bluuebunny/crossref_metadata_2025 huggingface dataset:
A simple assessment of dyspnoea as a prognostic indicator in idiopathic pulmonary fibrosis
Authors: Nishiyama O. , Taniguchi H. , Kondoh Y. , Kimura T. , Kato K. , Kataoka K. , Ogawa T. , Watanabe F. , Arizono S.
Published: April 2010

The prognosis in idiopathic pulmonary fibrosis (IPF) is poor. No therapy has been shown to prolong survival. The objective of this study was to examine the prognostic significance of dyspnoea in daily living at baseline in IPF using a simple assessment tool.

93 consecutive patients with IPF, who had undergone evaluation at diagnosis, were included. The level of dyspnoea was assessed using the modified Medical Research Council (MRC) scale. The relationship between data at baseline and survival was examined.

A univariate Cox proportional-hazard model showed that forced vital capacity % predicted (hazard ratio (HR) 0.965, 95% CI 0.948–0.982; p<0.0001), diffusing capacity of the lung for carbon monoxide % predicted (HR 0.978, 95% CI 0.963–0.993; p=0.0041), baseline arterial oxygen tension (HR 0.963, 95% CI 0.938–0.989; p = 0.0060) and modified MRC score (HR 2.402, 95% CI 1.495–3.858; p = 0.0003) were significantly predictive of survival. All variables of the 6-min walk test, including walk distance (HR 0.995, 95% CI 0.992–0.998; p = 0.0020), the lowest arterial oxygen saturation measured by pulse oximetry (Sp,O2) (HR 0.944, 95% CI 0.918–0.972; p<0.0001) and the Borg scale (HR 1.285, 95% CI 1.091–1.514; p = 0.0027), were also significant. With stepwise, multivariate Cox proportional analysis, the modified MRC score (HR 2.181, 95% CI 1.333–3.568; p = 0.0019) and the lowestSp,O2during the 6-min walk test (HR 0.952, 95% CI 0.924–0.981; p = 0.0014) were the most significant.

Dyspnoea in daily living, assessed with the modified MRC scale at baseline, provides additional prognostic information for patients with IPF.
Interactive inhibitory effects of formoterol and montelukast on activated human neutrophils
Authors: Gravett C.M. , Theron A.J. , Steel H.C. , Tintinger G.R. , Cockeran R. , Feldman C. , Anderson R.
Published: April 2010

The research question addressed in the current study was: do formoterol (1 and 10 nM) and montelukast (2 μM) possess interactive inhibitory effects on activated human neutrophils, particularly in relation to alterations in cyclic AMP and cytosolic Ca2+fluxes?

Isolated human blood neutrophils were activated with the chemoattractantN-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP) (1 μM) in combination with cytochalasin B (CB; 3 μM). Fura-2-acetoxymethyl ester-based spectrofluorimetry, lucigenin-enhanced chemiluminescence, colorimetric and flow cytometric procedures were used to measure cytosolic Ca2+fluxes, production of superoxide, elastase release and beta-2 integrin (CR3) expression, respectively, while cyclic AMP and leukotriene (LT)B4were assayed using competitive binding ELISA procedures.

Activation of the cells with fMLP/CB resulted in abrupt and sustained increases in cytosolic Ca2+, as well as release of elastase and production of superoxide and LTB4, and expression of CR3, all of which were attenuated by formoterol and montelukast individually, and especially by the combination of these agents. These anti-inflammatory effects of each agent, as well as the combination, were associated with significant increases in cyclic AMP.

The findings of the current study may explain the efficacy of montelukast and formoterol when used in combination with inhaled corticosteroids in the treatment of severe asthma, possibly by controlling neutrophil-driven inflammation of the airways.
Efficacy of standard rehabilitation in COPD outpatients with comorbidities
Authors: Crisafulli E. , Gorgone P. , Vagaggini B. , Pagani M. , Rossi G. , Costa F. , Guarriello V. , Paggiaro P. , Chetta A. , de Blasio F. , Olivieri D. , Fabbri L.M. , Clini E.M.
Published: April 2010

A prospective study was performed to confirm the prevalence pattern of the most frequent co-morbidities and to evaluate whether characteristics of patients, specific comorbidities and increasing number of comorbidities are independently associated with poorer outcomes in a population with complex chronic obstructive pulmonary disease (COPD) submitted for pulmonary rehabilitation (PR).

316 outpatients (mean±sdage 68±7 yrs) were studied. The outcomes recorded were comorbidities and proportion of patients with a pre-defined minimally significant change in exercise tolerance (6-min walk distance (6MWD) +54 m), breathlessness (Medical Research Council (MRC) score -1 point) and quality of life (St George’s Respiratory Questionnaire -4 points).

62% of patients reported comorbidities; systemic hypertension (35%), dyslipidaemia (13%), diabetes (12%) and coronary disease (11%) were the most frequent. Of these patients, >45% improved over the minimum clinically important difference in all the outcomes. In a logistic regression model, baseline 6MWD (OR 0.99, 95% CI 0.98–0.99; p = 0.001), MRC score (OR 12.88, 95% CI 6.89–24.00; p = 0.001) and arterial carbon dioxide tension (OR 1.08, 95% CI 1.00–1.15; p = 0.034) correlated with the proportion of patients who improved 6MWD and MRC, respectively. Presence of osteoporosis reduced the success rate in 6MWD (OR 0.28, 95% CI 0.11–0.70; p = 0.006).

