bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Variation in the Multidrug and Toxin Extrusion 1 Transporter Protein Influences the Glucose-Lowering Effect of Metformin in Patients With Diabetes: A Preliminary Study
Authors: Becker Matthijs L. , Visser Loes E. , van Schaik Ron H.N. , Hofman Albert , Uitterlinden André G. , Stricker Bruno H.Ch.
Published: February 2009

OBJECTIVE— Metformin, an oral glucose-lowering drug, is taken up in hepatocytes by the organic cation transporter (OCT) 1 and in renal epithelium by OCT2. In these cells, the multidrug and toxin extrusion (MATE) 1 protein, encoded by the SLC47A1 gene, is responsible for the excretion of metformin into the bile and urine, respectively. We studied the effect of single nucleotide polymorphisms (SNPs) in the SLC47A1 gene on the A1C-lowering effect of metformin.

RESEARCH DESIGN AND METHODS— We identified all incident metformin users in the Rotterdam Study, a population-based cohort study. Associations between 12 tagging SNPs in the SLC47A1 gene and change in A1C level were analyzed.

RESULTS— One hundred and sixteen incident metformin users were included in the study sample. The rs2289669 G>A SNP was significantly associated with metformin response. For the other SNPs, no associations were found. For each minor A allele at rs2289669, the A1C reduction was 0.30% (95% CI −0.51 to −0.10; P = 0.005) larger. After Bonferroni correction for multiple testing, the P value was 0.045.

CONCLUSIONS— The rs2289669 G>A SNP is associated with a reduction in A1C level, consistent with a reduction in MATE1 transporter activity. These results suggest that the transporter MATE1, encoded by SLC47A1, may have an important role in the pharmacokinetics of metformin, although replication is necessary.
A−β− Subtype of Ketosis-Prone Diabetes Is Not Predominantly a Monogenic Diabetic Syndrome
Authors: Haaland Wade C. , Scaduto Diane I. , Maldonado Mario R. , Mansouri Dena L. , Nalini Ramaswami , Iyer Dinakar , Patel Sanjeet , Guthikonda Anu , Hampe Christiane S. , Balasubramanyam Ashok , Metzker Michael L.
Published: February 2009

OBJECTIVE

Ketosis-prone diabetes (KPD) is an emerging syndrome that encompasses several distinct phenotypic subgroups that share a predisposition to diabetic ketoacidosis. We investigated whether the A−β− subgroup of KPD, characterized by complete insulin dependence, absent β-cell functional reserve, lack of islet cell autoantibodies, and strong family history of type 2 diabetes, represents a monogenic form of diabetes.

RESEARCH DESIGN AND METHODS

Over 8 years, 37 patients with an A−β− phenotype were identified in our longitudinally followed cohort of KPD patients. Seven genes, including hepatocyte nuclear factor 4A (HNF4A), glucokinase (GCK), HNF1A, pancreas duodenal homeobox 1 (PDX1), HNF1B, neurogenic differentiation 1 (NEUROD1), and PAX4, were directly sequenced in all patients. Selected gene regions were also sequenced in healthy, unrelated ethnically matched control subjects, consisting of 84 African American, 96 Caucasian, and 95 Hispanic subjects.

RESULTS

The majority (70%) of the A−β− KPD patients had no significant causal polymorphisms in either the proximal promoter or coding regions of the seven genes. The combination of six potentially significant low-frequency, heterozygous sequence variants in HNF-1α (A174V or G574S), PDX1 (putative 5′–untranslated region CCAAT box, P33T, or P239Q), or PAX4 (R133W) were found in 27% (10/37) of patients, with one additional patient revealing two variants, PDX1 P33T and PAX4 R133W. The A174V variant has not been previously reported.

CONCLUSIONS

Despite its well-circumscribed, robust, and distinctive phenotype of severe, nonautoimmune-mediated β-cell dysfunction, A−β− KPD is most likely not a predominantly monogenic diabetic syndrome. Several A−β− KPD patients have low-frequency variants in HNF1A, PDX1, or PAX4 genes, which may be of functional significance in their pathophysiology.
Cross-Sectional Associations Bet ween Abdominal and Thoracic Adipose Tissue Compartments and Adiponectin and Resistin in the Framingham Heart Study
Authors: Jain Shilpa H. , Massaro Joseph M. , Hoffmann Udo , Rosito Guido A. , Vasan Ramachandran S. , Raji Annaswamy , O'Donnell Christopher J. , Meigs James B. , Fox Caroline S.
Published: February 2009

OBJECTIVE

To test the association of regional fat depots with circulating adiponectin and resistin concentrations and to assess the potential mediating effect of adipokines on associations between abdominal fat depots and cardiometabolic risk factors.

RESEARCH DESIGN AND METHODS

Participants from the Framingham Heart Study offspring cohort (n = 916, 55% women; mean age 59 years) free of cardiovascular disease underwent computed tomography measurement of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), pericardial fat, and intrathoracic fat volumes and assays of circulating adiponectin and resistin.

RESULTS

VAT, SAT, pericardial fat, and intrathoracic fat were negatively correlated with adiponectin (r = −0.19 to −0.34, P < 0.001 [women]; r = −0.15 to −0.26, P < 0.01 [men] except SAT) and positively correlated with resistin (r = 0.16–0.21, P < 0.001 [women]; r = 0.11–0.14, P < 0.05 [men] except VAT). VAT increased the multivariable model R2 for adiponectin from 2–4% to 10–13% and for resistin from 3–4% to 3–6%. Adjustment for adipokines did not fully attenuate associations between VAT, SAT, and cardiometabolic risk factors.

