolescence, negatively affecting sleep. To cope with stress, adolescents may turn to social support figures. The present study tested the extent of main and moderating effects of various sources of social support on the association between stress and sleep. Adolescents (n = 202, meanage 14.6 years, standard deviation = 0.71) reported on academic stress, sleep, and support using questionnaires during a low‐ and high‐stress period, defined by the absence or presence of examinations, respectively. Inquiries were made regarding social support from parents, friends, and class supervisor. During both stress periods, academic stress was associated negatively with sleep quality and positively with sleep reduction. Social support increased sleep quality and lowered sleep reduction. In addition, social support moderated the effects of academic stress on sleep, thus improving sleep quality and lowering sleep reduction. Moderating effects were stronger during a period of high stress. The present study showed that adolescents can benefit from stress moderation through social support by improvements of sleep quality and sleep reduction. Such moderating effects should be taken into account when studying stress and sleep. Implications and recommendations based on these findings are discussed.
Hepatitis B reactivation in multiple myeloma patients with resolved hepatitis B undergoing chemotherapy
Authors: Lee Ji Yun , Lim Sung Hee , Lee Min‐Young , Kim Haesu , Sinn Dong Hyun , Gwak Geum‐Youn , Choi Moon Seok , Lee Joon Hyeok , Jung Chul Won , Jang Jun Ho , Kim Won Seog , Kim Seok Jin , Kim Kihyun
Published: April 2015

Background & Aims

Despite increasing reports of hepatitis B virus (HBV) reactivation in multiple myeloma (MM), HBV reactivation in patients with resolved hepatitis B [hepatitis B surface antigen (HBsAg)‐negative/anti‐hepatitis B core antigen antibody (anti‐HBc)‐positive] is still poorly characterized. The aim of this study was to clarify its frequency and risk factors.

Methods

A total of 230 MM patients with resolved hepatitis B were retrospectively reviewed for HBV reactivation and biochemical flare.

Results

During a median 2.4 years of follow‐up, HBV reactivation was diagnosed in 12 patients (5.2%). The cumulative rates of HBV reactivation at 2 years and 5 years were 5% and 8% respectively. A baseline anti‐HBs‐negative status (P = 0.033) and high‐dose therapy/autologous stem‐cell transplantation [HDT/ASCT (P = 0.025)] were significant risk factors that were positively associated with HBV reactivation. In subgroup analysis of patients treated with HDT/ASCT (n = 127), a baseline anti‐HBs‐negative status was the only significant risk factor for HBV reactivation (hazard ratio, 4.64; 95% CI, 1.47–14.7; P = 0.009).

Discussion

These data show that evaluation of anti‐HBc is needed for MM patients, and suggest that monitoring of HBV DNA should be considered for patients with resolved hepatitis B undergoing HDT/ASCT, especially those who are anti‐HBs‐negative.
Demystifying computer science for molecular ecologists
Authors: Belcaid Mahdi , Toonen Robert J.
Published: April 2015

In this age of data‐driven science and high‐throughput biology, computational thinking is becoming an increasingly important skill for tackling both new and long‐standing biological questions. However, despite its obvious importance and conspicuous integration into many areas of biology, computer science is still viewed as an obscure field that has, thus far, permeated into only a few of the biology curricula across the nation. A national survey has shown that lack of computational literacy in environmental sciences is the norm rather than the exception [Valle & Berdanier (2012) Bulletin of the Ecological Society of America, 93, 373–389]. In this article, we seek to introduce a few important concepts in computer science with the aim of providing a context‐specific introduction aimed at research biologists. Our goal was to help biologists understand some of the most important mainstream computational concepts to better appreciate bioinformatics methods and trade‐offs that are not obvious to the uninitiated.
Cytochrome c biogenesis in Campylobacter jejuni requires cytochrome c6 (CccA; Cj1153) to maintain apocytochrome cysteine thiols in a reduced state for haem attachment
Authors: Liu Yang‐Wei , Kelly David J.
Published: April 2015

