bluuebunny/crossref_metadata_2025 huggingface dataset:
Delayed Treatment of Diagnosed Pulmonary Tuberculosis in Taiwan
Authors: Chern Jimmy PS , Chen Duan-Rung , Wen Tzai-Hung
Published: July 2008

Background

Mycobacterium tuberculosis infection is an ongoing public health problem in Taiwan. The National Tuberculosis Registry Campaign, a case management system, was implemented in 1997. This study examined this monitoring system to identify and characterize delayed treatment of TB patients.

Methods

Records of all tuberculosis cases treated in Taiwan from 2002 through 2005 were obtained from the National Tuberculosis Registry Campaign. Initiation of treatment more than 7 days after diagnosis was considered a long treatment delay.

Results

The study included 31,937 patients. The mean day of delayed treatment was 3.6 days. Most patients were treated immediately after diagnosis. The relationship between number of TB patients and days of delayed treatment after diagnosis exhibited a Power-law distribution. The long tail of the power-law distribution indicated that an extreme number occur cannot be neglected. Tuberculosis patients treated after an unusually long delay require close observation and follow up.

Conclusion

This study found that TB control is generally acceptabl in Taiwan; however, delayed treatment increases the risk of transmission. Improving the protocol for managing confirmed TB cases can minimize disease transmission.
Analysis of transient phosphorylation-dependent protein-protein interactions in living mammalian cells using split-TEV
Authors: Wehr Michael C , Reinecke Lisa , Botvinnik Anna , Rossner Moritz J
Published: July 2008

Background

Regulated protein-protein interactions (PPIs) are pivotal molecular switches that are important for the regulation of signaling processes within eukaryotic cells. Cellular signaling is altered in various disease conditions and offers interesting options for pharmacological interventions. Constitutive PPIs are usually mediated by large interaction domains. In contrast, stimulus-regulated PPIs often depend on small post-translational modifications and are thus better suited targets for drug development. However, the detection of modification-dependent PPIs with biochemical methods still remains a labour- and material-intensive task, and many pivotal PPIs that are potentially suited for pharmacological intervention most likely remain to be identified. The availability of methods to easily identify and quantify stimulus-dependent, potentially also transient interaction events, is therefore essential. The assays should be applicable to intact mammalian cells, optimally also to primary cells in culture.

Results

In this study, we adapted the split-TEV system to quantify phosphorylation-dependent and transient PPIs that occur at the membrane and in the cytosol of living mammalian cells. Split-TEV is based on a PPI-induced functional complementation of two inactive TEV protease fragments fused to interaction partners of choice. Genetically encoded transcription-coupled and proteolysis-only TEV reporter systems were used to convert the TEV activity into an easily quantifiable readout. We measured the phosphorylation-dependent interaction between the pro-apoptotic protein Bad and the adapter proteins 14-3-3ε and ζ in NIH-3T3 fibroblasts and in primary cultured neurons. Using split-TEV assays, we show that Bad specifically interacts with 14-3-3 isoforms when phosphorylated by protein kinase Akt-1/PKB at Ser136. We also measured the phosphorylation-dependent Bad/14-3-3 interactions mediated by endogenous and transient Akt-1 activity. We furthermore applied split-TEV assays to measure the phosphorylation-dependent interactions of Neuregulin-1-stimulated ErbB4 receptors with several adapter proteins.

Conclusion

Split-TEV assays are well suited to measure phosphorylation-dependent and transient PPIs that occur specifically at the membrane and in the cytosol of heterologous and primary cultured mammalian cells. Given the high sensitivity of the split-TEV system, all assays were performed in multi-plate formats and could be adapted for higher throughput to screen for pharmacologically active substances.
Evaluation of light microscopy and rapid diagnostic test for the detection of malaria under operational field conditions: a household survey in Ethiopia
Authors: Endeshaw Tekola , Gebre Teshome , Ngondi Jeremiah , Graves Patricia M , Shargie Estifanos B , Ejigsemahu Yeshewamebrat , Ayele Berhan , Yohannes Gedeon , Teferi Tesfaye , Messele Ayenew , Zerihun Mulat , Genet Asrat , Mosher Aryc W , Emerson Paul M , Richards Frank O
Published: July 2008

Background

In most resource-poor settings, malaria is usually diagnosed based on clinical signs and symptoms and not by detection of parasites in the blood using microscopy or rapid diagnostic tests (RDT). In population-based malaria surveys, accurate diagnosis is important: microscopy provides the gold standard, whilst RDTs allow immediate findings and treatment. The concordance between RDTs and microscopy in low or unstable transmission areas has not been evaluated.