CONCLUSIONS

Adiponectin and resistin are correlated with fat depots cross-sectionally, but none of the adipokines can serve as surrogates for the fat depots. Relations between VAT, SAT, and cardiometabolic risk factors were not fully explained by adiponectin or resistin concentrations.
Macroalbuminuria and Renal Pathology in First Nation Youth With Type 2 Diabetes
Authors: Sellers Elizabeth A.C. , Blydt-Hansen Tom D. , Dean Heather J. , Gibson Ian W. , Birk Patricia E. , Ogborn Malcolm
Published: February 2009

OBJECTIVE

To determine the prevalence of macroalbuminuria and to describe the clinical and renal pathological changes associated with macroalbuminuria in a population of Canadian First Nation children and adolescents with type 2 diabetes.

RESEARCH DESIGN AND METHODS

We conducted a retrospective chart review at a single tertiary care pediatric diabetes center, and a case series was constructed. We collected data on microalbuminuria (≥3 mg/mmol creatinine [26.5 mg/g]) and macroalbuminuria (≥28 mg/mmol creatinine [247.5 mg/g]), estimated glomerular filtration rate, renal pathology, and aggravating risk factors (poor glycemic control, obesity, hypertension, glomerular hyperfiltration, hypercholesterolemia, smoking, and exposure to diabetes in utero).

RESULTS

We reviewed 90 charts of children and adolescents with type 2 diabetes. A total of 53% had at least one random urine albumin-to-creatinine ratio ≥3 mg/mmol (26.5 mg/g). There were 14 of 90 (16%) who had persistent macroalbuminuria at or within 8 years of diagnosis of diabetes. Of these 14 subjects, 1 had orthostatic albuminuria and 3 had spontaneous resolution of albuminuria. A total of 10 had renal biopsies performed. There were 9 of 10 who exhibited immune complex disease or glomerulosclerosis, and none had classic diabetic nephropathy.

CONCLUSIONS

This study suggests that the diagnosis of renal disease in children with type 2 diabetes cannot be reliably determined by clinical and laboratory findings alone. Renal biopsy is necessary for accurate diagnosis of renal disease in children and adolescents with type 2 diabetes and macroalbuminuria. The additional burden of nondiabetic kidney disease may explain the high rate of progression to end-stage kidney failure in this population.
Pedometers and Text Messaging to Increase Physical Activity
Authors: Newton Kirsty H. , Wiltshire Esko J. , Elley C. Raina
Published: February 2009

OBJECTIVE

To assess whether pedometers and text messaging increase physical activity in adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

A 12-week randomized controlled trial was conducted. A total of 78 subjects participated in the trial (mean ± SD age 14.4 ± 2.37 years, 36 [47%] male). Intervention participants wore an open pedometer and received regular motivational text messages. Control participants received usual care. Primary outcomes were daily step count (4-day closed pedometer) and physical activity questionnaire.

RESULTS

Baseline median step count was 11,063 steps/day (range 1,541–20,158). At 12 weeks, mean daily step count reduced by 840 (95% CI −1,947 to 266) in the control group and by 22 (−1,407 to 1,364) in the intervention group (P = 0.4). Mean self-reported moderate or vigorous physical activity increased by 38.5 min/week in the control group and by 48.4 in the intervention group (P = 0.9).

CONCLUSIONS

A 12-week intervention using pedometers and text messaging as motivational tools in adolescents with type 1 diabetes did not increase physical activity.
Depressive Symptoms and Glycemic Control in Adolescents With Type 1 Diabetes
Authors: McGrady Meghan E. , Laffel Lori , Drotar Dennis , Repaske David , Hood Korey K.
Published: February 2009

OBJECTIVE

To determine whether the association between depressive symptoms and glycemic control is mediated by blood glucose monitoring (BGM).

RESEARCH DESIGN AND METHODS

A total of 276 adolescents with type 1 diabetes (mean age ± SD, 15.6 ± 1.4 years) completed a measure of depressive symptoms. Sociodemographic and family characteristics were obtained from caregivers. BGM frequency and glycemic control were obtained at a clinic visit.

RESULTS

Separate regression analyses revealed that depressive symptoms were associated with lower BGM frequency (B = −0.03; P = 0.04) and higher A1C (B = 0.03; P = 0.05) and that lower BGM frequency was associated with higher A1C (B = −0.39; P < 0.001). With depressive symptoms and BGM frequency included together, only BGM frequency was associated with A1C and depressive symptoms became nonsignificant (B = 0.02; P = 0.19). The Sobel test was significant (Z = 1.96; P < 0.05) and showed that 38% of the depression-A1C link can be explained by BGM.