A substantial prevalence of comorbidities in COPD outpatients referred for PR was confirmed. Only the individual's disability and the presence of osteoporosis were independently associated with poorer rehabilitation outcomes.
Conditional random pattern model for copy number aberration detection
Authors: Li Fuhai , Zhou Xiaobo , Huang Wanting , Chang Chung-Che , Wong Stephen TC
Published: April 2010

Background

DNA copy number aberration (CNA) is very important in the pathogenesis of tumors and other diseases. For example, CNAs may result in suppression of anti-oncogenes and activation of oncogenes, which would cause certain types of cancers. High density single nucleotide polymorphism (SNP) array data is widely used for the CNA detection. However, it is nontrivial to detect the CNA automatically because the signals obtained from high density SNP arrays often have low signal-to-noise ratio (SNR), which might be caused by whole genome amplification, mixtures of normal and tumor cells, experimental noise or other technical limitations. With the reduction in SNR, many false CNA regions are often detected and the true CNA regions are missed. Thus, more sophisticated statistical models are needed to make the CNAs detection, using the low SNR signals, more robust and reliable.

Results

This paper presents a conditional random pattern (CRP) model for CNA detection where much contextual cues are explored to suppress the noise and improve CNA detection accuracy. Both simulated and the real data are used to evaluate the proposed model, and the validation results show that the CRP model is more robust and reliable in the presence of noise for CNA detection using high density SNP array data, compared to a number of widely used software packages.

Conclusions

The proposed conditional random pattern (CRP) model could effectively detect the CNA regions in the presence of noise.
Developmental iodine deficiency and hypothyroidism impair neural development in rat hippocampus: involvement of doublecortin and NCAM-180
Authors: Gong Jian , Liu Wanyang , Dong Jing , Wang Yi , Xu Hongde , Wei Wei , Zhong Jiapeng , Xi Qi , Chen Jie
Published: April 2010

Background

Developmental iodine deficiency results in inadequate thyroid hormone (TH), which damages the hippocampus. Here, we explored the roles of hippocampal doublecortin and neural cell adhesion molecule (NCAM)-180 in developmental iodine deficiency and hypothyroidism.

Methods

Two developmental rat models were established with either an iodine-deficient diet, or propylthiouracil (PTU)-adulterated water (5 ppm or 15 ppm) to impair thyroid function, in pregnant rats from gestational day 6 until postnatal day (PN) 28. Silver-stained neurons and protein levels of doublecortin and NCAM-180 in several hippocampal subregions were assessed on PN14, PN21, PN28, and PN42.

Results

The results show that nerve fibers in iodine-deficient and 15 ppm PTU-treated rats were injured on PN28 and PN42. Downregulation of doublecortin and upregulation of NCAM-180 were observed in iodine-deficient and 15 ppm PTU-treated rats from PN14 on. These alterations were irreversible by the restoration of serum TH concentrations on PN42.

Conclusion

Developmental iodine deficiency and hypothyroidism impair the expression of doublecortin and NCAM-180, leading to nerve fiber malfunction and thus impairments in hippocampal development.
Enhancement of L-3-hydroxybutyryl-CoA dehydrogenase activity and circulating ketone body levels by pantethine. Relevance to dopaminergic injury
Authors: Cornille Emilie , Abou-Hamdan Mhamad , Khrestchatisky Michel , Nieoullon André , de Reggi Max , Gharib Bouchra
Published: April 2010

Background

The administration of the ketone bodies hydroxybutyrate and acetoacetate is known to exert a protective effect against metabolic disorders associated with cerebral pathologies. This suggests that the enhancement of their endogenous production might be a rational therapeutic approach. Ketone bodies are generated by fatty acid beta-oxidation, a process involving a mitochondrial oxido-reductase superfamily, with fatty acid-CoA thioesters as substrates. In this report, emphasis is on the penultimate step of the process, i.e. L-3-hydroxybutyryl-CoA dehydrogenase activity. We determined changes in enzyme activity and in circulating ketone body levels in the MPTP mouse model of Parkinson's disease. Since the active moiety of CoA is pantetheine, mice were treated with pantethine, its naturally-occurring form. Pantethine has the advantage of being known as an anti-inflammatory and hypolipidemic agent with very few side effects.

Results

We found that dehydrogenase activity and circulating ketone body levels were drastically reduced by the neurotoxin MPTP, whereas treatment with pantethine overcame these adverse effects. Pantethine prevented dopaminergic neuron loss and motility disorders. In vivo and in vitro experiments showed that the protection was associated with enhancement of glutathione (GSH) production as well as restoration of respiratory chain complex I activity and mitochondrial ATP levels. Remarkably, pantethine treatment boosted the circulating ketone body levels in MPTP-intoxicated mice, but not in normal animals.

Conclusions

These finding demonstrate the feasibility of the enhancement of endogenous ketone body production and provide a promising therapeutic approach to Parkinson's disease as well as, conceivably, to other neurodegenerative disorders.
The Total Deviation Index estimated by Tolerance Intervals to evaluate the concordance of measurement devices
Authors: Escaramís Geòrgia , Ascaso Carlos , Carrasco Josep L
Published: April 2010

Background

In an agreement assay, it is of interest to evaluate the degree of agreement between the different methods (devices, instruments or observers) used to measure the same characteristic. We propose in this study a technical simplification for inference about the total deviation index (TDI) estimate to assess agreement between two devices of normally-distributed measurements and describe its utility to evaluate inter- and intra-rater agreement if more than one reading per subject is available for each device.