The microaerophilic food‐borne pathogen Campylobacter jejuni uses complex cytochrome‐rich respiratory chains for growth and host colonisation. Cytochrome c biogenesis requires haem ligation to reduced apocytochrome cysteines, catalysed by the cytochrome c synthase, CcsBA. While ccsBA could not be deleted, we showed that the thiol reductase DsbD and the CcsX homologue Cj1207 are involved in, but not essential for, cytochromes c biogenesis. Mutant phenotypic analyses and biochemical studies with purified proteins revealed that the mono‐haem c‐type cytochromes Cj1153 (CccA) and Cj1020 (CccB) and the di‐haem Cj0037 (CccC) are electron donors to the cb‐oxidase (CcoNOQP), with CccC being more efficient than CccA. Remarkably, cccA deletion or site‐directed mutagenesis resulted in an almost complete loss of all other c‐type cytochromes. Cytochrome c structural and biogenesis genes were still transcribed in the cccA deletion mutant and the quinol oxidase genes (cioAB) were up‐regulated. Cytochrome c production could be rescued in this mutant by growth with exogenous dithiothreitol or L‐cysteine, suggesting that in the absence of CccA, apocytochrome c haem binding motifs become oxidised, preventing haem attachment. Our results identify CccA, the most abundant periplasmic c‐type cytochrome in C. jejuni, as a novel and unexpected protein required for cytochrome c biogenesis in this pathogen.
A meta‐analysis of immunogenetic Case–Control Association Studies in irritable bowel syndrome
Authors: Czogalla B. , Schmitteckert S. , Houghton L. A. , Sayuk G. S. , Camilleri M. , Olivo‐Diaz A. , Spiller R. , Wouters M. M. , Boeckxstaens G. , Lorenzo Bermejo J. , Niesler B.
Published: April 2015

Background

To date, genetic‐association studies of single nucleotide polymorphisms (SNP) in selected candidate genes with the symptom phenotype of irritable bowel syndrome (IBS) have typically involved hundreds to 2000 patients. SNPs in immune‐related genes, such as cytokine and cytokine receptor encoding genes, have been reported to associate with IBS risk.

Methods

We conducted two independent case–control studies on 16 SNPs in IL1R1, IL4, IL6, IL8, IL10, IL23R, TNFA, and TNFSF15, one from the UK (194 patients and 92 healthy volunteers) and one from the USA (137 patients and 96 healthy volunteers). The main aim was to examine the relationship between inherited immunological diversity and IBS risk in a meta‐analysis which included 12 additional, earlier studies. The meta‐analysis comprised a total of 2894 patients (839 IBS‐C, 1073 IBS‐D, 502 IBS‐M), and 3138 healthy volunteers with self‐reported Caucasian ancestry.

Key Results

The association of SNP rs4263839 (TNFSF15) was investigated in four studies and confirmed in the meta‐analysis: IBS (OR 1.19, 95% CI 1.08–1.31), and IBS‐C (OR 1.24, 95% CI 1.08–1.42). No additional SNPs residing in immunogenes associated with IBS symptom phenotypes.

Conclusions & Inferences

Our meta‐analysis could not confirm a major role of most investigated SNPs, but a moderate association between rs4263839 TNFSF15 and IBS, in particular IBS‐C. The analysis emphasizes the importance of definition and phenotype homogeneity, adequate study size and representativeness of the patient and control collective.
Identification of amino acid residues involved in hemin binding in Porphyromonas gingivalis hemagglutinin 2
Authors: Yang Q.B. , Yu F.Y. , Sun L. , Zhang Q.X. , Lin M. , Geng X.Y. , Sun X.N. , Li J.L. , Liu Y.
Published: April 2015

Porphyromonas gingivalis (P. gingivalis) is a major etiological agent in the development and progression of chronic periodontitis. It produces cysteine proteases (gingipains), including a lysine‐specific gingipain and two arginine‐specific gingipains. Heme binding and uptake are fundamental to the growth and virulence of P. gingivalis. The recombinant hemagglutinin 2 domain (rHA2) of gingipain binds hemin with high affinity. The aim of the present work was to identify the key residues involved in its hemin‐binding activity. A functional rHA2 was expressed and bound to hemin‐agarose, and then digested with endopeptidases. The peptides bound to hemin‐agarose were identified by mass spectrometry and the amino acids were assessed by mutation and peptide binding inhibition analysis. The DHYAVMISK sequence was identified in peptides derived from both Asp‐N and Lys‐C endopeptidase digestions of rHA2. A monoclonal antibody, mAb QB, was produced and its epitope was associated with the DGFPGDHYAVMISK peptide within the HA2 domain. Hemin was shown to competitively inhibit the immunoreactivity of rHA2 or the peptide to mAb QB. The peptide DHYAVMISK inhibited hemin‐binding activity; although, this inhibition was not seen when the peptide contained the H1001E mutation (DEYAVMISK). Based on these results, we propose that residue His1001 is involved in the hemin‐binding mechanism of the P. gingivalis rHA2 and the peptide containing this residue, DHYAVMISK, may be an inhibitor of hemin binding.
Locke on Knowing Our Own Ideas (and Ourselves)
Authors: Weinberg Shelley
Published: April 2015