CONCLUSIONS

BGM is a mediator between depressive symptoms and glycemic control in adolescents with type 1 diabetes.
Evaporation mechanism of aluminum during electron beam cold hearth melting of Ti64 alloy
Authors: Zhang Yingming , Zhou Lian , Sun Jun , Han Mingchen , Zhao Yongqing
Published: February 2009

Using the Langmuir equation and penetration theory, the evaporation process of Al during the electron beam cold hearth melting of Ti64 alloy under steady state conditions was calculated and the evaporation mechanism was analyzed. The calculation results show that it is necessary to consider both the evaporation step at the liquid/gas surface and the diffusion step in the molten pool during calculation. Comparison of the mass transfer coefficient of the evaporation step and the diffusion step shows that the Al evaporation process is a double controlled process. The Al concentration at the interface decreases from 260 kg m– 3 to 140 kg m– 3, and the evaporation rate increases rapidly from 0.001 kg m– 2 s– 1 to 0.012 kg m– 2 s– 1 when the temperature increases from 1950 K to 2300 K. To control the evaporation loss of Al, surface temperature should be controlled during the electron beam melting of Ti64 alloy.
Dietary Intakes, Attitudes Toward Carbohydrates of Postmenopausal Women Following Low Carbohydrate Diets
Authors: Winham Donna M. , Collins Courtney B. , Hutchins Andrea M.
Published: February 2009

Purpose: Middle-aged women have the highest levels of obesity and comprise the largest group of dieters. Few investigators have examined how women apply weight-loss diet principles in an unsupervised setting. Dietary intakes and attitudes toward carbohydrates were examined in women who were selfreported low carbohydrate dieters (SRLCDs); these intakes and attitudes were compared with those of women who were following their normal diet (non-dieters [NDs]).

Methods: A convenience sample of 29 postmenopausal women aged 45 to 65 was recruited. Data were obtained by interview, questionnaire, and direct anthropometric measurement. Descriptive statistics, chi-square analysis, and analysis of variance were used to compare groups.

Results: Although total energy and protein intakes were similar, SRLCDs consumed significantly more fat and less carbohydrate (expressed as a percentage of total energy) and more cholesterol and less fibre than did NDs. Both groups had unfavourable attitudes toward carbohydrates.

Conclusions: The SRLCDs ate more fat than recommended. Women who are considering following a low carbohydrate diet need to know the nutritional risks of unbalanced self-designed low carbohydrate diets. Negative attitudes toward carbohydrates were not confined to dieters. Nutrition education is necessary to help consumers understand basic nutrition principles and to be more skeptical of fad diets.
Meanings That Youth AssociateWith Healthy and Unhealthy Food
Authors: Harrison Michelle , Jackson Lois A.
Published: February 2009

Purpose: The symbolic meanings that youth associate with food were explored, as were barriers to accessing healthy foods.

Methods: Qualitative methods and a constructivist approach were employed, and data were collected through semi-structured interviews and a card-sorting activity. Thirteen adolescents aged 13 to 15 (seven girls, six boys) were recruited through public schools and posters displayed in community settings. Thematic analytical techniques were used to analyze the data.

Results: Participants classified foods into healthy and unhealthy groups, as well as into an “in-between” group that included nutritionally enhanced foods. Healthy and unhealthy foods were linked to a variety of physical, social, and emotional meanings. Some meanings associated with foods were also discussed in gendered terms, and numerous barriers to accessing healthy foods were reported.

Conclusions: Foods hold multiple meanings for youth. Programs and policies aimed at fostering healthy eating need to capitalize on positive associations related to healthy foods. Negative associations related to healthy foods need to be acknowledged and strategies developed to recast such linkages. Likewise, the positive associations linked to unhealthy foods need to be addressed. Strategies also need to be developed to ensure access to healthy foods in all settings, especially within schools and community leisure settings.
Encoding of speed and direction of movement in the human supplementary motor area
Authors: Tankus Ariel , Yeshurun Yehezkel , Flash Tamar , Fried Itzhak
Published: February 2009

Object

The supplementary motor area (SMA) plays an important role in planning, initiation, and execution of motor acts. Patients with SMA lesions are impaired in various kinematic parameters, such as velocity and duration of movement. However, the relationships between neuronal activity and these parameters in the human brain have not been fully characterized. This is a study of single-neuron activity during a continuous volitional motor task, with the goal of clarifying these relationships for SMA neurons and other frontal lobe regions in humans.

Methods

The participants were 7 patients undergoing evaluation for epilepsy surgery requiring implantation of intracranial depth electrodes. Single-unit recordings were conducted while the patients played a computer game involving movement of a cursor in a simple maze.

Results

In the SMA proper, most of the recorded units exhibited a monotonic relationship between the unit firing rate and hand motion speed. The vast majority of SMA proper units with this property showed an inverse relation, that is, firing rate decrease with speed increase. In addition, most of the SMA proper units were selective to the direction of hand motion. These relationships were far less frequent in the pre-SMA, anterior cingulate gyrus, and orbitofrontal cortex.

Conclusions

The findings suggest that the SMA proper takes part in the control of kinematic parameters of endeffector motion, and thus lend support to the idea of connecting neuroprosthetic devices to the human SMA.
Development of the Basic Core Test Items of National Nurse's License Examination
Authors: Kim Cho Ja , Lee Hyang Yeon , Song Ji Ho , Lee Sook Ja , Kang Hyun Sook , Park Sung Ae , Lee Jeong Seop , June Kyung Ja
Published: February 2009

The purpose of this study is to develop a classification framework for the test elements of the National Registered Nurse's License Examination and to divide the test items into standard and basic core on the basis of the RN's job descriptions. And the adequa to proportion of the basic core test items is going to be identified. Method and results: In order to develop the classification framework of the National Registered Nurse's License Examination, RN's job descriptions, nursing standards, and the specific learning objectives of nursing courses were reviewed. And a survey was used to identify which entity would be appropriate for a reference to the basic core test items. 146 of professors from schools of nursing and members of each division of Korean Academic Society of Nursing(KASN) were participated in the survey. The study showed the 98% of respondents agreed to use RN's job descriptions in selecting the basic core test items and 30% for the basic core test would be appropriate. And the contents, the selection criteria, and the proportion of the basic core test items were developed by the members of this research, the members of the National RN's License Examination subcommittee, and the presidents of each division of KASN. The total of 1990 standard test items were selected among 3524 items, that 3 out of 7 members in the research team agreed to choose. Duplicated items in the standard items were deleted. 205 items out of the 1990 standard items were selected as the basic core test items. And 14 items were added in Medical Laws and Ethics which leads the total of 219 basic core test items. ln conclusion, the 99 items, 30% of total current examination items were chosen as the final basic core test items using the delphimethod. Further studies are needed to validate the current National License Examination for RN on the basis of the 99 basic core test items.
Critical Thinking and the Standards of Nursing Education
Authors: Ahn Yang Heui
Published: February 2009