Methods

We propose to estimate the TDI by constructing a probability interval of the difference in paired measurements between devices, and thereafter, we derive a tolerance interval (TI) procedure as a natural way to make inferences about probability limit estimates. We also describe how the proposed method can be used to compute bounds of the coverage probability.

Results

The approach is illustrated in a real case example where the agreement between two instruments, a handle mercury sphygmomanometer device and an OMRON 711 automatic device, is assessed in a sample of 384 subjects where measures of systolic blood pressure were taken twice by each device. A simulation study procedure is implemented to evaluate and compare the accuracy of the approach to two already established methods, showing that the TI approximation produces accurate empirical confidence levels which are reasonably close to the nominal confidence level.

Conclusions

The method proposed is straightforward since the TDI estimate is derived directly from a probability interval of a normally-distributed variable in its original scale, without further transformations. Thereafter, a natural way of making inferences about this estimate is to derive the appropriate TI. Constructions of TI based on normal populations are implemented in most standard statistical packages, thus making it simpler for any practitioner to implement our proposal to assess agreement.
Randomised controlled trial of the effects of physical activity feedback on awareness and behaviourin UK adults: the FAB study protocol [ISRCTN92551397]
Authors: Watkinson Clare , van Sluijs Esther MF , Sutton Stephen , Marteau Theresa , Griffin Simon J
Published: April 2010

Background

While there are increasing data implicating poor recognition of physical inactivity as a potential barrier to healthy behaviour change, the efficacy of feedback to promote physical activity is uncertain. Using a randomised controlled trial nested within a population-based cohort study, we plan to test three variations of physical activity feedback against a control group. Our primary objective is to assess the efficacy of physical activity feedback in promoting physical activity behaviour change. Secondary objectives are to determine the influence of feedback on physical activity awareness and cognitions, and to compare behavioural effects by type of feedback.

Methods/Design

We aim to recruit 500 healthy participants aged 30 to 55 years from the ongoing Fenland Study (Cambridge, UK). Following careful phenotyping during baseline measurement (anthropometric, clinical, body composition and fitness measurements, as well as questionnaires assessing self-reported and self-rated physical activity, psychosocial correlates of physical activity behaviour, diet, lifestyle and general health), participants wear a combined heart rate and movement sensor (Actiheart®) for six continuous days and nights. After receipt of the physical activity data (around 2 weeks later), participants are randomly allocated to either a control group (no feedback) or one of three types of personalised physical activity feedback ('simple', 'visualised' or 'contextualised'), and complete repeat measures of self-rated physical activity and psychosocial correlates. Approximately five weeks after receiving feedback, all participants wear the Actiheart® for another six-day follow-up period and complete repeat questionnaires. Values at outcome, adjusted for baseline, will be compared between randomised groups.

Discussion

Given the randomised trial design and use of objective measure of physical activity, this study is likely to provide valuable insights into the efficacy of a feedback intervention in changing physical activity behaviour, as well as the psychological mechanisms involved.

Trial Registration

Current Controlled Trials: ISRCTN92551397
Dietary intakes and food sources of fat and fatty acids in Guatemalan schoolchildren: A cross-sectional study
Authors: Bermudez Odilia I , Toher Claire , Montenegro-Bethancourt Gabriela , Vossenaar Marieke , Mathias Paul , Doak Colleen , Solomons Noel W
Published: April 2010

Background

Consumption of healthy diets that contribute with adequate amounts of fat and fatty acids is needed for children. Among Guatemalan children, there is little information about fat intakes. Therefore, the present study sought to assess intakes of dietary fats and examine food sources of those fats in Guatemalan children.

Methods

The study subjects consisted of a convenience sample of 449 third- and fourth-grade schoolchildren (8-10 y), attending public or private schools in Quetzaltenango City, Guatemala. Dietary data was obtained by means of a single pictorial 24-h record.

Results

The percentages of total energy (%E) from total fat, saturated fat (SFA) and monounsaturated fat (MUFA) reached 29%E for total fat and 10%E for each SFA and MUFA, without gender differences. %E from fats in high vs. low-socio economic status (SES) children were significantly higher for boys, but not for girls, for total fat (p = 0.002) and SFA (p < 0.001). Large proportions of the children had low levels of intakes of some fatty acids (FA), particularly for n-3 FA, with >97% of all groups consuming less than 1%E from this fats. Fried eggs, sweet rolls, whole milk and cheese were main sources of total fat and, SFA. Whole milk and sweet bread were important sources of n-3 FA for high- and low-SES boys and girls, respectively. Fried plantain was the main source of n-3 FA for girls in the high-SES group. Fried fish, seafood soup, and shrimp, consumed only by boys in low amounts, were sources of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, which may explain the low intakes of these nutrients.

Conclusions

α-linolenic acid, EPA and DHA were the most limiting fatty acids in diets of Guatemalan schoolchildren, which could be partially explained by the low consumption of sources of these nutrients, particularly fish and seafood (for EPA and DHA). This population will benefit from a higher consumption of culturally acceptable foods that are rich in these limiting nutrients.
A Thymidine Kinase recombinant protein-based ELISA for detecting antibodies to Duck Plague Virus
Authors: Wen Yongping , Cheng Anchun , Wang Mingshu , Ge Han , Shen Chanjuan , Liu Sitong , Xiang Jun , Jia Renyong , Zhu Dekang , Chen Xiaoyue , Lian Bei , Chang Hua , Zhou Yi
Published: April 2010

Background

Duck plague virus (DPV) is the causative agent of Duck Plague (DP) that causes significant morbidity and mortality throughout duck-producing areas of the world. The diagnosis of DP currently relies on the use of live or inactivated whole DPV virion as antigens in ELISA, but it is too laborious and expensive for routine application, and it is still difficult to get purified DPV virion with current technology.