Locke defines knowledge as the perception of the agreement or disagreement of ideas. Nevertheless, he claims that we know particular things: the identity of our ideas, our own existence, and the existence of external objects. Although much has been done to reconcile the definition of knowledge with our knowledge of external objects, there is virtually nothing in the scholarship when it comes to knowing ideas or our own existence. I fill in this gap by arguing that perceptions of ideas are complex mental states that convey propositional knowledge due to agreeing elements therein.
Metabolic and transcriptomic signatures of rice floral organs reveal sugar starvation as a factor in reproductive failure under heat and drought stress
Authors: Li Xia , Lawas Lovely M. F. , Malo Richard , Glaubitz Ulrike , Erban Alexander , Mauleon Ramil , Heuer Sigrid , Zuther Ellen , Kopka Joachim , Hincha Dirk K. , Jagadish Krishna S. V.
Published: April 2015

Heat and drought stress are projected to become major challenges to sustain rice (Oryza sativa L.) yields with global climate change. Both stresses lead to yield losses when they coincide with flowering. A significant knowledge gap exists in the mechanistic understanding of the responses of rice floral organs that determine reproductive success under stress. Our work connects the metabolomic and transcriptomic changes in anthers, pistils before pollination and pollinated pistils in a heat‐tolerant (N22) and a heat‐sensitive (Moroberekan) cultivar. Systematic analysis of the floral organs revealed contrasts in metabolic profiles across anthers and pistils. Constitutive metabolic markers were identified that can define reproductive success in rice under stress. Six out of nine candidate metabolites identified by intersection analysis of stressed anthers were differentially accumulated in N22 compared with Moroberekan under non‐stress conditions. Sugar metabolism was identified to be the crucial metabolic and transcriptional component that differentiated floral organ tolerance or susceptibility to stress. While susceptible Moroberekan specifically showed high expression of the Carbon Starved Anthers (CSA) gene under combined heat and drought, tolerant N22 responded with high expression of genes encoding a sugar transporter (MST8) and a cell wall invertase (INV4) as markers of high sink strength.
Biochemical markers subtyping major depressive disorder
Authors: Kunugi Hiroshi , Hori Hiroaki , Ogawa Shintaro
Published: April 2015

The pathophysiology of major depressive disorder (MDD) remains elusive, and there is no established biochemical marker used in the daily clinical setting. This situation may result in part from the heterogeneity of MDD, which might include heterogeneous subgroups with different biological mechanisms. In this review, we discuss three promising biological systems/markers to potentially subtype MDD: the dopamine system, the hypothalamic–pituitary–adrenal axis, and chronic inflammatory markers. Several lines of evidence suggest that a facet of MDD is a dopamine agonist‐responsive subtype. Focusing on the hypothalamic–pituitary–adrenal axis, depressive spectrum disorders show hypercortisolism to hypocortisolism, which could be detected by hormonal challenge tests, such as the dexamethasone/corticotrophin‐releasing hormone test. Finally, accumulating evidence suggests that at least some MDD patients show characteristics similar to those of chronic inflammatory diseases, including neuroinflammatory markers and reduced tryptophan due to the increased activation of the tryptophan–kynurenine pathway. Future studies should examine the inter‐relations between these systems/markers to subtype and integrate the pathophysiology of MDD.
Assessing allocation of responsibility for health management in pediatric liver transplant recipients
Authors: Bilhartz Jacob L. , Lopez M. James , Magee John C. , Shieck Victoria L. , Eder Sally J. , Fredericks Emily M.
Published: April 2015

Given the increased risk for non‐adherence and poor health outcomes in late adolescence, there is a need for better methods to evaluate and improve the transition process as adolescent patients are prepared to be independent adults. This study assessed the psychometrics and concurrent validity of a newly developed measure of AoR for health management in pediatric liver transplant patients. A total of 48 patients and 37 parents completed a 13‐item measure of AoR. We performed an exploratory PCA on survey results and used component scores to assess the relationship between AoR and age, age at transplant, adherence, and health outcomes. Two primary components were identified: communication with the healthcare system and self‐management tasks. Parent perception of adolescent responsibility for tasks related to communicating with the healthcare system was correlated, in younger patients, with increased non‐adherence while responsibility for tasks related to self‐management was correlated, in older patients, with decreased non‐adherence. These results support AoR as a two‐domain construct, and they provide targets for monitoring and intervention as adolescent patients advance toward transfer.
Molecular analysis of isolated tumor glands from endometrial endometrioid adenocarcinomas
Authors: Suga Yasuko , Sugai Tamotsu , Uesugi Noriyuki , Kawasaki Tomonori , Fukagawa Tomoyuki , Yamamoto Eiichiro , Ishida Kazuyuki , Suzuki Hiromu , Sugiyama Toru
Published: April 2015

