bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of shortened host life span on the evolution of parasite life history and virulence in a microbial host-parasite system
Authors: Nidelet Thibault , Koella Jacob C , Kaltz Oliver
Published: March 2009

Background

Ecological factors play an important role in the evolution of parasite exploitation strategies. A common prediction is that, as shorter host life span reduces future opportunities of transmission, parasites compensate with an evolutionary shift towards earlier transmission. They may grow more rapidly within the host, have a shorter latency time and, consequently, be more virulent. Thus, increased extrinsic (i.e., not caused by the parasite) host mortality leads to the evolution of more virulent parasites. To test these predictions, we performed a serial transfer experiment, using the protozoan Paramecium caudatum and its bacterial parasite Holospora undulata. We simulated variation in host life span by killing hosts after 11 (early killing) or 14 (late killing) days post inoculation; after killing, parasite transmission stages were collected and used for a new infection cycle.

Results

After 13 cycles (≈ 300 generations), parasites from the early-killing treatment were less infectious, but had shorter latency time and higher virulence than those from the late-killing treatment. Overall, shorter latency time was associated with higher parasite loads and thus presumably with more rapid within-host replication.

Conclusion

The analysis of the means of the two treatments is thus consistent with theory, and suggests that evolution is constrained by trade-offs between virulence, transmission and within-host growth. In contrast, we found little evidence for such trade-offs across parasite selection lines within treatments; thus, to some extent, these traits may evolve independently. This study illustrates how environmental variation (experienced by the host) can lead to the evolution of distinct parasite strategies.
Transcription and splicing regulation in human umbilical vein endothelial cells under hypoxic stress conditions by exon array
Authors: Hang Xingyi , Li Peiyao , Li Zhifeng , Qu Wubin , Yu Ying , Li Hualing , Shen Zhiyong , Zheng Hao , Gao Yan , Wu Yonghong , Deng Minghua , Sun Zhixian , Zhang Chenggang
Published: March 2009

Background

The balance between endothelial cell survival and apoptosis during stress is an important cellular process for vessel integrity and vascular homeostasis, and it is also pivotal in angiogenesis during the development of many vascular diseases. However, the underlying molecular mechanisms remain largely unknown. Although both transcription and alternative splicing are important in regulating gene expression in endothelial cells under stress, the regulatory mechanisms underlying this state and their interactions have not yet been studied on a genome-wide basis.

Results

Human umbilical vein endothelial cells (HUVECs) were treated with cobalt chloride (CoCl2) both to mimic hypoxia and to induce cell apoptosis and alternative splicing responses. Cell apoptosis rate analysis indicated that HUVECs exposed to 300 μM CoCl2 for 24 hrs were initially counterbalancing apoptosis with cell survival. We therefore used the Affymetrix exon array system to determine genome-wide transcript- and exon-level differential expression. Other than 1583 differentially expressed transcripts, 342 alternatively spliced exons were detected and classified by different splicing types. Sixteen alternatively spliced exons were validated by RT-PCR. Furthermore, direct evidence for the ongoing balance between HUVEC survival and apoptosis was provided by Gene Ontology (GO) and protein function, as well as protein domain and pathway enrichment analyses of the differentially expressed transcripts. Importantly, a novel molecular module, in which the heat shock protein (HSP) families play a significant role, was found to be activated under mimicked hypoxia conditions. In addition, 46% of the transcripts containing stress-modulated exons were differentially expressed, indicating the possibility of combinatorial regulation of transcription and splicing.

Conclusion

The exon array system effectively profiles gene expression and splicing on the genome-wide scale. Based on this approach, our data suggest that transcription and splicing not only regulate gene expression, but also carry out combinational regulation of the balance between survival and apoptosis of HUVECs under mimicked hypoxia conditions. Since cell survival following the apoptotic challenge is pivotal in angiogenesis during the development of many vascular diseases, our results may advance the knowledge of multilevel gene regulation in endothelial cells under physiological and pathological conditions.
Proteomic and functional analysis of NCS-1 binding proteins reveals novel signaling pathways required for inner ear development in zebrafish
Authors: Petko Jessica A , Kabbani Nadine , Frey Colleen , Woll Matthew , Hickey Katharine , Craig Michael , Canfield Victor A , Levenson Robert
Published: March 2009

Background

The semicircular canals, a subdivision of the vestibular system of the vertebrate inner ear, function as sensors of angular acceleration. Little is currently known, however, regarding the underlying molecular mechanisms that govern the development of this intricate structure. Zebrafish represent a particularly tractable model system for the study of inner ear development. This is because the ear can be easily visualized during early embryogenesis, and both forward and reverse genetic techniques are available that can be applied to the discovery of novel genes that contribute to proper ear development. We have previously shown that in zebrafish, the calcium sensing molecule neuronal calcium sensor-1 (NCS-1) is required for semicircular canal formation. The function of NCS-1 in regulating semicircular canal formation has not yet been elucidated.