Objectives

This study aimed to estimate the prevalence of malaria parasites in randomly selected malarious areas of Amhara, Oromia, and Southern Nations, Nationalities and Peoples' (SNNP) regions of Ethiopia, using microscopy and RDT, and to investigate the agreement between microscopy and RDT under field conditions.

Methods

A population-based survey was conducted in 224 randomly selected clusters of 25 households each in Amhara, Oromia and SNNP regions, between December 2006 and February 2007. Fingerpick blood samples from all persons living in even-numbered households were tested using two methods: light microscopy of Giemsa-stained blood slides; and RDT (ParaScreen device for Pan/Pf).

Results

A total of 13,960 people were eligible for malaria parasite testing of whom 11,504 (82%) were included in the analysis. Overall slide positivity rate was 4.1% (95% confidence interval [CI] 3.4–5.0%) while ParaScreen RDT was positive in 3.3% (95% CI 2.6–4.1%) of those tested. Considering microscopy as the gold standard, ParaScreen RDT exhibited high specificity (98.5%; 95% CI 98.3–98.7) and moderate sensitivity (47.5%; 95% CI 42.8–52.2) with a positive predictive value of 56.8% (95% CI 51.7–61.9) and negative predictive value of 97.6% (95% CI 97.6–98.1%) under field conditions.

Conclusion

Blood slide microscopy remains the preferred option for population-based prevalence surveys of malaria parasitaemia. The level of agreement between microscopy and RDT warrants further investigation in different transmission settings and in the clinical situation.
Performance of self-diagnosis and standby treatment of malaria in international oilfield service employees in the field
Authors: Roukens Anna H , Berg Johannes , Barbey Alex , Visser Leo G
Published: July 2008

Background

Falciparum malaria remains a major occupational illness that accounts for several deaths per year and numerous lost working days among the expatriate population, working or living in high-risk malarious areas. Compliance to preventive strategies is poor in travellers, especially business travellers, expatriates and long-term travellers.

Methods

In this cross-sectional, web-based study the adherence to and outcome of a preventive malaria programme on knowledge, attitudes and practices, including the practice of self-diagnosis and standby treatment (curative malaria kit, CMK) was evaluated in 2,350 non-immune expatriates, who had been working in highly malaria endemic areas.

Results

One-third (N = 648) of these expatriates visited a doctor for malaria symptoms and almost half (29 of 68) of all hospitalizations were due to malaria. The mandatory malaria training for non-immunes was completed by 92% of those who visited or worked in a high risk malaria country; 70% of the respondents at risk also received the CMK. The malaria awareness training and CMK significantly increased malaria knowledge [relative risk (RR) of 1.5, 95%CI 1.2–2.1], attitudes and practices, including compliance to chemoprophylaxis [RR = 2.2, 95%CI 1.6–3.2]. Hospitalization for malaria tended to be reduced by the programme [RR = 0.4, 95%CI 0.1–1.1], albeit not significantly. Respondents who did not receive instructions on the rapid diagnostic test were two times [RR = 2.3, 95%CI 1.6–3.3] more likely to have difficulties. Those who did receive instructions adhered poorly to the timing of repeating the test. Moreover, 6% (31 of 513) of those with a negative test result were diagnosed with malaria by a local doctor. 77% (N = 393) of the respondents with a negative test result did not take curative medication. 57% (252 of 441) of the respondents who took the curative medication that was included in the kit did not have a positive self-test or clinical malaria diagnosis made by a doctor.

Conclusion

This survey demonstrated that a comprehensive programme targeting malaria prevention in expatriates can be effectively implemented and that it significantly increased malaria awareness.
Correlates of preclinical cardiovascular disease in Indigenous and Non-Indigenous Australians: a case control study
Authors: Haluska Brian A , Chan Lionel , Jeffriess Leanne , Shaw A Andrew , Shaw Joanne , Marwick Thomas H
Published: July 2008

Background

The high frequency of premature death from cardiovascular disease in indigenous Australians is often attributed to the high prevalence of risk factors, especially type II diabetes mellitus (DM). We evaluated the relationship of ethnicity to atherosclerotic burden, as evidenced by carotid intima-media thickness (IMT), independent of risk factor status.

Methods

We studied 227 subjects (147 men; 50 ± 13 y): 119 indigenous subjects with (IDM, n = 54), and without DM (InDM, n = 65), 108 Caucasian subjects with (CDM, n = 52), and without DM (CnDM, n = 56). IMT was measured according to standard methods and compared with clinical data and cardiovascular risk factors.