Critical thinking is the basis of professional nursing practice and is essential in the current complex health care delivery system. A major goal of baccalaureate nursing education is the development and promotion of students' ability to think critically. In America, the National League for nursing outcome-oriented accreditation process challenged nursing faculty to think about teaching and evaluating critical thinking. Based on nursing literature, the findings were inconsistent because of a lack of consensus on a definition of critical thinking and the measurement of critical thinking utilizing critical thinking instruments non-specific for nursing. However, a variety of teaching-learning strategies in nursing education were effective in the development of critical thinking dispositions and skills among nursing students. The author provides insight and ideas for nursing faculty as follows: 1) nursing programs must define critical thinking operationally in relation to their curricula; 2)nursing faculty must be knowledgeable concerning evaluation of critical thinking disposition and skills and construct a standardized critical-thinking instrument that is specific to the discipline of nursing; 3) nursing faculty must develop teaching-learning strategy in nursing education for improving students' critical thinking abilities. These are prerequisite for critical thinking which should be considered as a criterion in The Standards of Nursing Education in Korea.
Development of Standards and Criteria for Accreditation of Baccalaureate Nursing Education Program
Authors: Ahn Yang Heui , Park Kyung Sook , Yang Soon Ok , Shin Kyung Rim , Kim Mi Ja
Published: February 2009

The goal of accreditation is to ensure that the education provided by an institution of higher education meets an acceptable level of quality. This study developed standards and criteria for accreditation of baccalaureate nursing education programs, by comparing accreditation in South Korea and in the United States, and validating standards and criteria. A main comparative analysis was made between Nursing League for Nursing Accrediting Commission (NLNAC) standards, Commission on Collegiate Nursing Education (CCNE) standards for accreditation of baccalaureate nursing education programs, and Korean Accreditation Board of Nursing standards for accreditation of nursing education programs. The research team developed and validated standards and criteria for South Korean baccalaureate nursing education programs. Using the results of the analysis, revisions are proposed to standards for accreditation of baccalaureate nursing education programs, and categorized into 24 criteria and six domains: mission and governance, curriculum and teaching-learning practices, students, faculty, resources, effectiveness. Further studies are required to refine the standards and criteria and make them sophisticated enough to be applied globally.
Feminist Lines of Flight from the Majoritarian Subject
Authors: Lorraine Tamsin
Published: February 2009

This paper characterises Deleuze and Guattari's conception of the majoritarian subject in A Thousand Plateaus as a particular – and inevitably transitory – manifestation of sexed and gendered subjectivity emerging with late capitalism from the always mutating flows of creative life and suggests that their notion of the schizo or nomadic subject can inspire feminist solutions to the impasses posed by contemporary forms of sexed, gendered, and sexual identity. Feminism can thus be conceived as a schizoanalytic practice that fosters the kind of alternative subjects for which Deleuze and Guattari call: subjects that move beyond oppressive self–other relations towards a form of subjectivity that can welcome differences as well as the differentiating force of life itself.
Becoming-Woman: A Flight into Abstraction
Authors: Howie Gillian
Published: February 2009

In this paper I argue that the idea ‘becoming-woman’ is an attempt to transform embodied experience but, because it is unable to concern itself with mechanisms, structures and processes of sexual differentiation, fails in this task. In the first section I elaborate the relationship between becoming-woman and Deleuze's ‘superior’ or ‘transcendental’ empiricism and suggest that problems can be traced back to an underlying Humean empiricism. Along with Hume, Deleuze, it seems, presumes a bundle model of the object which dissolves things into episodic objects of perception and leaves the subject unable to distinguish between fanciful objects, erroneous perception and any other thing. The empiricist ontology thus has consequences for epistemology and leaves us unable to question the conservative tendencies of common sense. As an alternative to transcendental empiricism, the second section considers how transcendental realism, with its ontological commitment to the mind-independent character of things, may provide a more fruitful and productive line of enquiry. Given that there is such a choice, in the third section I speculate as to the specific desires that drive such philosophical abstraction; abstraction which culminates in the non sex-specific figure becoming-woman whilst disguising the mind-independent character of the mechanisms, structures and objects that affect the subject. So I conclude that, despite all appearances of radicalism, the philosophical model ‘becoming-woman’ – aligned as it is with schizo-processes and the philosophical loss of mind-independent things – is more of the same and sexual difference remains a hidden term. Due to this, I believe that feminists should view it with suspicion.
Microalgal and Terrestrial Transport Biofuels to Displace Fossil Fuels
Authors: Reijnders Lucas
Published: February 2009