Results

We initiated a multistep functional proteomic strategy to identify neuronal calcium sensor-1 (NCS-1) binding partners (NBPs) that contribute to inner ear development in zebrafish. By performing a Y2H screen in combination with literature and database searches, we identified 10 human NBPs. BLAST searches of the zebrafish EST and genomic databases allowed us to clone zebrafish orthologs of each of the human NBPs. By investigating the expression profiles of zebrafish NBP mRNAs, we identified seven that were expressed in the developing inner ear and overlapped with the ncs-1a expression profile. GST pulldown experiments confirmed that selected NBPs interacted with NCS-1, while morpholino-mediated knockdown experiments demonstrated an essential role for arf1, pi4kβ, dan, and pink1 in semicircular canal formation.

Conclusion

Based on their functional profiles, the hypothesis is presented that Ncs-1a/Pi4kβ/Arf1 form a signaling pathway that regulates secretion of molecular components, including Dan and Bmp4, that are required for development of the vestibular apparatus. A second set of NBPs, consisting of Pink1, Hint2, and Slc25a25, are destined for localization in mitochondria. Our findings reveal a novel signalling pathway involved in development of the semicircular canal system, and suggest a previously unrecognized role for NCS-1 in mitochondrial function via its association with several mitochondrial proteins.
Acute viral hepatitis morbidity and mortality associated with hepatitis E virus infection: Uzbekistan surveillance data
Authors: Sharapov Makhmudkhan B , Favorov Michael O , Yashina Tatiana L , Brown Matthew S , Onischenko Gennady G , Margolis Harold S , Chorba Terence L
Published: March 2009

Background

In Uzbekistan, routine serologic testing has not been available to differentiate etiologies of acute viral hepatitis (AVH). To determine the age groups most affected by hepatitis E virus (HEV) during documented AVH epidemics, trends in AVH-associated mortality rate (MR) per 100,000 over a 15-year period and reported incidence of AVH over a 35-year period were examined.

Methods

Reported AVH incidence data from 1971 to 2005 and AVH-associated mortality data from 1981 to 1995 were examined. Serologic markers for infection with hepatitis viruses A, B, D, and E were determined from a sample of hospitalized patients with AVH from an epidemic period (1987) and from a sample of pregnant women with AVH from a non-epidemic period (1992).

Results

Two multi-year AVH outbreaks were identified: one during 1975–1976, and one during 1985–1987. During 1985–1987, AVH-associated MRs were 12.3–17.8 per 100,000 for the general population. Highest AVH-associated MRs occurred among children in the first 3 years of life (40–190 per 100,000) and among women aged 20–29 (15–21 per 100,000). During 1988–1995 when reported AVH morbidity was much lower in the general population, AVH-associated MRs were markedly lower among these same age groups. In 1988, AVH-associated MRs were higher in rural (21 per 100,000) than in urban (8 per 100,000) populations (RR 2.6; 95% CI 1.16–5.93; p < 0.05). Serologic evidence of acute HEV infection was found in 280 of 396 (71%) patients with AVH in 1987 and 12 of 99 (12%) pregnant patients with AVH in 1992.

Conclusion

In the absence of the availability of confirmatory testing, inferences regarding probable hepatitis epidemic etiologies can sometimes be made using surveillance data, comparing AVH incidence with AVH-associated mortality with an eye to population-based viral hepatitis control measures. Data presented here implicate HEV as the probable etiology of high mortality observed in pregnant women and in children less than 3 years of age in Uzbekistan during 1985–1987. High mortality among pregnant women but not among children less than 3 years has been observed in previous descriptions of epidemic hepatitis E. The high mortality among younger children observed in an AVH outbreak associated with hepatitis E merits corroboration in future outbreaks.
Androgen deprivation modulates the inflammatory response induced by irradiation
Authors: Wu Chun-Te , Chen Wen-Cheng , Lin Paul-Yang , Liao Shuen-Kuei , Chen Miao-Fen
Published: March 2009

Background

The aim of this study was to determine whether radiation (RT)-induced inflammatory responses and organ damage might be modulated by androgen deprivation therapies.

Methods

The mRNA and tissue sections obtained from the lungs, intestines and livers of irradiated mice with or without androgen deprivation were analyzed by real-time PCR and histological analysis. Activation of NF-kappa B was examined by measuring nuclear protein levels in the intestine and lung 24 h after irradiation. We also examined the levels of cyclooxygenase-2 (COX-2), TGF-β1 and p-AKT to elucidate the related pathway responsible to irradiation (RT) -induced fibrosis.

Results

We found androgen deprivation by castration significantly augmented RT-induced inflammation, associated with the increase NF-κB activation and COX-2 expression. However, administration of flutamide had no obvious effect on the radiation-induced inflammation response in the lung and intestine. These different responses were probably due to the increase of RT-induced NF-κB activation and COX-2 expression by castration or lupron treatment. In addition, our data suggest that TGF-β1 and the induced epithelial-mesenchymal transition (EMT) via the PI3K/Akt signaling pathway may contribute to RT-induced fibrosis.

Conclusion

When irradiation was given to patients with total androgen deprivation, the augmenting effects on the RT-induced inflammation and fibrosis should take into consideration for complications associated with radiotherapy.
Relationships among body mass, brain size, gut length, and blood tryptophan and serotonin in young wild-type mice
Authors: Albay Ricardo , Chen Angela , Anderson George M , Tatevosyan Maggie , Janušonis Skirmantas
Published: March 2009

Background

The blood hyperserotonemia of autism is one of the most consistent biological findings in autism research, but its causes remain unclear. A major difficulty in understanding this phenomenon is the lack of information on fundamental interactions among the developing brain, gut, and blood in the mammalian body. We therefore investigated relationships among the body mass, the brain mass, the volume of the hippocampal complex, the gut length, and the whole-blood levels of tryptophan and 5-hydroxytryptamine (5-HT, serotonin) in young, sexually immature wild-type mice.