Results

In subjects both with and without DM, IMT was significantly greater in indigenous subjects. There were no significant differences in gender, body mass index (BMI), systolic blood pressure (SBP), or diastolic blood pressure (DBP) between any of the groups, and subjects with DM showed no difference in plasma HbA1c. Cardiovascular risk factors were significantly more prevalent in indigenous subjects. Nonetheless, ethnicity (β = -0.34; p < 0.0001), age (β = 0.48; p < 0.0001), and smoking (β = 0.13; p < 0.007) were independent predictors of IMT in multiple linear regression models.

Conclusion

Ethnicity appears to be an independent correlate of preclinical cardiovascular disease, even after correction for the high prevalence of cardiovascular risk factors in indigenous Australians. Standard approaches to control currently known risk factors are vital to reduce the burden of cardiovascular disease, but in themselves may be insufficient to fully address the high prevalence in this population.
Do estimates of cost-utility based on the EQ-5D differ from those based on the mapping of utility scores?
Authors: Barton Garry R , Sach Tracey H , Jenkinson Claire , Avery Anthony J , Doherty Michael , Muir Kenneth R
Published: July 2008

Background

Mapping has been used to convert scores from condition-specific measures into utility scores, and to produce estimates of cost-effectiveness. We sought to compare the QALY gains, and incremental cost per QALY estimates, predicted on the basis of mapping to those based on actual EQ-5D scores.

Methods

In order to compare 4 different interventions 389 individuals were asked to complete both the EQ-5D and the Western Ontartio and McMaster Universities Osteoarthritis Index (WOMAC) at baseline, 6, 12, and 24 months post-intervention. Using baseline data various mapping models were developed, where WOMAC scores were used to predict the EQ-5D scores. The performance of these models was tested by predicting the EQ-5D post-intervention scores. The preferred model (that with the lowest mean absolute error (MAE)) was used to predict the EQ-5D scores, at all time points, for individuals who had complete WOMAC and EQ-5D data. The mean QALY gain associated with each intervention was calculated, using both actual and predicted EQ-5D scores. These QALY gains, along with previously estimated changes in cost, were also used to estimate the actual and predicted incremental cost per QALY associated with each of the four interventions.

Results

The EQ-5D and the WOMAC were completed at baseline by 348 individuals, and at all time points by 259 individuals. The MAE in the preferred model was 0.129, and the mean QALY gains for each of the four interventions was predicted to be 0.006, 0.058, 0.058, and 0.136 respectively, compared to the actual mean QALY gains of 0.087, 0.081, 0.120, and 0.149. The most effective intervention was estimated to be associated with an incremental cost per QALY of £6,068, according to our preferred model, compared to £13,154 when actual data was used.

Conclusion

We found that actual QALY gains, and incremental cost per QALY estimates, differed from those predicted on the basis of mapping. This suggests that though mapping may be of value in predicting the cost-effectiveness of interventions which have not been evaluated using a utility measure, future studies should be encouraged to include a method of actual utility measurement.

Trial registration

Current Controlled Trials ISRCTN93206785
Using deliberative techniques to engage the community in policy development
Authors: Gregory Judy , Hartz-Karp Janette , Watson Rebecca
Published: July 2008

Background

This paper examines work in deliberative approaches to community engagement used in Western Australia by the Department of Planning and Infrastructure and other planning and infrastructure agencies between 2001 and 2005, and considers whether the techniques could be applied to the development of health policy in Australia.

Results

Deliberative processes were used in WA to address specific planning and infrastructure problems. Using deliberative techniques, community participants contributed to joint decision making and policy development. Outcomes from deliberative processes were seriously considered by the Minister and used to influence policy decisions. In many cases, the recommendations generated through deliberative processes were fully adopted by the Minister.

Conclusion

The experiences in WA demonstrate that deliberative engagement processes can be successfully implemented by government and can be used to guide policy. The techniques can be adapted to suit the context and issues experienced by a portfolio, and the skills required to conduct deliberative processes can be fostered amongst the portfolio's staff. Health policy makers may be able to learn from the experiences in WA, and adopt approaches to community engagement that allow for informed deliberation and debate in the community about the future of Australia's health system.
PKA and ERK, but not PKC, in the Amygdala Contribute to Pain-Related Synaptic Plasticity and Behavior
Authors: Fu Yu , Han Jeong , Ishola Titilope , Scerbo Michelle , Adwanikar Hita , Ramsey Cara , Neugebauer Volker
Published: July 2008