Terrestrial transport biofuels differ in their ability to replace fossil fuels. When both the conversion of solar energy into biomass and the life cycle inputs of fossil fuels are considered, ethanol from sugarcane and biodiesel from palm oil do relatively well, if compared with ethanol from corn, sugar beet or wheat and biodiesel from rapeseed. When terrestrial biofuels are to replace mineral oil-derived transport fuels, large areas of good agricultural land are needed: about 5x108 ha in the case of biofuels from sugarcane or oil palm, and at least 1.8-3.6x109 ha in the case of ethanol from wheat, corn or sugar beet, as produced in industrialized countries. Biofuels from microalgae which are commercially produced with current technologies do not appear to outperform terrestrial plants such as sugarcane in their ability to displace fossil fuels. Whether they will able to do so on a commercial scale in the future, is uncertain.
The Control of Environmental Tobacco Smoke: A Policy Review
Authors: McNabola Aonghus , Gill Laurence William
Published: February 2009

According to World Health Organisation figures, 30% of all cancer deaths, 20% of all coronary heart diseases and strokes and 80% of all chronic obstructive pulmonary disease are caused by cigarette smoking. Environmental Tobacco Smoke (ETS) exposure has also been shown to be associated with disease and premature death in non-smokers. In response to this environmental health issue, several countries have brought about a smoking ban policy in public places and in the workplace. Countries such as the U.S., France, Italy, Ireland, Malta, the Netherlands, Sweden, Scotland, Spain, and England have all introduced policies aimed at reducing the population exposure to ETS. Several investigations have monitored the effectiveness of these smoking ban policies in terms of ETS concentrations, human health and smoking prevalence, while others have also investigated a number of alternatives to smoking ban policy measures. This paper reviews the state of the art in research, carried out in the field of ETS, smoking bans and Tobacco Control to date and highlights the need for future research in the area.
Genetic Exchange of Multidrug Efflux Pumps among Two Enterobacterial Species with Distinctive Ecological Niches
Authors: Al-Karablieh Nehaya , Weingart Helge , Ullrich Matthias S.
Published: February 2009

AcrAB-TolC is the major multidrug efflux system in Enterobacteriaceae recognizing structurally unrelated molecules including antibiotics, dyes, and detergents. Additionally, in Escherichia coli it mediates resistance to bile salts. In the plant pathogen Erwinia amylovora AcrAB-TolC is required for virulence and phytoalexin resistance. Exchange analysis of AcrAB-TolC was conducted by complementing mutants of both species defective in acrB or tolC with alleles from either species. The acrB and tolC mutants exhibited increased susceptibility profiles for 24 different antibiotics. All mutants were complemented with acrAB or tolC, respectively, regardless of the taxonomic origin of the alleles. Importantly, complementation of E. amylovora mutants with respective E. coli genes restored virulence on apple plants. It was concluded that AcrAB and TolC of both species could interact and that these interactions did not yield in altered functions despite the divergent ecological niches, to which E. coli and E. amylovora have adopted.
Quantum Dots — Characterization, Preparation and Usage in Biological Systems
Authors: Drbohlavova Jana , Adam Vojtech , Kizek Rene , Hubalek Jaromir
Published: February 2009

The use of fluorescent nanoparticles as probes for bioanalytical applications is a highly promising technique because fluorescence-based techniques are very sensitive. Quantum dots (QDs) seem to show the greatest promise as labels for tagging and imaging in biological systems owing to their impressive photostability, which allow long-term observations of biomolecules. The usage of QDs in practical applications has started only recently, therefore, the research on QDs is extremely important in order to provide safe and effective biosensing materials for medicine. This review reports on the recent methods for the preparation of quantum dots, their physical and chemical properties, surface modification as well as on some interesting examples of their experimental use.
A Better Understanding of Our Earth through Remote Sensing
Authors: Wagner Wolfgang
Published: February 2009

We are so accustomed to seeing satellite pictures of the earth that it seems as if there is nothing left to be discovered. In the daily weather reports on television we regularly see images taken by geostationary satellites and with the help of web-based virtual globes we can zoom in from the full-earth disk to detailed views of any place on the earth in a matter of seconds. Yet, does this truly mean that all the secrets of the earth have now been disclosed? Can we extract all the information we need from existing earth observation data? [...]
Synthesis of new Cα-tetrasubstituted α-amino acids
Authors: Grauer Andreas A , König Burkhard
Published: February 2009

Cα-Tetrasubstituted α-amino acids are important building blocks for the synthesis of peptidemimetics with stabilized secondary structure, because of their ability to rigidify the peptide backbone. Recently our group reported a new class of cyclic Cα-tetrasubstituted tetrahydrofuran α-amino acids prepared from methionine and aromatic aldehydes. We now report the extension of this methodology to aliphatic aldehydes. Although such aldehydes are prone to give aldol products under the reaction conditions used, we were able to obtain the target cyclic amino acids in low to moderate yields and in some cases with good diastereoselectivity.
Th1/Th2 Patterns and Balance in Cytokine Production in the Parents and Infants of a Large Birth Cohort
Authors: Halonen Marilyn , Lohman I. Carla , Stern Debra A. , Spangenberg Amber , Anderson Dayna , Mobley Sara , Ciano Kathy , Peck Michael , Wright Anne L.
Published: February 2009