Results

Three-dimensional reconstructions of the hippocampal complex were obtained from serial, Nissl-stained sections and the gut was allowed to attain its maximal relaxed length prior to measurements. The tryptophan and 5-HT concentrations in the blood were assessed with high-performance liquid chromatography (HPLC) and the sex of mice was confirmed by genotyping. Statistical analysis yielded information about correlative relationships among all studied variables. It revealed a strong negative correlation between blood 5-HT concentration and body mass and a strong negative correlation between the brain mass/body mass ratio and gut length. Also, a negative correlation was found between the volume of the hippocampal complex and blood tryptophan concentration.

Conclusion

The study provides information on the covariance structure of several central and peripheral variables related to the body serotonin systems. In particular, the results indicate that body mass should be included as a covariate in studies on platelet 5-HT levels and they also suggest a link between brain growth and gut length.
Validation of the Clinical COPD Questionnaire (CCQ) in primary care
Authors: Ställberg Björn , Nokela Mika , Ehrs Per-Olof , Hjemdal Paul , Jonsson Eva Wikström
Published: March 2009

Background

Patient centred outcomes, such as health status, are important in Chronic Obstructive Pulmonary Disease (COPD). Extensive questionnaires on health status have good measurement properties, but are not suitable for use in primary care. The newly developed, short Clinical COPD Questionnaire, CCQ, was therefore validated against the St George's Respiratory Questionnaire (SGRQ).

Methods

111 patients diagnosed by general practitioners as having COPD completed the questionnaires twice, 2–3 months apart, without systematic changes in treatment. Within this sample of patients with "clinical COPD" a subgroup of patients with spirometry verified COPD was identified. All analyses was performed on both groups.

Results

The mean FEV1 (% predicted) was 58.1% for all patients with clinical COPD and 52.4% in the group with verified COPD (n = 83). Overall correlations between SGRQ and CCQ were strong for all patients with clinical COPD (0.84) and the verified COPD subgroup (0.82). The concordance intra-class correlation between SGRQ and CCQ was 0.91 (p < 0.05). Correlations between CCQ and SGRQ were moderate to good, regardless of COPD severity.

Conclusion

The CCQ is a valid and reliable instrument for assessments of health status on the group level in patients treated for COPD in primary care but its reliability may not be sufficient for the monitoring of individual patients.
Disagreement in physical activity assessed by accelerometer and self-report in subgroups of age, gender, education and weight status
Authors: Slootmaker Sander M , Schuit Albertine J , Chinapaw Marijke JM , Seidell Jacob C , van Mechelen Willem
Published: March 2009

Background

The purpose of this study is to compare self-reported time (by questionnaire) and objectively measured time (by accelerometer) spent on physical activity at moderate (MPA) and vigorous intensity (VPA) in subgroups of age, gender, education and weight status.

Methods

In total, 236 adolescents (aged 12–18) and 301 adults (aged 22–40), completed the questionnaire and wore an accelerometer for two weeks.

Results

Adolescents reported exceptionally more time spent on MPA (mean difference 596 ± 704 min/wk) and VPA (mean difference 178 ± 315 min/wk) than was assessed objectively by the accelerometer. Based on the questionnaire, high educated adolescents spent more time on MPA (205 min/wk, p = 0.002) and VPA (120 min/wk, p = 0.01) than low educated adolescents, but according to the accelerometer they spent less time on MPA (149 min/wk, p = 0.001) and VPA (47 min/wk, p = 0.001). Among adults there was moderate agreement between self-reported time and objectively measured time spent on MPA, but in general the reported time spent on MPA (mean difference 107 ± 334 min/wk) and VPA (mean difference 169 ± 250 min/wk) exceeded the time measured with the accelerometer. Overweight adults reported significantly more VPA (57 min/wk, p = 0.04) than normal weight adults, but this was not confirmed by the accelerometer data.

Conclusion

We observed large differences in time spent on MPA and VPA measured by questionnaire and accelerometer in adolescents but reasonably good agreement in adults. Differences between methods varied by gender, education and weight status. This finding raises serious questions about the use of questionnaires to quantify MPA and VPA in adolescents. There is a clear need in advanced valid assessments of PA in adolescents.

Trial number

ISRCTN93896459
Connecting extracellular metabolomic measurements to intracellular flux states in yeast
Authors: Mo Monica L , Palsson Bernhard Ø , Herrgård Markus J
Published: March 2009

Background

Metabolomics has emerged as a powerful tool in the quantitative identification of physiological and disease-induced biological states. Extracellular metabolome or metabolic profiling data, in particular, can provide an insightful view of intracellular physiological states in a noninvasive manner.