The laterocapsular division of the central nucleus of the amygdala (CeLC) has emerged as an important site of pain-related plasticity and pain modulation. Glutamate and neuropeptide receptors in the CeLC contribute to synaptic and behavioral changes in the arthritis pain model, but the intracellular signaling pathways remain to be determined. This study addressed the role of PKA, PKC, and ERK in the CeLC. Adult male Sprague-Dawley rats were used in all experiments. Whole-cell patch-clamp recordings of CeLC neurons were made in brain slices from normal rats and from rats with a kaolin/carrageenan-induced monoarthritis in the knee (6 h postinduction). Membrane-permeable inhibitors of PKA (KT5720, 1 μM; cAMPS-Rp, 10 μM) and ERK (U0126, 1 μM) activation inhibited synaptic plasticity in slices from arthritic rats but had no effect on normal transmission in control slices. A PKC inhibitor (GF109203x, 1 μM) and an inactive structural analogue of U0126 (U0124, 1 μM) had no effect. The NMDA receptor-mediated synaptic component was inhibited by KT5720 or U0126; their combined application had additive effects. U0126 did not inhibit synaptic facilitation by forskolin-induced PKA-activation. Administration of KT5720 (100 μM, concentration in microdialysis probe) or U0126 (100 μM) into the CeLC, but not striatum (placement control), inhibited audible and ultrasonic vocalizations and spinal reflexes of arthritic rats but had no effect in normal animals. GF109203x (100 μM) and U0124 (100 μM) did not affect pain behavior. The data suggest that in the amygdala PKA and ERK, but not PKC, contribute to pain-related synaptic facilitation and behavior by increasing NMDA receptor function through independent signaling pathways.
Organizational model for a telepathology system
Authors: Mencarelli Roberto , Marcolongo Adriano , Gasparetto Alessio
Published: July 2008

The technological development of telemedicine has performed important progress, assuming a diagnostic relief role inside of the processes. Among the fields in fast evolution, telepathology is placed among those of greater interest. Up to some years ago, telepathology allowed us to observe at a distance and in real time, histological or cytological slides through the Internet, using a motorized microscope (dynamic telepathology). Currently, telepathology has completed an important step in ahead being possible to digitize completely a slide and to store it. This allows observation of the whole surface of histological or cytological slides remotely with a customary PC, without human intervention (virtual slide). The described systems have exclusive characteristics, so that a "hybrid system" supporting both technologies, turns out to be the best solution applicable in a wide range program. In order to realize the theoretical aspects previously described, we report an organizational model practicable and applicable to a territory in which three hospitals operate. An essential prerequisite in order to arrange an efficient telepathology system turns out to be one structured data transmission network, equipped with elevated guaranteed bandwidth, and one consolidated experience in the registration and management of digital images.
Genome-wide identification of microsatellites in white clover (Trifolium repens L.) using FIASCO and phpSSRMiner
Authors: Zhang Yan , He Ji , Zhao Patrick X , Bouton Joseph H , Monteros Maria J
Published: July 2008

Background

Allotetraploid white clover (Trifolium repens L.) is an important forage legume widely cultivated in most temperate regions. Only a small number of microsatellite markers are publicly available and can be utilized in white clover breeding programs. The objectives of this study were to develop an integrated approach for microsatellite development and to evaluate the approach for the development of new SSR markers for white clover.

Results

Genomic libraries containing simple sequence repeat (SSR) sequences were constructed using a modified Fast Isolation by AFLP of Sequences COntaining repeats (FIASCO) procedure and phpSSRMiner was used to develop the microsatellite markers. SSR motifs were isolated using two biotin-labeled probes, (CA)17 and (ATG)12. The sequences of 6,816 clones were assembled into 1,698 contigs, 32% of which represented novel sequences based on BLASTN searches. Approximately 32%, 28%, and 16% of these SSRs contained hexa-, tri-, and di-nucleotide repeats, respectively. The most frequent motifs were the CA and ATG complementary repeats and the associated compound sequences. Primer pairs were designed for 859 SSR loci based on sequences from these genomic libraries and from GenBank white clover nucleotide sequences. A total of 191 SSR primers developed from the two libraries were tested for polymorphism in individual clones from the parental genotypes GA43 ('Durana'), 'SRVR' and six F1 progeny from a mapping population. Ninety two percent produced amplicons and 66% of these were polymorphic.

Conclusion

The combined approach of identifying SSR-enriched fragments by FIASCO coupled with the primer design and in silico amplification using phpSSRMiner represents an efficient and low cost pipeline for the large-scale development of microsatellite markers in plants.

The approach described here could be readily adapted and utilized in other non-related species with none or limited genomic resources.
A biomechanical study of plate versus intramedullary devices for midshaft clavicle fixation
Authors: Golish S. Raymond , Oliviero Jason A. , Francke Eric I. , Miller Mark D.
Published: July 2008

Background

Non-operative management of midshaft clavicle fractures is standard; however, surgical management is increasing. The purpose of this study is to compare the biomechanical performance of plate versus intramedullary fixation in cyclic bending for matched pairs of cadaveric clavicles. We hypothesized that the biomechanical properties are similar.