Results

In this study, we describe the expression and purification of a recombinant Thymidine Kinase (TK) protein which makes antigen in an in-house developed, optimized and standardized ELISA. The specificity of the optimized TK-ELISA was evaluated by antisera against Duck Plague Virus (DPV), Duck Hepatitis B Virus (DHBV), Duck Hepatitis Virus (DHV),Riemerella Anatipestifer(R. A),Escherichia coli(E. coli) andSalmonella anatum(S. anatum). Only antisera against DPV yielded a specific and strong signal. In order to determine the sensitivity of the TK-ELISA, a panel of diluted sera was tested, and the minimum detection limit of 1:2560 (OD450 nm = 0.401) was obtained according to the endpoint cut-off (0.2438). The repeatability and reproducibility under the experimental conditions demonstrates a low variability (P > 0.05). The suspected sera samples (n = 30) were determined by TK-ELISA and the positive rate is 90% (27/30), and the TK-ELISA showed 83.33% (22+3/30) coincidence rate with the Serum Neutralization Test (SNT) and 90% (24+3/30) coincidence rate with the whole DPV virion based-ELISA (DPV-ELISA). When defining the dynamics of antibody response to attenuated live DPV vaccine, the maximum antibodies is reached after 4 weeks.

Conclusions

The results suggest that the TK-ELISA provides high specificity, sensitivity, repeatability and reproducibility for detection of anti-DPV antibodies in duck sera, and has the potential to be much simpler than DPV-ELISA and SNT for the sera epidemiological investigation.
The effect of transforming growth factor-β1 on nasopharyngeal carcinoma cells: insensitive to cell growth but functional to TGF-β/Smad pathway
Authors: Xiao Jian , Xiang Qi , Xiao Ye-Chen , Su Zhi-Jian , Huang Zhi-Feng , Zhang Qi-Hao , Tan Yi , Li Xiao-Kun , Huang Ya-Dong
Published: April 2010

Objectives

This study explored the response of nasopharyngeal carcinoma cells to TGF-β1-induced growth suppression and investigated the roles of the TGF-β/Smad signaling pathway in nasopharyngeal carcinoma cells.

Methods

The cells of nasopharyngeal carcinoma cell line CNE2 were treated with TGF-β1. The growth responses of CNE2 cells were analyzed by MTT assay. The mRNA expression and protein subcellular localization of the TGF-β/Smad signaling components in the CNE2 were determined by real time RT-PCR and immunocytochemical analysis.

Results

We found that the growth of CNE2 cells was not suppressed by TGF-β1. The signaling proteins TβRII, Smad 7 were expressed normally, while Smad2, Smad3, and Smad4 increased significantly at the mRNA level. TGF-β type II receptor and Smad7 had no change compared to the normal nasopharyngeal epithelial cells. In addition, Smad2 was phosphorylated to pSmad2, and the activated pSmad2 translocated into the nucleus from the cytoplasm, while the inhibitory Smad-Smad7 translocated from the nucleus to the cytoplasm after TGF-β1 stimulation.

Conclusion

The results suggested that CNE2 cells are not sensitive to growth suppression by TGF-β1, but the TGF-β/Smad signaling transduction is functional. Further work is needed to address a more detailed spectrum of the TGF-β/Smad signaling pathway in CNE2 cells.
A simplified protocol for evaluating and monitoring urethral stricture patients minimizes cost without compromising patient outcome
Authors: Okorie Chukwudi O , Pisters Louis L , Ndasi Henry T , Fekadu Arega
Published: April 2010

Uroflowmetry, urethrocystoscopy and urethrography are either not readily available or the cost is prohibitive for many patients in low-resource countries. This paper examines the use of clinical history in post-urethroplasty follow-up. We retrospectively reviewed the outcome of 54 post-urethroplasty patients. Preoperative diagnostic work-up included simple blood tests and a retrograde urethrography, and postoperatively we did not perform any immediate diagnostic work-up. Follow-up of these patients was done through mobile phone calls and personal contacts. Eighty-nine per cent of our patients reported acceptable voiding over a mean follow-up period of 48.4 months – 79.6% were followed using mobile phone contact. In the majority of the urethral strictures cases, diagnostic work up can be kept to a minimum, thereby reducing cost. Follow-up can be done via phone calls and personal contact in many African countries where compliance is frequently less than encouraging. The spread of mobile phone networks across the continent has been remarkable.
Evaluation of the information content of RNA structure mapping data for secondary structure prediction
Authors: Quarrier Scott , Martin Joshua S. , Davis-Neulander Lauren , Beauregard Arthur , Laederach Alain
Published: April 2010

Structure mapping experiments (using probes such as dimethyl sulfate [DMS], kethoxal, and T1 and V1 RNases) are used to determine the secondary structures of RNA molecules. The process is iterative, combining the results of several probes with constrained minimum free-energy calculations to produce a model of the structure. We aim to evaluate whether particular probes provide more structural information, and specifically, how noise in the data affects the predictions. Our approach involves generating “decoy” RNA structures (using the sFold Boltzmann sampling procedure) and evaluating whether we are able to identify the correct structure from this ensemble of structures. We show that with perfect information, we are always able to identify the optimal structure for five RNAs of known structure. We then collected orthogonal structure mapping data (DMS and RNase T1 digest) under several solution conditions using our high-throughput capillary automated footprinting analysis (CAFA) technique on two group I introns of known structure. Analysis of these data reveals the error rates in the data under optimal (low salt) and suboptimal solution conditions (high MgCl2). We show that despite these errors, our computational approach is less sensitive to experimental noise than traditional constraint-based structure prediction algorithms. Finally, we propose a novel approach for visualizing the interaction of chemical and enzymatic mapping data with RNA structure. We project the data onto the first two dimensions of a multidimensional scaling of the sFold-generated decoy structures. We are able to directly visualize the structural information content of structure mapping data and reconcile multiple data sets.
Romantic Relationships and Interpersonal Violence Among Adults With Developmental Disabilities
Authors: Ward Karen M. , Bosek Rebecca L. , Trimble Erin L.
Published: April 2010