Regulation of human immune cell cytokine production in vivo is not well understood due in part to limitations on imposing experimental conditions. We proposed that life-imposed conditions (pregnancy, birth, age, gender), combined with large sample size, repeat sampling, and family-based recruitment would serve to reveal peripheral blood cell-derived cytokine patterns reflective of in vivo regulation regarding Th1/Th2 balance and familial correlation. Mononuclear cells were obtained from 483 trios in the Tucson Infant Immune Study: from mothers pre- and postpartum, infants at birth and at 3 mo, and fathers. Con A/PMA-stimulated supernatants were assayed by ELISA for IFN-γ, IL-4, IL-13, IL-5, and IL-10 and allergen-stimulated supernatants for IFN-γ, IL-4, and IL-13. Mitogen-stimulated prepartum samples were not globally Th2 biased, differing from postpartum only by a modestly reduced IFN-γ:IL-5 ratio. Prepartum samples actually produced less IL-10 and IL-13 although more IL-5 than paternal samples. Newborns were also not globally Th2 biased, with mitogen stimulation producing ∼10-fold less IL-4, IL-5, and IFN-γ than adults but only 2- to 3-fold less IL-13 and IL-10. Despite these group differences, all cytokines showed marked positive intraindividual correlations (all p < 0.001). Allergen stimulation gave results consistent with a lack of global Th2 bias. Mitogen stimulation revealed parent-child and parent-parent correlations. Thus, rather than a global Th2 bias, cytokine production in pregnant mothers and newborns appears regulated so as to maintain a relative balance among the cytokines, with the nature of the balance differing in mothers and infants and with production influenced by familial factors that include shared environment.
Herpesvirus Entry Mediator-Ig Treatment during Immunization Aggravates Rheumatoid Arthritis in the Collagen-Induced Arthritis Model
Authors: Pierer Matthias , Schulz Anett , Rossol Manuela , Kendzia Eva , Kyburz Diego , Haentzschel Holm , Baerwald Christoph , Wagner Ulf
Published: February 2009

Previous studies attempting to influence the severity of collagen-induced arthritis (CIA) by modulating the LIGHT (lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator (HVEM) on T cells)/lymphotoxin pathway have yielded conflicting results. To further clarify the role of LIGHT in autoimmune arthritis, a HVEM-Ig fusion protein was used. CIA was induced in DBA1 mice, which were injected i.p. with recombinant HVEM-Ig fusion protein and control Ig at different time points. Severity of clinical arthritis and histologic joint destruction were significantly increased in HVEM-Ig-treated mice compared with control-Ig-treated mice. Collagen II-induced in vitro T cell proliferation and IFN-γ production was augmented in mice treated with HVEM-Ig, as was the production of IgG2a anti-collagen II Ab. Accordingly, serum concentrations of IFN-γ and IL-6 were higher in mice treated with HVEM-Ig. In conclusion, HVEM-Ig aggravates autoimmunity in collagen-induced arthritis, which is possibly mediated by interaction with B and T lymphocyte attenuator (BTLA) or CD160, despite the blockade of LIGHT. Hence, HVEM-Ig seems not to be a valid therapeutic option in autoimmune arthritis.
Chemokine Receptor CXCR5 Supports Solitary Intestinal Lymphoid Tissue Formation, B Cell Homing, and Induction of Intestinal IgA Responses
Authors: Velaga Sarvari , Herbrand Heike , Friedrichsen Michaela , Jiong Tian , Dorsch Martina , Hoffmann Matthias W. , Förster Reinhold , Pabst Oliver
Published: February 2009

Solitary intestinal lymphoid tissue (SILT) comprises a spectrum of phenotypically diverse lymphoid aggregates interspersed throughout the small intestinal mucosa. Manifestations of SILT range from tiny lymphoid aggregates almost void of mature lymphocytes to large structures dominated by B cells. Large SILT phenotypically resemble a single Peyer’s patch follicle, suggesting that SILT might contribute to intestinal humoral immune responses. In this study, we track the fate of individual SILT in vivo over time and analyze SILT formation and function in chemokine receptor CXCR5-deficient mice. We show that, in analogy to Peyer’s patches, formation of SILT is invariantly determined during ontogeny and depends on CXCR5. Young CXCR5-deficient mice completely lack SILT, suggesting that CXCR5 is essential for SILT formation during regular postnatal development. However, microbiota and other external stimuli can induce the formation of aberrant SILT distinguished by impaired development of B cell follicles in CXCR5-deficient mice. Small intestinal transplantation and bone marrow transplantation reveal that defect follicle formation is due to impaired B cell homing. Moreover, oral immunization with cholera toxin or infection with noninvasive Salmonella fail to induce efficient humoral immune responses in CXCR5-deficient mice. Bone marrow transplantation of CXCR5-deficient recipients with wild-type bone marrow rescued B cell follicle formation in SILT but failed to restore full humoral immune responses. These results reveal an essential role of CXCR5 in Peyer’s patch and SILT development and function and indicate that SILT do not fully compensate for the lack of Peyer’s patches in T cell-dependent humoral immune responses.
Macrophage Oxygen Sensing Modulates Antigen Presentation and Phagocytic Functions Involving IFN-γ Production through the HIF-1α Transcription Factor
Authors: Acosta-Iborra Bárbara , Elorza Ainara , Olazabal Isabel M. , Martín-Cofreces Noa B. , Martin-Puig Silvia , Miró Marta , Calzada María J. , Aragonés Julián , Sánchez-Madrid Francisco , Landázuri Manuel O.
Published: February 2009