Methods

Eight sets of matched clavicles with vertical, midshaft osteotomies were prepared from fresh, frozen cadavers. A 3.5 mm dynamic compression plate or a 3.8 or 4.5 mm intramedullary device were used for fixation. Clavicles were loaded in a four-point bend at 6 different loads for 3000 cycles at 1 Hz starting with 180 N and increasing by 180 N with sampling at 2 Hz. Failure was defined as 10 mm of displacement or catastrophic construct failure prior to 10 mm of displacement.

Results

Between constructs, there was a significant difference with large effect size in displacement at fixed loads of 180 N (P = 0.001; Cohen's d = 1.85), 360 N (P = 0.033; Cohen's d = 1.39), 540 N (P = 0.003; Cohen's d = 0.73) and 720 N (P = 0.018; Cohen's d = 0.72). There was a significant difference with large effect size in load at fixed displacements of 5 mm (P = 0.001; Cohen's d = 1.49), 7.5 mm (P = 0.011; Cohen's d = 1.06), and 10 mm (P = 0.026; Cohen's d = 0.84).

Conclusion

Plate constructs are superior in showing less displacement at fixed loads and greater loads at fixed displacements over a broad range of loads and displacements with cyclic four-point bending. The clinical relevance is that plate fixation may provide a stronger construct for early rehabilitation protocols that focus on repetitive movements in the early pre-operative period.
The ubiquitin-like molecule interferon-stimulated gene 15 (ISG15) is a potential prognostic marker in human breast cancer
Authors: Bektas Nuran , Noetzel Erik , Veeck Jürgen , Press Michael F , Kristiansen Glen , Naami Amjad , Hartmann Arndt , Dimmler Arno , Beckmann Matthias W , Knüchel Ruth , Fasching Peter A , Dahl Edgar
Published: July 2008

Introduction

ISG15 is an ubiquitin-like molecule that is strongly upregulated by type I interferons as a primary response to diverse microbial and cellular stress stimuli. However, alterations in the ISG15 signalling pathway have also been found in several human tumour entities. To the best of our knowledge, in the current study we present for the first time a systematic characterisation of ISG15 expression in human breast cancer and normal breast tissue both at the mRNA and protein level.

Method

Using semiquantitative real-time PCR, cDNA dot-blot hybridisation and immunohistochemistry, we systematically analysed ISG15 expression in invasive breast carcinomas (n = 910) and normal breast tissues (n = 135). ISG15 protein expression was analysed in two independent cohorts on tissue microarrays; in an initial evaluation set of 179 breast carcinomas and 51 normal breast tissues; and in a second large validation set of 646 breast carcinomas and 10 normal breast tissues. In addition, a collection of benign and malignant mammary cell lines (n = 9) were investigated for ISG15 expression.

Results

ISG15 was overexpressed in breast carcinoma cells compared with normal breast tissue, both at the RNA and protein level. Recurrence-free (p = 0.030), event-free (p = 0.001) and overall (p = 0.001) survival analyses showed a significant correlation between ISG15 overexpression and unfavourable prognosis.

Conclusion

Therefore, ISG15 may represent a novel breast tumour marker with prognostic significance and may be helpful in selecting patients for and predicting response to the treatment of human breast cancer.
Comparison of functional residual capacity and static compliance of the respiratory system during a positive end-expiratory pressure (PEEP) ramp procedure in an experimental model of acute respiratory distress syndrome
Authors: Lambermont Bernard , Ghuysen Alexandre , Janssen Nathalie , Morimont Philippe , Hartstein Gary , Gerard Paul , D'Orio Vincent
Published: July 2008

Introduction

Functional residual capacity (FRC) measurement is now available on new ventilators as an automated procedure. We compared FRC, static thoracopulmonary compliance (Crs) and PaO2 evolution in an experimental model of acute respiratory distress syndrome (ARDS) during a reversed, sequential ramp procedure of positive end-expiratory pressure (PEEP) changes to investigate the potential interest of combined FRC and Crs measurement in such a pathologic state.

Methods

ARDS was induced by oleic acid injection in six anesthetised pigs. FRC and Crs were measured, and arterial blood samples were taken after induction of ARDS during a sequential ramp change of PEEP from 20 cm H2O to 0 cm H2O by steps of 5 cm H2O.