Romantic relationships are important in the lives of adults with developmental disabilities. The purpose of this study was to explore dating and romantic relationships among these adults and to identify the nature and extent of interpersonal violence in their relationships. A random sample of 47 women and men participated in semistructured interviews. The authors found that relationships sounded very typical of people without disabilities, but their time together was more limited than they wanted. A high percentage of participants had experienced interpersonal violence, primarily in the form of name calling, yelling, screaming, and physical assault. Although the police and family or friends were the first sources of assistance following an abusive incident, more than one third of the participants said they did not seek any help.
Narrating Disability, Narrating Religious Practice: Reconciliation and Fragile X Syndrome
Authors: Michie Marsha , Skinner Debra
Published: April 2010

This article examines the place of religion in the narratives of mothers of children with fragile X syndrome. In semistructured interviews, a majority of women combined narratives of religious practice with illness narratives, interpreting their children's disabilities within a religious framework. Informed by Arthur Frank's (1995) concept of “wounded storytellers,” the authors articulate a reconciliation narrative that mothers commonly used to describe their transition from viewing disability as a burden or challenge to seeing it as a blessing, or as a part of God's purpose or plan for their lives. The authors discuss the significance of narrative for better understanding religious perspectives on disability and conclude with the implications of these findings for practitioners and future research.
Hyaluronan (HA) content, the ratio of HA fragments and the expression of CD44 in the ovine cervix vary with the stage of the oestrous cycle
Authors: Perry K , Haresign W , Wathes D C , Khalid M
Published: April 2010

The complex anatomy of the ovine cervix limits the success of trans-cervical artificial insemination in sheep. However, there is a degree of natural relaxation of cervix at oestrus that is accompanied by an increase in the water content. As hyaluronan (HA) has a high affinity for water molecules, in this study, we tested the hypothesis that the HA content of the cervix, the proportion of different size fragments of HA and expression of its receptor CD44 vary with the stage of the oestrous cycle. Oestrous was synchronized in 25 Welsh mountain ewes, and their cervices were collected either during luteal phase (n=8) or pre-LH (n=8) or post-LH (n=9) surge stage of the oestrous cycle. The pre-LH surge group had the highest HA content (2.96 ng/mg of cervical tissue), which was significantly (P≤0.05) higher than that observed for the post-LH surge (2.04 ng/mg) group. The luteal phase group had a mean HA content intermediate between the pre- and post-LH surge groups, and was significantly different from either. The frequency of cervical samples containing both sizes of HA fragments (small and large) was significantly higher (P≤0.05) in the pre-LH surge group compared with the luteal and the post-LH surge groups, whereas that in post-LH surge group was significantly (P≤0.05) higher than that in the luteal group. The number of cervical samples that contained only small HA fragments was significantly (P≤0.05) higher in the luteal group compared with both the pre- and post-LH surge groups, whereas the number of samples containing only large HA fragments was significantly (P≤0.05) higher in the post-LH surge group compared with the luteal or pre-LH surge groups. Overall mean expression of CD44 in the vaginal and mid regions was significantly (P≤0.001) higher than that in the uterine region, with no difference between the vaginal and mid regions of the cervix. Pattern of CD44 expression depended on the stage of the oestrous cycle. At the luteal stage, CD44 expression did not vary among epithelial, sub-epithelial, circular and longitudinal smooth muscle layers, whereas at the pre- and post-LH surge stages, the expression in the epithelial layer was significantly (P≤0.001) higher than that in the other three layers. In general, CD44 expression in the transverse smooth muscle layer was significantly (P≤0.05) lower than the expression in all the other layers at all the stages of the oestrous cycle. The results indicated that the HA varied with the steroid status. Higher HA values at a time when cervical relaxation is naturally higher may indicate its involvement in remodelling of the cervix at oestrus.
Length of Stay and Hospital Costs Associated with a Pharmacodynamic‐Based Clinical Pathway for Empiric Antibiotic Choice for Ventilator‐Associated Pneumonia
Authors: Nicasio Anthony M. , Eagye Kathryn J. , Kuti Effie L. , Nicolau David P. , Kuti Joseph L.
Published: April 2010

Study Objective. To determine hospital costs associated with the use of a clinical pathway implemented in our intensive care units (ICUs) to optimize antibiotic regimen selection for patients with ventilator‐associated pneumonia (VAP) compared with costs in a historical control group treated according to prescriber preference.

Design. Retrospective cost analysis from the hospital perspective.

Setting. Single, tertiary‐care medical center.

Patients. One hundred sixty‐six adults with VAP from the medical, surgical, and neurotrauma ICUs (73 historical control patients [2004–2005] and 93 patients given an empiric antibiotic clinical pathway for VAP [2006–2007]).