Results

We used an updated genome-scale metabolic network model of Saccharomyces cerevisiae, i MM904, to investigate how changes in the extracellular metabolome can be used to study systemic changes in intracellular metabolic states. The i MM904 metabolic network was reconstructed based on an existing genome-scale network, i ND750, and includes 904 genes and 1,412 reactions. The network model was first validated by comparing 2,888 in silico single-gene deletion strain growth phenotype predictions to published experimental data. Extracellular metabolome data measured in response to environmental and genetic perturbations of ammonium assimilation pathways was then integrated with the i MM904 network in the form of relative overflow secretion constraints and a flux sampling approach was used to characterize candidate flux distributions allowed by these constraints. Predicted intracellular flux changes were consistent with published measurements on intracellular metabolite levels and fluxes. Patterns of predicted intracellular flux changes could also be used to correctly identify the regions of the metabolic network that were perturbed.

Conclusion

Our results indicate that integrating quantitative extracellular metabolomic profiles in a constraint-based framework enables inferring changes in intracellular metabolic flux states. Similar methods could potentially be applied towards analyzing biofluid metabolome variations related to human physiological and disease states.
The child and adolescent psychiatry trials network (CAPTN): infrastructure development and lessons learned
Authors: Shapiro Mark , Silva Susan G , Compton Scott , Chrisman Allan , DeVeaugh-Geiss Joseph , Breland-Noble Alfiee , Kondo Douglas , Kirchner Jerry , March John S
Published: March 2009

Background

In 2003, the National Institute of Mental Health funded the Child and Adolescent Psychiatry Trials Network (CAPTN) under the Advanced Center for Services and Intervention Research (ACSIR) mechanism. At the time, CAPTN was believed to be both a highly innovative undertaking and a highly speculative one. One reviewer even suggested that CAPTN was "unlikely to succeed, but would be a valuable learning experience for the field."

Objective

To describe valuable lessons learned in building a clinical research network in pediatric psychiatry, including innovations intended to decrease barriers to research participation.

Methods

The CAPTN Team has completed construction of the CAPTN network infrastructure, conducted a large, multi-center psychometric study of a novel adverse event reporting tool, and initiated a large antidepressant safety registry and linked pharmacogenomic study focused on severe adverse events. Specific challenges overcome included establishing structures for network organization and governance; recruiting over 150 active CAPTN participants and 15 child psychiatry training programs; developing and implementing procedures for site contracts, regulatory compliance, indemnification and malpractice coverage, human subjects protection training and IRB approval; and constructing an innovative electronic casa report form (eCRF) running on a web-based electronic data capture system; and, finally, establishing procedures for audit trail oversight requirements put forward by, among others, the Food and Drug Administration (FDA).

Conclusion

Given stable funding for network construction and maintenance, our experience demonstrates that judicious use of web-based technologies for profiling investigators, investigator training, and capturing clinical trials data, when coupled to innovative approaches to network governance, data management and site management, can reduce the costs and burden and improve the feasibility of incorporating clinical research into routine clinical practice. Having successfully achieved its initial aim of constructing a network infrastructure, CAPTN is now a capable platform for large safety registries, pharmacogenetic studies, and randomized practical clinical trials in pediatric psychiatry.
Triple-negative breast cancers are increased in black women regardless of age or body mass index
Authors: Stead Lesley A , Lash Timothy L , Sobieraj Jerome E , Chi Dorcas D , Westrup Jennifer L , Charlot Marjory , Blanchard Rita A , Lee John C , King Thomas C , Rosenberg Carol L
Published: March 2009

Introduction

We investigated clinical and pathologic features of breast cancers (BC) in an unselected series of patients diagnosed in a tertiary care hospital serving a diverse population. We focused on triple-negative (Tneg) tumours (oestrogen receptor (ER), progesterone receptor (PR) and HER2 negative), which are associated with poor prognosis.

Methods

We identified female patients with invasive BC diagnosed between 1998 and 2006, with data available on tumor grade, stage, ER, PR and HER2 status, and patient age, body mass index (BMI) and self-identified racial/ethnic group. We determined associations between patient and tumour characteristics using contingency tables and multivariate logistic regression.

Results

415 cases were identified. Patients were racially and ethnically diverse (born in 44 countries, 36% white, 43% black, 10% Hispanic and 11% other). 47% were obese (BMI > 30 kg/m2). 72% of tumours were ER+ and/or PR+, 20% were Tneg and 13% were HER2+. The odds of having a Tneg tumour were 3-fold higher (95% CI 1.6, 5.5; p = 0.0001) in black compared with white women. Tneg tumours were equally common in black women diagnosed before and after age 50 (31% vs 29%; p = NS), and who were obese and non-obese (29% vs 31%; p = NS). Considering all patients, as BMI increased, the proportion of Tneg tumours decreased (p = 0.08).

Conclusions

Black women of diverse background have 3-fold more Tneg tumours than non-black women, regardless of age and BMI. Other factors must determine tumour subtype. The higher prevalence of Tneg tumours in black women in all age and weight categories likely contributes to black women's unfavorable breast cancer prognosis.
Integrated analysis of breast cancer cell lines reveals unique signaling pathways
Authors: Heiser Laura M , Wang Nicholas J , Talcott Carolyn L , Laderoute Keith R , Knapp Merrill , Guan Yinghui , Hu Zhi , Ziyad Safiyyah , Weber Barbara L , Laquerre Sylvie , Jackson Jeffrey R , Wooster Richard F , Kuo Wen Lin , Gray Joe W , Spellman Paul T
Published: March 2009

Background

Cancer is a heterogeneous disease resulting from the accumulation of genetic defects that negatively impact control of cell division, motility, adhesion and apoptosis. Deregulation in signaling along the EgfR-MAPK pathway is common in breast cancer, though the manner in which deregulation occurs varies between both individuals and cancer subtypes.