We studied the extensive molecular alterations of endometrial endometrioid adenocarcinoma (EEA) using a crypt isolation method. We analyzed copy number variation (CNV) using a single nucleotide polymorphism (SNP) array, genetic mutations (KRAS, BRAF, p53, PIK3CA), DNA methylation and microsatellite instability (MSI) status. In addition, loss of PTEN protein expression was examined. Increased chromosome copy numbers of 1q21.2–44 (22%) and 10q11.21–23.31 (28%) were seen relatively frequently in EEA, and copy‐neutral loss of heterozygosity (LOH) was also observed in 10q22.1–26.3 (22%). The CNV patterns of EEA were classified into four groups through hierarchical cluster analysis. Cluster 1 had many CNVs of 10q, and cluster 2 was characterized by MSI status. In cluster 3, increased CNVs of 1q were often seen. In cluster 4, p53 mutations were detected. KRAS and PIK3CA mutations and reduced PTEN protein expression were common to all groups. On the other hand, CpG island methylator phenotype (CIMP) was rare in all groups. The data indicated an association with chromosomal gain of 1q and 10q or 10q copy‐neutral LOH in some cases. We suggest that EEA consists of four groups that are characterized with molecular alterations.
Addressing the Challenge of Modeling for Decision‐Making in Socially Responsible Operations
Authors: Besiou Maria , Van Wassenhove Luk N.
Published: April 2015

Companies seek sustainability by combining the quest for profitability with the pursuit of social responsibility. Since socially responsible operations are characterized by the presence of multiple stakeholders with conflicting goals, applying classical optimization models would seem premature; we first need to capture the behavior of the entire system before attempting to optimize sub‐systems to ensure that we focus on the ones driving the behavior of interest. Alternative methodologies are required if we are to gain insight into the most important drivers of socially responsible operations in order to apply traditional operations research (OR)/management science (MS) models correctly. This study presents an umbrella approach which combines different methodologies to tackle the complexity, unfamiliar context, and counter‐intuitive behavior of socially responsible operations at the overall system level.
Seeing what we hear: an eye to help the ear
Authors: Joshi Manish , Bartter Thaddeus
Published: April 2015

See article, page 633
Florence on foot: an eye‐level mapping of the early modern city in time of plague
Authors: Eckstein Nicholas A.
Published: April 2015

As plague approached in August 1630, Florence's health officials commissioned the aristocratic lay brothers of the confraternity of the Archangel Michael (‘San Michele’) to search the city's streets and alleys for signs of disease. While the extraordinary record of this ‘Visitation’ is known to health historians, the present article instead relates it to a long history of urban surveys and censuses in which Florentines fashioned themselves in intimate relation to the physical spaces and places of the urban environment. In August 1630 this process of mental mapping produced a malodorous inversion of the patriotic visions we popularly associate with the birthplace of the Italian Renaissance. Florence emerges in the Visitation as a nightmare city drowning in ordure, suffocating on its own fumes and leaking like a sieve. Spatial intimacy, usually associated with notions of productive neighbourhood sociability and community, appears here as an existential threat. Meanwhile, San Michele's fratelli were forced to balance genuine Christian compassion for the suffering men and women whom they were pledged to assist with long‐standing suspicion of the poor, both as a class and as the potential vectors of pestilence.
Nonlinear Model Predictive Control of Integrated Diesel Engine and Selective Catalytic Reduction System for Simultaneous Fuel Economy Improvement and Emissions Reduction
Authors: Chen Pingen , Wang Junmin
Published: April 2015

The applications of diesel engines in ground vehicles have attracted much attention over the past decade for the reasons of outstanding fuel economy, power capability, and reliability. With the increasing demand of less greenhouse gas emissions, the current diesel engine fuel efficiency remains unsatisfactory partially due to the conflict between the engine fuel efficiency and engine-out NOx emissions. While advanced aftertreatment systems, such as selective catalytic reduction (SCR) systems or lean NOx trap, have been integrated to diesel engines for reducing the tailpipe NOx emissions, the integrated controls for coordinating diesel engine and SCR system to achieve high engine efficiency and low tailpipe emissions are still limited. The purpose of this study is to develop such an integrated diesel engine and SCR system control method using nonlinear model predictive control (NMPC) approach with both start of injection (SOI) timing and urea solution injection rate as the control inputs. Control-oriented engine models were developed to quantify the influences of SOI timing on engine efficiency and engine-out NOx emissions. Simulation results under US06 driving cycle demonstrate that, given the same catalyst size in total, the proposed controllers are capable of reducing total engine fuel consumption over the driving cycle by 9.36% and 9.50%, respectively, for lumped SCR system and two-cell SCR system, while maintaining high NOx conversion efficiencies and low tailpipe ammonia slip.