Measurements and Main Results. The VAP clinical pathway consisted of an ICU‐specific three‐drug regimen that considered local minimum inhibitory concentration distributions and a pharmacodynamically optimized dosing strategy. Hospital cost data were collected and inflated to 2007 according to the consumer price index. The VAP‐related length of treatment, hospitalization costs, and antibiotic costs were compared between groups. The median VAP length of treatment was 24 days (interquartile range [IQR] 13–35 days] and 11 days (IQR 7–17 days) for historical and clinical pathway groups, respectively (p<0.001). Daily hospital costs were similar for both cohorts over the first 7 days, after which costs declined significantly for patients treated with the clinical pathway (p<0.001). When controlling for baseline differences between groups and length of stay before development of VAP, patients treated with the clinical pathway had shorter lengths of ICU stay after VAP, shorter total hospital lengths of stay after VAP, and lower hospital costs after the treatment of VAP. Median total antibiotic costs for individual patients were similar between groups ($535 [IQR $261–998] vs $482 [IQR $222–985] clinical pathway vs control, p=0.45), and the proportion of VAP hospital resources consumed by antibiotics for both groups was low.

Conclusion. Although aggressive dosing of more costly antibiotics was empirically prescribed using the clinical pathway, patients in this group exhibited a shorter duration of treatment, reduced hospital length of stay after VAP, and lower hospital costs without any significant increase in antibiotic expenditures.
Acute Ischemic Stroke Update
Authors: Baldwin Kathleen , Orr Sean , Briand Mary , Piazza Carolyn , Veydt Annita , McCoy Stacey
Published: April 2010

Stroke is the third most common cause of death in the United States and is the number one cause of long‐term disability. Legislative mandates, largely the result of the American Heart Association, American Stroke Association, and Brain Attack Coalition working cooperatively, have resulted in nationwide standardization of care for patients who experience a stroke. Transport to a skilled facility that can provide optimal care, including immediate treatment to halt or reverse the damage caused by stroke, must occur swiftly. Admission to a certified stroke center is recommended for improving outcomes. Most strokes are ischemic in nature. Acute ischemic stroke is a heterogeneous group of vascular diseases, which makes targeted treatment challenging. To provide a thorough review of the literature since the 2007 acute ischemic stroke guidelines were developed, we performed a search of the MEDLINE database (January 1, 2004‐July 1, 2009) for relevant English‐language studies. Results (through July 1, 2009) from clinical trials included in the Internet Stroke Center registry were also accessed. Results from several pivotal studies have contributed to our knowledge of stroke. Additional data support the efficacy and safety of intravenous alteplase, the standard of care for acute ischemic stroke since 1995. Due to these study results, the American Stroke Association changed its recommendation to extend the time window for administration of intravenous alteplase from within 3 hours to 4.5 hours of symptom onset; this recommendation enables many more patients to receive the drug. Other findings included clinically useful biomarkers, the role of inflammation and infection, an expanded role for placement of intracranial stents, a reduced role for urgent carotid endarterectomy, alternative treatments for large‐vessel disease, identification of nontraditional risk factors, including risk factors for women, and newly published pediatric stroke guidelines. In addition, new devices for thrombolectomy are being developed, and neuroprotective therapies such as the use of magnesium, statins, and induced hypothermia are being explored. As treatment interventions become more clearly defined in special subgroups of patients, outcomes in patients with acute ischemic stroke will likely continue to improve.
Procarbazine‐Induced Hepatotoxicity: Case Report and Review of the Literature
Authors: Fesler Mark J. , Becker‐Koepke Stephanie , Di Bisceglie Adrian M. , Petruska Paul J.
Published: April 2010

Procarbazine hydrochloride is an oral alkylating agent primarily used as a component of chemotherapy regimens for Hodgkin's lymphoma, as well as in regimens for primary central nervous system lymphoma and high‐grade gliomas. Although the prescribing information for procarbazine lists hepatic dysfunction as a potential adverse reaction, we found only one published report with a probable link between procarbazine and liver injury. We describe a 65–year‐old man who developed liver injury due to procarbazine during salvage chemotherapy for non‐Hodgkin's lymphoma. The patient had no preexisting liver disease, his lymphoma was without hepatic involvement, and no liver injury developed after initial chemotherapy with R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Due to relapse of his non‐Hodgkin's lymphoma, salvage chemotherapy with C‐MOPP‐R (cyclophosphamide, vincristine, procarbazine, prednisone, and rituximab) was administered, and the patient developed fever and amino‐transferase level elevation during the second cycle. After discontinuation of all drug therapy, exclusion of other potential etiologies, and resolution of hepatic injury, the patient was rechallenged with procarbazine and again experienced fever with aminotransferase level elevation. His aminotransferase levels promptly returned to normal after discontinuation of procarbazine, and he experienced no further evidence of liver disease. Use of validated scoring systems of drug‐induced liver injury indicated a definitive association between the patient's hepatic injury and procarbazine. Based on our experience with this patient, periodic assessment of hepatic function, as suggested in the package insert, is recommended in patients receiving procarbazine.
Public‐Private Coproduction of Risk: Government Indemnification of the Commercial Space Launch Industry
Authors: Brennan Timothy J , Kousky Carolyn , Macauley Molly
Published: April 2010