Results

We were interested in identifying subnetworks within the EgfR-MAPK pathway that are similarly deregulated across subsets of breast cancers. To that end, we mapped genomic, transcriptional and proteomic profiles for 30 breast cancer cell lines onto a curated Pathway Logic symbolic systems model of EgfR-MAPK signaling. This model was composed of 539 molecular states and 396 rules governing signaling between active states. We analyzed these models and identified several subtype-specific subnetworks, including one that suggested Pak1 is particularly important in regulating the MAPK cascade when it is over-expressed. We hypothesized that Pak1 over-expressing cell lines would have increased sensitivity to Mek inhibitors. We tested this experimentally by measuring quantitative responses of 20 breast cancer cell lines to three Mek inhibitors. We found that Pak1 over-expressing luminal breast cancer cell lines are significantly more sensitive to Mek inhibition compared to those that express Pak1 at low levels. This indicates that Pak1 over-expression may be a useful clinical marker to identify patient populations that may be sensitive to Mek inhibitors.

Conclusions

All together, our results support the utility of symbolic system biology models for identification of therapeutic approaches that will be effective against breast cancer subsets.
Acute Pancreatitis in Primary Hyperparathyroidism: A Population-Based Study
Authors: Khoo Teck Kim , Vege Santhi Swaroop , Abu-Lebdeh Haitham S. , Ryu Euijung , Nadeem Sarah , Wermers Robert A.
Published: March 2009

Context: The association between acute pancreatitis and primary hyperparathyroidism (PHPT) is controversial.

Objective: The aim of the study was to address the incidence and disease characteristics of acute pancreatitis in PHPT from a large inception cohort of community residents.

Design and Setting: Patients with acute pancreatitis were identified in an Olmsted County, Minnesota, cohort of PHPT subjects diagnosed from 1965–2001 and compared to matched control subjects.

Main Outcome Measures: The estimated rate of developing acute pancreatitis was calculated by person-years method. Cox models assessed the effect of PHPT disease status on the development of acute pancreatitis.

Results: Of 684 patients with PHPT, 10 patients (1.5%) developed acute pancreatitis, compared to 32 of 1364 control patients (2.3%). The estimated rate of development of acute pancreatitis in PHPT was 114 per 100,000 person-years, compared to 140 per 100,000 person-years in control subjects (P = 0.56). The estimated hazard ratio of acute pancreatitis for PHPT relative to the control subjects was 0.84 (P = 0.89). The majority of subjects with PHPT and acute pancreatitis were women (n = 7), and the mean age was 70.6 yr at the time of acute pancreatitis. PHPT was present an average of 137 months before the development of acute pancreatitis, and contributing causes for acute pancreatitis were in identified in four patients. Maximal serum calcium levels in PHPT were not significantly associated with the development of acute pancreatitis.

Conclusions: Acute pancreatitis was not increased in community patients with PHPT, and therefore, there does not appear to be a causal relationship between PHPT and acute pancreatitis.
Conjugated Oral versus Transdermal Estrogen Replacement in Girls with Turner Syndrome: A Pilot Comparative Study
Authors: Nabhan Zeina M. , DiMeglio Linda A. , Qi Rong , Perkins Susan M. , Eugster Erica A.
Published: March 2009

Background: The optimal route of estrogen replacement in Turner syndrome (TS) is unknown.

Objective: The objective of the study was to compare conjugated oral vs. transdermal estrogen (TD E2) on bone accrual, uterine growth, pubertal development, IGF-I, and lipids in girls with TS.

Methods: Prepubertal GH-treated girls aged 10 yr or older with TS were eligible. Subjects were randomized to conjugated oral estrogen or TD E2 for 1 yr. Assessments included dual-emission x-ray absorptiometry, pelvic ultrasound, Tanner staging, growth velocity, IGF-I, and lipid profile.

Results: Twelve girls (14.0 ± 1.7 yr) were enrolled. TD E2 resulted in a significantly greater change in spine bone density at 12 months compared with conjugated oral estrogen (bone mineral content 9.0 ± 0.9 vs. 5.8 ± 0.9 g, P = 0.04; bone mineral density 0.12 ± 0.01 vs. 0.06 ± 0.01 g/cm2, P = 0.004; Z-score 0.7 ± 0.1 vs. 0.3 ± 0.1, P = 0.03). Greater increases in uterine length (4.13 ± 0.39 vs. 1.98 ± 0.39 cm, P = 0.003) and volume (22.2 ± 4.4 vs. 4.0 ± 4.4 ml, P = 0.02) were also found in the TD vs. the oral group at 1 yr. At study end, 66% of subjects in the TD group had a mature uterus vs. 0% in the oral group. No significant differences in other parameters examined were seen.

Conclusion: In girls with TS, TD E2 resulted in faster bone accrual at the spine and increased uterine growth compared with conjugated oral estrogen. This pilot study provides preliminary information for optimizing estrogen replacement in this population.
Association of Serum C-Reactive Protein Level with Sex-Specific Type 2 Diabetes Risk: A Prospective Finnish Study
Authors: Hu Gang , Jousilahti Pekka , Tuomilehto Jaakko , Antikainen Riitta , Sundvall Jouko , Salomaa Veikko
Published: March 2009

Objective: Our objective was to assess whether the association of serum C-reactive protein (CRP) with type 2 diabetes risk is modified by sex.