Low oxygen tension areas are found in inflamed or diseased tissues where hypoxic cells induce survival pathways by regulating the hypoxia-inducible transcription factor (HIF). Macrophages are essential regulators of inflammation and, therefore, we have analyzed their response to hypoxia. Murine peritoneal elicited macrophages cultured under hypoxia produced higher levels of IFN-γ and IL-12 mRNA and protein than those cultured under normoxia. A similar IFN-γ increment was obtained with in vivo models using macrophages from mice exposed to atmospheric hypoxia. Our studies showed that IFN-γ induction was mediated through HIF-1α binding to its promoter on a new functional hypoxia response element. The requirement of HIF-α in the IFN-γ induction was confirmed in RAW264.7 cells, where HIF-1α was knocked down, as well as in resident HIF-1α null macrophages. Moreover, Ag presentation capacity was enhanced in hypoxia through the up-regulation of costimulatory and Ag-presenting receptor expression. Hypoxic macrophages generated productive immune synapses with CD8 T cells that were more efficient for activation of TCR/CD3ε, CD3ζ and linker for activation of T cell phosphorylation, and T cell cytokine production. In addition, hypoxic macrophages bound opsonized particles with a higher efficiency, increasing their phagocytic uptake, through the up-regulated expression of phagocytic receptors. These hypoxia-increased immune responses were markedly reduced in HIF-1α- and in IFN-γ-silenced macrophages, indicating a link between HIF-1α and IFN-γ in the functional responses of macrophages to hypoxia. Our data underscore an important role of hypoxia in the activation of macrophage cytokine production, Ag-presenting activity, and phagocytic activity due to an HIF-1α-mediated increase in IFN-γ levels.
Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity
Authors: Fletcher Anne L. , Seach Natalie , Reiseger Jessica J. , Lowen Tamara E. , Hammett Maree V. , Scott Hamish S. , Boyd Richard L.
Published: February 2009

The thymic stromal niche normally directs the production and export of a self-tolerant T cell repertoire. Many models of spontaneous autoimmunity, however, develop thymic architectural abnormalities before disease onset. Although this is suspected to affect central tolerance induction, creating an autoimmune predisposition, in-depth analysis of the microenvironment within these thymi is lacking, such that the mechanisms and likely direct effects on the T cell repertoire are unknown or speculative. Here we show that NZB mice, the first described model for systemic autoimmunity, demonstrate a complex thymic phenotype, including a lack of the autoimmune regulator (Aire), early defects in thymic epithelial cell (TEC) expansion, and evidence for altered NF-κB2 signaling. Analysis of medullary TEC revealed a numerical loss of the Aire-expressing MHC class IIhigh (mTEC-high) subset as well reduced Aire protein and mRNA per cell. RelB expression was also reduced, while chemokines CCL19 and CCL21 were increased. Unexpectedly, the proportion of cortex and medulla in the NZB mice was normal from 36 wk, despite worsening architectural abnormalities. These data show that the NZB defect is more complex than previously appreciated, segregating into early numerical TEC deficiencies that correct with age, late degeneration of the niche architecture that does not affect TEC number, and a persistent reduction in Aire and RelB expression per cell acquired upon mTEC-high differentiation.
Human SCAMP5, a Novel Secretory Carrier Membrane Protein, Facilitates Calcium-Triggered Cytokine Secretion by Interaction with SNARE Machinery
Authors: Han Chaofeng , Chen Taoyong , Yang Mingjin , Li Nan , Liu Haibo , Cao Xuetao
Published: February 2009

Cytokines produced by immune cells play pivotal roles in the regulation of both innate and adaptive immunity. However, the mechanisms controlling secretion of cytokines have not been fully elucidated. Secretory carrier membrane proteins (SCAMPs) are widely distributed integral membrane molecules implicated in regulating vesicular transport. In this study, we report the functional characterization of human SCAMP5 (hSCAMP5), a novel SCAMP protein that is widely expressed by a variety of neuronal and nonneuronal tissues and cells. By measuring the cytokine secretion (RANTES/CCL5 and IL-1β) as an exocytotic model, we show that hSCAMP5 can promote the calcium-regulated signal peptide-containing cytokine (CCL5 but not IL-1β) secretion in human epithelial cancer cells, human monocytes, and mouse macrophages. By using subcellular fractionation, immunofluorescence confocal microscopy, and membrane vesicle immunoisolation methods, we find that hSCAMP5 is mainly localized in the Golgi-associated compartments, and the calcium ionophore ionomycin can trigger a rapid translocation of hSCAMP5 from Golgi apparatus to plasma membrane along the classical exocytosis pathway. During the translocation of hSCAMP5 from Golgi apparatus to plasma membrane, hSCAMP5 can codistribute and complex with local soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs) molecules. We further demonstrate that hSCAMP5 can directly interact with the calcium sensor synaptotagmins via the cytosolic C-terminal tail of hSCAMP5, thus providing a potential molecular mechanism linking SCAMPs with the SNARE molecules. Our findings suggest that hSCAMP5, in cooperation with the SNARE machinery, is involved in calcium-regulated exocytosis of signal peptide-containing cytokines.
Peripheral T Cell Functions Correlate with the Severity of Chronic Obstructive Pulmonary Disease
Authors: Zhu Xuehai , Gadgil Aneal S. , Givelber Rachel , George M. Patricia , Stoner Michael W. , Sciurba Frank C. , Duncan Steven R.
Published: February 2009