Using rockets to launch communications satellites and other spacecraft poses risks to the uninvolved public, including persons and property under the flight path of the launch vehicle. The federal government plays a pivotal technical role during the actual launch by carrying out certain risk‐related procedures, thus causing third‐party risk to be jointly produced by the company and the government. In addition, under the Commercial Space Launch Act, the government partially indemnifies commercial launch companies for third‐party damages. We compare the indemnification policy to optimal liability rules under public‐private co‐production of risk. Under modest assumptions, shared liability created by the indemnification rules decreases the incentive of both parties to take care relative to the optimum. If care were observable, it would be preferable for the government to fully indemnify companies that take due care. The role of the government as an agent for third parties may qualify these findings.
Inhibition of β-Cell Sodium-Calcium Exchange Enhances Glucose-Dependent Elevations in Cytoplasmic Calcium and Insulin Secretion
Authors: Hamming Kevin S.C. , Soliman Daniel , Webster Nicola J. , Searle Gavin J. , Matemisz Laura C. , Liknes David A. , Dai Xiao-Qing , Pulinilkunnil Thomas , Riedel Michael J. , Dyck Jason R.B. , MacDonald Patrick E. , Light Peter E.
Published: April 2010

OBJECTIVE

The sodium-calcium exchanger isoform 1 (NCX1) regulates cytoplasmic calcium (Ca2+c) required for insulin secretion in β-cells. NCX1 is alternatively spliced, resulting in the expression of splice variants in different tissues such as NCX1.3 and -1.7 in β-cells. As pharmacological inhibitors of NCX1 splice variants are in development, the pharmacological profile of β-cell NCX1.3 and -1.7 and the cellular effects of NCX1 inhibition were investigated.

RESEARCH DESIGN AND METHODS

The patch-clamp technique was used to examine the pharmacological profile of the NCX1 inhibitor KB-R7943 on recombinant NCX1.3 and -1.7 activity. Ca2+ imaging and membrane capacitance were used to assess the effects of KB-R7943 on Ca2+c and insulin secretion in mouse and human β-cells and islets.

RESULTS

NCX1.3 and -1.7 calcium extrusion (forward-mode) activity was ∼16-fold more sensitive to KB-R7943 inhibition compared with cardiac NCX1.1 (IC50s = 2.9 and 2.4 vs. 43.0 μmol/l, respectively). In single mouse/human β-cells, 1 μmol/l KB-R7943 increased insulin granule exocytosis but was without effect on α-cell glucagon granule exocytosis. KB-R7943 also augmented sulfonylurea and glucose-stimulated Ca2+c levels and insulin secretion in mouse and human islets, although KB-R7943 was without effect under nonstimulated conditions.

CONCLUSIONS

Islet NCX1 splice variants display a markedly greater sensitivity to pharmacological inhibition than the cardiac NCX1.1 splice variant. NCX1 inhibition resulted in glucose-dependent increases in Ca2+c and insulin secretion in mouse and human islets. Thus, we identify β-cell NCX1 splice variants as targets for the development of novel glucose-sensitive insulinotropic drugs for type 2 diabetes.
β-Cell Replication Is Increased in Donor Organs From Young Patients After Prolonged Life Support
Authors: Veld Peter In't , De Munck Neelke , Van Belle Kristien , Buelens Nicole , Ling Zhidong , Weets Ilse , Haentjens Patrick , Pipeleers-Marichal Miriam , Gorus Frans , Pipeleers Daniel
Published: April 2010

OBJECTIVE

This study assesses β-cell replication in human donor organs and examines possible influences of the preterminal clinical conditions.

RESEARCH DESIGN AND METHODS

β-Cell replication was quantified in a consecutive series of n = 363 human organ donors using double immunohistochemistry for Ki67 and insulin. Uni- and multivariate analysis was used to correlate replication levels to clinical donor characteristics and histopathologic findings.

RESULTS

β-Cell replication was virtually absent in most donors, with ≤0.1% Ki67-positive β-cells in 72% of donors. A subpopulation of donors, however, showed markedly elevated levels of replication of up to 7.0% Ki67-positive β-cells. β-Cell replication was accompanied by the increased replication of glucagon-, somatostatin-, and CA19.9-positive cells. Prolonged life support, kidney dysfunction, relatively young donor age, inflammatory infiltration, and prolonged brain death before organ retrieval were all found to be significantly associated with an increased level (≥90th percentile) of β-cell replication, with the first three risk factors being independent predictors. Increased β-cell replication was most often noted in relatively young donors (≤25 years) who received prolonged (≥3 days) life support (68%); in contrast, it was rare in donors with a short duration of life support regardless of age (1%). Prolonged life support was accompanied by increased levels of CD68+ and LCA/CD45+ infiltration in the pancreatic parenchyma.

CONCLUSION

These results indicate that preterminal clinical conditions in (young) organ donors can lead to increased inflammatory infiltration of the pancreas and to increased β-cell replication.
Development and Progression of Renal Insufficiency With and Without Albuminuria in Adults With Type 1 Diabetes in the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Study
Authors: Molitch Mark E. , Steffes Michael , Sun Wanjie , Rutledge Brandy , Cleary Patricia , de Boer Ian H. , Zinman Bernard , Lachin John ,   for the Epidemiology of Diabetes Interventions and Complications (EDIC) Study Group
Published: April 2010

OBJECTIVE

This multicenter study examined the impact of albumin excretion rate (AER) on the course of estimated glomerular filtration rate (eGFR) and the incidence of sustained eGFR <60 ml/min/1.73 m2 in type 1 diabetes up to year 14 of the Epidemiology of Diabetes Interventions and Complications (EDIC) study (mean duration of 19 years in the Diabetes Control and Complications Trial [DCCT]/EDIC).

RESEARCH DESIGN AND METHODS

Urinary albumin measurements from 4-h urine collections were obtained from participants annually during the DCCT and every other year during the EDIC study, and serum creatinine was measured annually in both the DCCT and EDIC study. GFR was estimated from serum creatinine using the abbreviated Modification of Diet in Renal Disease equation.