Results

ARDS was responsible for significant decreases in FRC, Crs and PaO2 values. During ARDS, 20 cm H2O of PEEP was associated with FRC values that increased from 6.2 ± 1.3 to 19.7 ± 2.9 ml/kg and a significant improvement in PaO2. The maximal value of Crs was reached at a PEEP of 15 cm H2O, and the maximal value of FRC at a PEEP of 20 cm H2O. From a PEEP value of 15 to 0 cm H2O, FRC and Crs decreased progressively.

Conclusion

Our results indicate that combined FRC and Crs measurements may help to identify the optimal level of PEEP. Indeed, by taking into account the value of both parameters during a sequential ramp change of PEEP from 20 cm H2O to 0 cm H2O by steps of 5 cm H2O, the end of overdistension may be identified by an increase in Crs and the start of derecruitment by an abrupt decrease in FRC.
CD56bright cells increase expression of α4 integrin at ovulation in fertile cycles
Authors: Peralta Crystal G , Han Victor K , Horrocks Julie , Croy B Anne , van den Heuvel Marianne J
Published: July 2008

Leukocyte content of human endometrium changes rapidly after ovulation, particularly as a result of gains in CD56bright uterine NK (uNK) cells. We have proposed that uNK precursor cells are found within the blood CD56bright pool and are recruited to decidualizing endometrium through functional changes in their adhesion molecules and chemokine receptors. This study sought to quantify alterations in adhesion molecules, cytokines, chemokines, and receptors induced in circulating CD56+ cells of fertile and infertile women by ovulation. Blood was drawn from 12 fertile volunteers and six female-infertility patients at Menstrual Cycle Day (d) 5 and on the day following the preovulatory surge of luteinizing hormone (LH). CD56bright, CD56dim, and CD56+CD3+ cell subsets were isolated and evaluated by flow cytometry, quantitative PCR, or Western blotting. In CD56bright cells from fertile but not infertile women, α4 integrin increased between d5 and the preovulatory LH surge. CD56dim and NKT cells did not show a change in α4 integrin but differed significantly between fertile and infertile donors, and infertile donors had reduced homing molecule expression in CD56dim and NKT cells, and at ovulation, their NKT cells showed elevated cytokine production. None of the circulating CD56+ cell subsets had transcripts for receptors for estrogen, progesterone, LH, or prolactin. Thus, immunological events associated with the LH surge induce alterations in all subsets of CD56+ cells, and the unique induction of α4 integrin in CD56bright cells of fertile women constitutes a potential method to promote uterine homing.
Imaging internal multiples from subsalt VSP data — Examples of target-oriented interferometry
Authors: Vasconcelos Ivan , Snieder Roel , Hornby Brian
Published: July 2008

Seismic interferometry has become a technology of growing interest for imaging borehole seismic data. We demonstrate that interferometry of internal multiples can be used to image targets above a borehole receiver array. By internal multiples, we refer to all types of waves that scatter multiple times inside the model. These include, for instance, interbed, intrasalt, and water-bottom multiples as well as conversions among them. We use an interferometry technique that is based on representation theorems for perturbed media and targets the reconstruction of specific primary reflections from multiply reflected waves. In this interferometry approach, we rely on shot-domain wavenumber separation to select the directions of waves arriving at a given receiver. Using a numerical walkaway (WAW) VSP experiment recorded by a subsalt borehole receiver array in the Sigsbee salt model, we use the interference of internal multiples to image the salt structure from below. In this numerical example, the interferometric image that uses internal multiples reconstructs the bottom- and top-of-salt reflectors above the receiver array as well as the subsalt sediment structure between the array and the salt. Because of the limited source summation in this interferometry example, the interferometric images show artifact reflectors within the salt body. We apply this method to a field walkaway VSP from the Gulf of Mexico. With the field data, we demonstrate that the choice of shot-domain wavenumbers in the target-oriented interferometry procedure controls the wavenumbers in the output pseudoshot gathers. Target-oriented interferometric imaging from the 20-receiver array recovers the top-of-salt reflector that is consistent with surface seismic images. We present our results with both correlation-based and deconvolution-based interferometry.
International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes
Authors:   International T-Cell Lymphoma Project
Published: July 2008

Purpose

Peripheral T-cell lymphoma (PTCL) and natural killer/T-cell lymphoma (NKTCL) are rare and heterogeneous forms of non-Hodgkin's lymphoma (NHL) that, in general, are associated with a poor clinical outcome.

Patients and Methods

A cohort of 1,314 cases of PTCL and NKTCL was organized from 22 centers worldwide, consisting of patients with previously untreated PTCL or NKTCL who were diagnosed between 1990 and 2002. Tissue biopsies, immunophenotypic markers, molecular genetic studies, and clinical information from consecutive patients at each site were reviewed by panels of four expert hematopathologists and classified according to the WHO classification.