Design and Subjects: We prospectively followed 12,861 Finnish men and women who were 35–74 yr of age, and free of diabetes, coronary heart disease, stroke, and cancer at baseline. Hazard ratios of type 2 diabetes were estimated for different levels of serum CRP.

Results: During the follow-up, 208 men and 113 women developed diabetes. The multivariable-adjusted (age, physical activity, education, smoking, alcohol and coffee drinking, family history of diabetes, use of antihypertensive drugs, cholesterol-lowering agents, and hormone replacement therapy in women, systolic blood pressure, serum high-density lipoprotein cholesterol, serum triglycerides, and body mass index) hazard ratios of diabetes at three different levels of CRP (0.05–0.99, 1.0–2.99, and ≥3.0 mg/liter) based on the recommendation by Centers for Disease Control and the American Heart Association were 1.00, 1.46, and 1.85 (P for trend = 0.006) in men, and 1.00, 3.83, and 8.37 (P for trend <0.001) in women, respectively. CRP had a stronger association with diabetes risk in women than men (P for interaction: χ2 = 6.42; 1 df; P < 0.025). This positive association between CRP and diabetes risk did not change when participants were stratified by age group, smoking status, level of obesity, alcohol drinking habit, or family history of diabetes.

Conclusions: High baseline level of serum CRP was associated with an increased risk of diabetes among both men and women, but this association was stronger in women than men.
Adrenal Androgen Production Capacity Remains High up to Menopause in Women with Polycystic Ovary Syndrome
Authors: Puurunen Johanna , Piltonen Terhi , Jaakkola Päivi , Ruokonen Aimo , Morin-Papunen Laure , Tapanainen Juha S.
Published: March 2009

Introduction: Hyperandrogenism is one of the main features of polycystic ovary syndrome (PCOS). Of circulating androgens, 50% of androstenedione and testosterone are of ovarian and adrenal origin, whereas dehydroepiandrosterone (DHEA) and DHEA sulfate are almost uniquely of adrenal origin. Our previous studies have indicated that ovarian androgen production capacity is enhanced in women with PCOS, and it remains high until late reproductive age. To study whether this also applies to adrenal androgen production, ACTH tests were performed in healthy women and in women with PCOS.

Materials: Sixty-nine healthy women (aged 19–62 yr; body mass index 19.2–35.0 kg/m2) and 58 women with previously diagnosed PCOS (aged 18–59 yr; body mass index 19.0–42.9 kg/m2) participated in the study.

Methods: The subjects underwent ACTH stimulation tests, and serum cortisol, 17-hydroxyprogesterone, androstenedione, testosterone, DHEA, and DHEA sulfate levels were analyzed at 0, 30, and 60 min.

Results: Basal and ACTH-stimulated levels of most adrenal androgens decreased in healthy women with age, whereas in women with PCOS, only the concentrations of basal serum 17-hydroxyprogesterone decreased, and all areas under the curve (AUCs) remained unchanged and significantly higher (except for DHEA) than those in control women. Likewise, at the menopausal transition, pre- and postmenopausal women with PCOS exhibited mainly unchanged and higher basal androgen and AUC levels.

Conclusions: Similarly to ovarian endocrine function, serum adrenal steroid levels and adrenal steroid production capacity remain enhanced at least up to menopause in women with PCOS.
Differential kinematics of parallel manipulators using Assur virtual chains
Authors: Campos A , Guenther R , Martins D
Published: March 2009

This article introduces the concept of Assur virtual chains and its applications in differential kinematics of parallel manipulators. Using Assur virtual chains, the differential kinematics has a simple matricial formulation and the choice between direct and inverse kinematics is reduced to select primary variables in a homogeneous linear system. Assur virtual chains are also useful for obtaining information about the relative movements or to imposing particular kinematic constraints between two links of a kinematic chain. Additionally, a new systematic algorithm is established to analytically eliminate passive joint velocities and calculate the Jacobian matrices. This elimination approach is based on screw theory concepts such as twist, wrench, and reciprocity; also, graph theory is used for kinematic chain representation. At the end of the article, the method is applied to a 3RRR planar parallel manipulator and a general universal-prismatic-spheric Stewart—Gough platform.
On analysing certain, typically intractable, six-bar linkages
Authors: Baker J E
Published: March 2009

A pair of six-bar linkages, one of long vintage and the other very recent, are used as exemplars for considering their overall structures and the nature of their articulations. The two issues raised are the installation of an effective means for analysing a six-bar's gross mobility, and the extent to which exchanges might be made between linear and non-linear screw joints. Although the analytical tool applied is the well-known algebra of displacement—closure equations, it is the novel form of the relationships employed here that results in a successful outcome.
Radiation effect on natural convection boundary layer flow over a vertical wavy frustum of a cone
Authors: Molla M M , Hossain M A , Gorla R S R
Published: March 2009