RESULTS

A total of 89 of 1,439 subjects developed an eGFR <60 ml/min/1.73 m2 (stage 3 chronic kidney disease on two or more successive occasions (sustained) during the DCCT/EDIC study (cumulative incidence 11.4%). Of these, 20 (24%) had AER <30 mg/24 h at all prior evaluations, 14 (16%) had developed microalbuminuria (AER 30–300 mg/24 h) before they reached stage 3 chronic kidney disease, and 54 (61%) had macroalbuminuria (AER >300 mg/24 h) before they reached stage 3 chronic kidney disease. Macroalbuminuria is associated with a markedly increased rate of fall in eGFR (5.7%/year vs. 1.2%/year with AER <30 mg/24 h, P < 0.0001) and risk of eGFR <60 ml/min/1.73 m2 (adjusted hazard ratio 15.3, P < 0.0001), whereas microalbuminuria had weaker and less consistent effects on eGFR.

CONCLUSIONS

Macroalbuminuria was a strong predictor of eGFR loss and risk of developing sustained eGFR <60 ml/min/1.73 m2. However, screening with AER alone would have missed 24% of cases of sustained impaired eGFR.
Metabolic Syndrome, Independent of Its Components, Is a Risk Factor for Stroke and Death But Not for Coronary Heart Disease Among Hypertensive Patients in the ASCOT-BPLA
Authors: Gupta Ajay K. , Dahlof Bjorn , Sever Peter S. , Poulter Neil R. ,   for the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) investigators
Published: April 2010

OBJECTIVE

To evaluate whether in hypertensive patients the risk of cardiovascular disease is greater in association with the metabolic syndrome (MetS) or the sum of its individual components.

RESEARCH DESIGN AND METHODS

Cox regression analysis models were developed to assess the influence of age, sex, ethnicity, and the individual components of MetS on risk associated with the MetS (using several definitions) of coronary outcomes, stroke, and all-cause mortality.

RESULTS

MetS was significantly associated with coronary outcomes, stroke, and all-cause mortality after adjusting for age, sex, and ethnicity. However, when the model was further adjusted for the individual components, MetS was associated with significantly increased risk of stroke (hazard ratio 1.34 [95% CI 1.07–1.68]) and all-cause mortality (1.35 [1.16–1.58]) but not coronary outcomes (fatal coronary heart disease plus nonfatal myocardial infarction 1.16 [0.95–1.43] and total coronary events 1.06 [0.91–1.24]).

CONCLUSIONS

MetS, independent of its individual components, is associated with increased risk of stroke and all-cause mortality but not coronary outcomes.
Is the Recent Rise in Type 2 Diabetes Incidence From 1984 to 2007 Explained by the Trend in Increasing BMI?
Authors: Hardoon Sarah L. , Morris Richard W. , Thomas Mary C. , Wannamethee S. Goya , Lennon Lucy T. , Whincup Peter H.
Published: April 2010

OBJECTIVE

To estimate the extent to which increasing BMI may explain the rise in type 2 diabetes incidence in British men from 1984 to 2007.

RESEARCH DESIGN AND METHODS

A representative cohort ratio of 6,460 British men was followed-up for type 2 diabetes incidence between 1984 (aged 45–65 years) and 2007 (aged 67–89 years). BMI was ascertained at regular intervals before and during the follow-up.

RESULTS

Between 1984–1992 and 1999–2007, the age-adjusted hazard of type 2 diabetes more than doubled (hazard ratio 2.33 [95% CI 1.75–3.10]). Mean BMI rose by 1.42 kg/m2 (95% CI 1.10–1.74) between 1984 and 1999; this could explain 26% (95% CI 17–38) of the type 2 diabetes increase.

CONCLUSIONS

An appreciable portion of the rise in type 2 diabetes can be attributed to BMI changes. A substantial portion remains unexplained, possibly associated with other determinants such as physical activity. This merits further research.
Copeptin, IGFBP-1, and Cardiovascular Prognosis in Patients With Type 2 Diabetes and Acute Myocardial Infarction
Authors: Mellbin Linda G. , Rydén Lars , Brismar Kerstin , Morgenthaler Nils G. , Öhrvik John , Catrina Sergiu B.
Published: April 2010

OBJECTIVE

To determine whether C-terminal provasopressin (copeptin) explains the prognostic importance of insulin growth factor binding protein-1 (IGFBP-1) in patients with myocardial infarction and type 2 diabetes.

RESEARCH DESIGN AND METHODS

Copeptin and IGFBP-1 were analyzed in 393 patients participating in the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 trial.

RESULTS

Copeptin was associated with IGFBP-1 (Spearman rank correlation test, r = 0.53; P < 0.001). During follow-up there were 138 cardiovascular events (cardiovascular death, myocardial infarction, and stroke). In univariate Cox proportional hazard regression analyses both biomarkers were predictors of events: the hazard ratio for log copeptin was 1.59 (95% CI 1.41–1.81; P < 0.001) and for log IGFBP-1 was 1.49 (1.26–1.77; P < 0.001). In the final model, adjusting for age and renal function, copeptin was the only independent predictor (1.35 [1.16–1.57]; P < 0.001).

CONCLUSIONS

Copeptin is an independent predictor of cardiovascular events and appears to at least partly explain the prognostic impact of IGFBP-1 in patients with type 2 diabetes and myocardial infarction. Copeptin may be a pathogenic factor to address to improve outcome in these patients.