Results

A diagnosis of PTCL or NKTCL was confirmed in 1,153 (87.8%) of the cases. The most common subtypes were PTCL not otherwise specified (NOS; 25.9%), angioimmunoblastic type (18.5%), NKTCL (10.4%), and adult T-cell leukemia/lymphoma (ATLL; 9.6%). Misclassification occurred in 10.4% of the cases including Hodgkin's lymphoma (3%), B-cell lymphoma (1.4%), unclassifiable lymphoma (2.8%), or a diagnosis other than lymphoma (2.3%). We found marked variation in the frequency of the various subtypes by geographic region. The use of an anthracycline-containing regimen was not associated with an improved outcome in PTCL-NOS or angioimmunoblastic type, but was associated with an improved outcome in anaplastic large-cell lymphoma, ALK positive.

Conclusion

The WHO classification is useful for defining subtypes of PTCL and NKTCL. However, expert hematopathology review is important for accurate diagnosis. The clinical outcome for patients with most of these lymphoma subtypes is poor with standard therapies, and novel agents and new modalities are needed to improve survival.
Incretin-Based Therapies in Type 2 Diabetes Mellitus
Authors: Chia Chee W. , Egan Josephine M.
Published: July 2008

Context: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are incretins secreted from enteroendocrine cells postprandially in part to regulate glucose homeostasis. Dysregulation of these hormones is evident in type 2 diabetes mellitus (T2DM). Two new drugs, exenatide (GLP-1 mimetic) and sitagliptin [dipeptidyl peptidase (DPP) 4 inhibitor], have been approved by regulatory agencies for treating T2DM. Liraglutide (GLP-1 mimetic) and vildagliptin (DPP 4 inhibitor) are expected to arrive on the market soon.

Evidence Acquisition: The background of incretin-based therapy and selected clinical trials of these four drugs are reviewed. A MEDLINE search was conducted for published articles using the key words incretin, glucose-dependent insulinotropic polypeptide, GLP-1, exendin-4, exenatide, DPP 4, liraglutide, sitagliptin, and vildagliptin.

Evidence Synthesis: Exenatide and liraglutide are injection based. Three-year follow-up data on exenatide showed a sustained weight loss and glycosylated hemoglobin (HbA1c) reduction of 1%. Nausea and vomiting are common. Results from phase 3 studies are pending on liraglutide. Sitagliptin and vildagliptin are orally active. In 24-wk studies, sitagliptin reduces HbA1c by 0.6–0.8% as monotherapy, 1.8% as initial combination therapy with metformin, and 0.7% as add-on therapy to metformin. Vildagliptin monotherapy lowered HbA1c by 1.0–1.4% after 24 wk. Their major side effects are urinary tract and nasopharyngeal infections and headaches. Exenatide and liraglutide cause weight loss, whereas sitagliptin and vildagliptin do not.

Conclusions: The availability of GLP-1 mimetics and DPP 4 inhibitors has increased our armamentarium for treating T2DM. Unresolved issues such as the effects of GLP-1 mimetics and DPP 4 inhibitors on β-cell mass, the mechanism by which GLP-1 mimetics lowers glucagon levels, and exactly how DPP 4 inhibitors lead to a decline in plasma glucose levels without an increase in insulin secretion, need further research.
Selective Loss of MEG3 Expression and Intergenic Differentially Methylated Region Hypermethylation in the MEG3/DLK1 Locus in Human Clinically Nonfunctioning Pituitary Adenomas
Authors: Gejman Roger , Batista Dalia L. , Zhong Ying , Zhou Yunli , Zhang Xun , Swearingen Brooke , Stratakis Constantine A. , Hedley-Whyte E. Tessa , Klibanski Anne
Published: July 2008

Context: MEG3 is an imprinted gene encoding a novel noncoding RNA that suppresses tumor cell growth. Although highly expressed in the normal human pituitary, it is unknown which of the normal pituitary cell types and pituitary tumors express MEG3.

Objectives: Our objectives were 1) to investigate cell-type- and tumor-type-specific expression of MEG3 in the human pituitary and 2) to investigate whether methylation in the intergenic differentially methylated region (IG-DMR) at the DLK1/MEG3 locus is involved in the loss of MEG3 expression in tumors.

Design and Methods: RT-PCR, quantitative RT-PCR, Northern blot, and a combination of in situ hybridization and immunofluorescence were used to determine the cell-type- and tumor-type-specific MEG3 expression. Bisulfite treatment and PCR sequencing of genomic DNA were used to measure the CpG methylation status in the normal and tumor tissues. Five normal human pituitaries and 17 clinically nonfunctioning, 11 GH-secreting, seven prolactin-secreting, and six ACTH-secreting pituitary adenomas were used.