Adaptive immune processes have been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). We hypothesized that peripheral T cell abnormalities may be present in afflicted patients. We tested this hypothesis by characterizing circulating T cells in COPD patients and correlated these findings with disease severity, smoking status, and use of inhaled glucocorticosteroids (ICS). Compared with normal controls, a lesser proportion of peripheral CD4 T cells from COPD subjects produced IL-10, whereas the CD8 T cells from these patients were more often activated and more frequently produced both IFN-γ and IL-4. COPD severity was significantly and inversely associated with the proportion of circulating CD4 T cells and directly correlated with CD4 production of IL-2, as well as frequency of CD8 T cell activation and CD8 IFN-γ production. Adjustments for current smoking status and ICS use by linear regression showed independent, and generally inhibitory, effects of these clinical variables on the abnormal T cell functions of these patients. We conclude that circulating T cells from COPD patients are abnormally activated and elaborate proinflammatory mediators with admixed features of Th1 and Th2 responses. Furthermore, many of these effector processes are significantly correlated with disease severity. These findings further implicate adaptive immune processes in COPD progression and indicate that facile assays of peripheral lymphocytes may provide useful insights into disease mechanisms. Current smoking and ICS use had independent effects on T cell functions among the COPD subjects, illustrating the importance of controlling for clinical parameters as covariates in immunological studies of patients afflicted with this disease.
Ultraviolet B Radiation Generated Platelet-Activating Factor Receptor Agonist Formation Involves EGF-R-Mediated Reactive Oxygen Species
Authors: Yao Yongxue , Wolverton Jay E. , Zhang Qiwei , Marathe Gopal K. , Al-Hassani Mohammed , Konger Raymond L. , Travers Jeffrey B.
Published: February 2009

Recent studies have implicated the lipid mediator platelet-activating factor (PAF) in UVB-mediated systemic immunosuppression known to be a major cause for skin cancers. Previously, our group has demonstrated that UVB irradiation triggers the production of PAF and oxidized glycerophosphocholines that act as PAF-receptor (PAF-R) agonists. The present studies explored the mechanisms by which UVB generates PAF-R agonists. UVB irradiation of human epidermal KB cells resulted in both increased levels of reactive oxygen species (ROS) and PAF-R agonistic activity. Pretreatment of KB cells with antioxidants vitamin C and N-acetylcysteine or the pharmacological inhibitor PD168393 specific for the epidermal growth factor receptor all inhibited UVB-induced ROS as well as PAF-R agonists, yet had no effect on fMLP-mediated PAF-R agonist production. In addition, in vivo production of PAF-R agonists from UVB-irradiated mouse skin was blocked by both systemic vitamin C administration and topical PD168393 application. Moreover, both vitamin C and PD168393 abolished UVB-mediated but not the PAF-R agonist 1-hexadecyl-2-N-methylcarbamoyl glycerophosphocholine-mediated immunosuppression as measured by the inhibition of delayed type contact hypersensitivity to the chemical dinitrofluorobenzene. These studies suggest that UVB-induced systemic immunosuppression is due to epidermal growth factor receptor-mediated ROS which results in PAF-R agonist formation.
IL-21 Mediates Suppressive Effects via Its Induction of IL-10
Authors: Spolski Rosanne , Kim Hyoung-Pyo , Zhu Wei , Levy David E. , Leonard Warren J.
Published: February 2009

IL-21 is a pleiotropic cytokine that is required for normal Ig production. We previously showed that IL-21 was elevated in BXSB-Yaa mice with systemic lupus erythematosus. These mice also had elevated IL-10 levels, and we now show that IL-21 induces IL-10 mRNA and protein, suggesting unexpected immunosuppressive activities for IL-21. Indeed, Th1 priming with IL-21 leads to accumulation of cells with immunosuppressive activity, and IL-21 overexpression decreases specific Ab production after immunization in an IL-10-dependent fashion. Moreover, we show that IL-21 signaling is required for maximal induction of IL-10 by IL-6 or IL-27. Overall, our data indicate that IL-21 regulates immune responses at least in part by inducing IL-10 and reveal unanticipated immunosuppressive actions for this cytokine.
High Resolution Mapping of Cia3: A Common Arthritis Quantitative Trait Loci in Different Species
Authors: Yu Xinhua , Teng Haidong , Marques Andreia , Ashgari Farahnaz , Ibrahim Saleh M.
Published: February 2009

Murine collagen induced arthritis (CIA) is a widely used model of rheumatoid arthritis (RA). Identification of CIA susceptibility genes will aid in the understanding of RA pathogenesis and development of therapeutic targets. This study aims to identify and refine quantitative trait loci (QTL) controlling CIA. Major CIA clinical traits were evaluated in both (DBA/1×FVB/N) F2 and advanced intercross line (AIL) mice; QTLs were confirmed and refined in AIL. To search for candidate genes, we applied multiple approaches, including gene expression profiling, identification of nonsynonymous polymorphism, and comparative genomic mapping. We identified six suggestive QTLs controlling CIA clinical traits in the F2 progeny; one of these was confirmed and refined in AIL. This QTL is located on chromosome 6 and overlaps with Cia3, which was identified previously. We refined the 2-log support interval of Cia3 into a 5.6 Mb genomic region; 15 of 77 genes are differentially expressed or carry nonsynonymous polymorphisms between two parental strains. The counterpart genomic region of Cia3 on the rat and human genomes are linked to RA. Twenty-nine of 77 genes are located in the arthritis-linked genomic regions of all three species. Five of those 29 genes are differentially expressed or carry nonsynonymous polymorphisms between parental strains: Timp4, Tmem40, Mbd4, Cacna1c, and Lrtm2. Taken together, we refined Cia3 into a 5.6 Mb genomic region on mouse chromosome 6 and identified candidate genes. This will aid in the search for susceptibility gene(s) controlling arthritis development within Cia3 and its counterpart regions in rat and human genomes.