The effect of thermal radiation on a steady two-dimensional natural convection laminar boundary layer flow of a viscous incompressible optically thick fluid over a vertical wavy frustum of a cone has been investigated. The boundary layer regime when the Grashof number Gr is large is considered. Using appropriate transformations, the basic governing equations are transformed into a dimensionless form and then solved numerically employing two efficient methods, namely: (a) implicit finite difference method together with Keller-box scheme and (b) direct numerical scheme. Numerical results are presented by streamline, isotherms, velocity and temperature distribution of the fluid, as well as the local shearing stress in terms of the local skin-friction coefficient, the local heat transfer rate in terms of local Nusselt number, and the average rate of heat transfer for a wide range of the radiation—conduction parameter or Planck number Rd and the surface heating parameter θw.
Load bearing ability of interference-fitted assemblies: A roundness profile analysis
Authors: Sogalad I , Udupa N G S
Published: March 2009

This article makes a detailed study of the influence of harmonics and the average undulation number of roundness profiles on the load bearing ability of interference-fitted assemblies. For this purpose, a plan of experiments was prepared by taking 32 factorial design with interference and the average undulation number as parameters. The analysis reveals that both the parameters influence the load bearing ability of interference-fitted assemblies. Further, it is found that harmonics influence the load bearing ability of interference-fitted assemblies.
Hybrid actuator: Motion control using genetic algorithms
Authors: Al S , Dülger L C , Kirecci A
Published: March 2009

A hybrid actuator refers to a configuration combining the motions of two different electric motors with a mechanism to obtain a programmable output. This article presents an application of the genetic algorithm (GA) to determine optimal proportional-plus-integral-plus-derivative (PID) controller parameters to drive a seven link mechanism with an adjustable crank. A previously built model for a hybrid actuator system is used to explore the application. Simulation results are included to show how position control on both servomotors is achieved using GAs in off-line implementation.
Automatic identification of epileptic electroencephalography signals using higher-order spectra
Authors: Chua K C , Chandran V , Acharya U R , Lim C M
Published: March 2009

Epilepsy is a pathological condition characterized by the spontaneous and unforeseeable occurrence of seizures, during which the perception or behaviour of patients is disturbed. An automatic early detection of the seizure onsets would help the patients and observers to take appropriate precautions. Various methods have been proposed to predict the onset of seizures based on electroencephalography (EEG) recordings. The use of non-linear features motivated by the higher-order spectra (HOS) has been reported to be a promising approach to differentiate between normal, background (pre-ictal), and epileptic EEG signals. In this work, these features are used to train both a Gaussian mixture model classifier and a support vector machine classifier. Results show that the classifiers were able to achieve 93.11 per cent and 92.67 per cent classification accuracy respectively, with selected HOS-based features. About 2 h of EEG recordings from ten patients were used in this study.
Toughening of porous bioceramic scaffolds by bioresorbable polymeric coatings
Authors: Dorozhkin S , Ajaal T
Published: March 2009

The mechanical properties of poly(ɛ-caprolactone) (PCL)-coated porous bioceramic scaffolds made of calcium phosphates were studied and analysed using a statistical experimental design and Taguchi methods. In this study, both the flexural strength of the coated scaffolds and the amount of deposited PCL were considered as the measured responses. A statistical experimental design using the analysis of means and orthogonal array was applied to optimize these responses. The removal technique of excess polymer solution, the concentration of PCL in the solution, a heat treatment temperature, and the number of times that the scaffolds were dipped in the solution were chosen as the significant processing variables. The removal technique of excess polymer solution and the number of times that the scaffolds were dipped in the solution showed the major effects on the flexural strength, while the technique for removal of excess polymer solution was found to have the major effect on the mass of the deposited PCL. The optimal conditions for achieving the maximal flexural strength of the coated scaffolds at the minimal amount of the deposited PCL were determined and tested. High-quality porous bioresorbable scaffolds with approximately 19 MPa flexural strength and approximately 0.4 g of the total (PCL coating + calcium phosphates) mass with dimensions of 8.5 mm diameter and 13 mm width were manufactured as a result.
A three-dimensional finite element model of maximal grip loading in the human wrist
Authors: Gislason M K , Nash D H , Nicol A , Kanellopoulos A , Bransby-Zachary M , Hems T , Condon B , Stansfield B
Published: March 2009

The aim of this work was to create an anatomically accurate three-dimensional finite element model of the wrist, applying subject-specific loading and quantifying the internal load transfer through the joint during maximal grip. For three subjects, representing the anatomical variation at the wrist, loading on each digit was measured during a maximal grip strength test with simultaneous motion capture. The internal metacarpophalangeal joint load was calculated using a biomechanical model. High-resolution magnetic resonance scans were acquired to quantify bone geometry. Finite element analysis was performed, with ligaments and tendons added, to calculate the internal load distribution. It was found that for the maximal grip the thumb carried the highest load, an average of 72.2 ± 20.1 N in the neutral position. Results from the finite element model suggested that the highest regions of stress were located at the radial aspect of the carpus. Most of the load was transmitted through the radius, 87.5 per cent, as opposed to 12.5 per cent through the ulna with the wrist in a neutral position. A fully three-dimensional finite element analysis of the wrist using subject-specific anatomy and loading conditions was performed. The study emphasizes the importance of modelling a large ensemble of subjects in order to capture the spectrum of the load transfer through the wrist due to anatomical variation.
An energy optimization model for a combined heat and power production energy supply system with a heat pump
Authors: Dragićević S , Bojić M
Published: March 2009

This article deals with the problem of optimal system energy management for combined heat and power production (CHP) with a heat pump. To generate steam and electric power by applying internal sources, an analysed energy system inside its power plant uses a steam boiler, an extraction steam turbine, and a heat pump. Electric power is also purchased from external sources, such as a grid. This leads to the decision problem of determining the economically optimum energy-mix for a given set of conditions. In this article, to select the energy inputs, an optimization method of mixed-integer linear programming is used. Depending on the unit cost of different types of energy the optimal cost-region diagram for the system can be found. This diagram presents a recommendation for the use of an optimum energy consumption of particular composition yielding the minimum energy-operating costs for a CHP system with a heat pump.
The dawn of the RNA World: Toward functional complexity through ligation of random RNA oligomers
Authors: Briones Carlos , Stich Michael , Manrubia Susanna C.
Published: March 2009

A main unsolved problem in the RNA World scenario for the origin of life is how a template-dependent RNA polymerase ribozyme emerged from short RNA oligomers obtained by random polymerization on mineral surfaces. A number of computational studies have shown that the structural repertoire yielded by that process is dominated by topologically simple structures, notably hairpin-like ones. A fraction of these could display RNA ligase activity and catalyze the assembly of larger, eventually functional RNA molecules retaining their previous modular structure: molecular complexity increases but template replication is absent. This allows us to build up a stepwise model of ligation-based, modular evolution that could pave the way to the emergence of a ribozyme with RNA replicase activity, step at which information-driven Darwinian evolution would be triggered.
Inventory Centralization Games with Price-Dependent Demand and Quantity Discount
Authors: Chen Xin
Published: March 2009

Consider a distribution system consisting of a set of retailers facing a single-period price-dependent demand of a single product. By taking advantage of the risk-pooling effect and the quantity/volume discount provided by suppliers or third-party carriers, the retailers may place joint orders and keep inventory at central warehouses before demand realization, and allocate inventory among themselves after demand realization to reduce their operating costs. Under rather general assumptions, we prove that there is a stable allocation of profits among the retailers in the sense that the resulting inventory centralization game has a nonempty core. We also show how to compute an allocation in the core.
OR Practice—Supporting 3PL Decisions in the Automotive Industry by Generating Diverse Solutions to a Large-Scale Location-Routing Problem
Authors: Schittekat Patrick , Sörensen Kenneth
Published: March 2009

For the distribution of spare parts to car dealers, many automotive companies use a transport network of intermediate hubs or transport platforms, operated by a set of third-party logistics (3PL) partners. The optimization of this network, particularly the selection of 3PL providers and corresponding transport platforms, is a complex decision that needs to be supported by appropriate software tools. In this paper, we develop such a tool, implement it, and show its results on a real-life case study provided by Toyota. The tool is currently in active use at Toyota to study and improve the distribution of spare parts in Germany.

Using a tabu search metaheuristic, the developed tool essentially solves a large location-routing problem, but has several innovative features to increase its usefulness. First, the tool generates a set of high-quality but structurally different solutions, rather than a single one. This increases Toyota's negotiating power, increases its ability to analyze its current transport network against possible alternatives, and allows it to quickly switch between different transport networks if unexpected events occur. Second, a commercial vehicle-routing solver is integrated into the tool, to allow for a far more realistic modeling of the vehicle-routing decision.
Clinical Outcomes and Pharmacists' Acceptance of a Community Hospital's Anticoagulation Management Service Utilizing Decentralized Clinical Staff Pharmacists
Authors: Airee Anita , Guirguis Alexander B , Mohammad Rima A
Published: March 2009

Background:

In 2008, the Joint Commission released an updated National Patient Safety Goals document that requires institutions to implement practices that reduce the likelihood of patient harm associated with use of anticoagulation therapy. One of the expectations associated with this goal was that each organization would establish an anticoagulant management program. To our knowledge, few data exist to describe the implementation and assessment of anticoagulation programs in smaller, nonteaching community hospitals using decentralized pharmacists in an integrated practice model.

Objective:

To compare the performance of a protocol-driven anticoagulation management service led by decentralized pharmacists in a nonteaching community hospital with that of usual medical care provided by hospitalist physicians before this program was implemented. Based on these results, as well as a pharmacist satisfaction survey, evaluate the service and identify barriers to expansion.

Methods:

We conducted a retrospective cohort study comparing 50 consecutive patients who were starting warfarin for the first time beginning in November 2003 with 50 patients managed by hospitalist physicians prior to November 2002 (the time of program implementation).

Results:

There were no significant differences between groups with regard to time in therapeutic range once therapeutic, length of stay, international normalized ratios (INRs) greater than 3.5, or INRs less than 2. Patients in the pharmacy management group had significantly fewer drug interactions with antimicrobials than did the usual medical care group. Although time to therapeutic range was longer in the pharmacy protocol group, there were fewer patients with INRs greater than 3.5, although this did not reach statistical significance.

Conclusions:

The efficacy of the pharmacist-led anticoagulation management service was no different from that of usual medical care. Patient safety appeared improved, in part due to more careful initial dose selection based on patient-specific factors. Although this program was accepted by pharmacists, time limitations were perceived to be a major barrier to quality care and expansion of the service.