Results: All normal human pituitary cell types express MEG3. However, loss of MEG3 expression occurs only in nonfunctioning pituitary adenomas of a gonadotroph origin. All other pituitary tumor phenotypes examined express MEG3. Hypermethylation of the IG-DMR at the DLK1/MEG3 locus is present in nonfunctioning pituitary adenomas.

Conclusions: MEG3 is the first human gene identified expressed in multiple normal human pituitary cell types with loss of expression specifically restricted to clinically nonfunctioning pituitary adenomas. The IG-DMR hypermethylation may be an additional mechanism for MEG3 gene silencing in such tumors.
The Effect of Strength and Endurance Training on Insulin Sensitivity and Fat Distribution in Human Immunodeficiency Virus-Infected Patients with Lipodystrophy
Authors: Lindegaard B. , Hansen T. , Hvid T. , van Hall G. , Plomgaard P. , Ditlevsen S. , Gerstoft J. , Pedersen B. K.
Published: July 2008

Context: Fat redistribution, insulin resistance, and low-grade inflammation characterize HIV-infected patients with lipodystrophy. Currently, no effective therapies exist for the combined treatment of fat redistribution and insulin resistance.

Objective: Our objective was to evaluate the effects of strength and endurance training on insulin sensitivity and fat distribution in HIV-infected patients with lipodystrophy.

Subjects and Methods: Twenty sedentary HIV-infected men with lipodystrophy were randomly assigned to supervised strength or endurance training three times a week for 16 wk. The primary endpoints were improved peripheral insulin sensitivity (euglycemic-hyperinsulinemic clamp combined with isotope-tracer infusion) and body fat composition (dual-energy x-ray absorptiometry scan). Secondary endpoints included fasting lipids and inflammatory markers.

Results: Insulin-mediated glucose uptake increased with both endurance training (55.7 ± 11 to 63.0 ± 11 μmol glucose/kg lean mass·min, P = 0.02) and strength training (49.0 ± 12 to 57.8 ± 18 μmol glucose/kg lean mass·min, P = 0.005), irrespective of training modality (P = 0.24). Only strength training increased total lean mass 2.1 kg [95% confidence interval (CI), 0.8–3.3], decreased total fat 3.3 kg (95% CI, −4.6 to −2.0), trunk fat 2.5 kg (95% CI, −3.5 to −1.5), and limb fat 0.75 kg (95% CI, −1.1 to −0.4). Strength training significantly decreased total and limb fat mass to a larger extent than endurance training (P < 0.05). Endurance training reduced total cholesterol, low-density lipoprotein cholesterol, free fatty acids, high-sensitivity C-reactive protein, IL-6, IL-18, and TNF-α and increased high-density lipoprotein cholesterol, whereas strength training decreased triglycerides, free fatty acids, and IL-18 and increased high-density lipoprotein cholesterol (P < 0.05 for all measurements).

Conclusion: This study demonstrates that both strength and endurance training improve peripheral insulin sensitivity, whereas only strength training reduces total body fat in HIV-infected patients with lipodystrophy.
Patterns of Alcohol Consumption and the Metabolic Syndrome
Authors: Fan Amy Z. , Russell Marcia , Naimi Timothy , Li Yan , Liao Youlian , Jiles Ruth , Mokdad Ali H.
Published: July 2008

Context and Objective: Protective and detrimental associations have been reported between alcohol consumption and the metabolic syndrome. This may be due to variations in drinking patterns and different alcohol effects on the metabolic syndrome components. This study is designed to examine the relationship between alcohol consumption patterns and the metabolic syndrome.

Design, Setting, Participants, and Measures: The 1999–2002 National Health and Nutrition Examination Survey is a population-based survey of noninstitutionalized U.S. adults. Current drinkers aged 20–84 yr without cardiovascular disease who had complete data on the metabolic syndrome and drinking patterns were included in the analysis (n = 1529). The metabolic abnormalities comprising the metabolic syndrome included having three of the following: impaired fasting glucose/diabetes mellitus, high triglycerides, abdominal obesity, high blood pressure, and low high-density-lipoprotein cholesterol. Measures of alcohol consumption included usual quantity consumed, drinking frequency, and frequency of binge drinking.

Results: In multinomial logistic regression models controlling for demographics, family history of cardiovascular disease and diabetes, and lifestyle factors, increased risk of the metabolic syndrome was associated with daily consumption that exceeded U.S. dietary guideline recommendations (more than one drink per drinking day for women and more than two drinks per drinking day for men (odds ratio 1.60, 95% confidence interval 1.22–2.11) and binge drinking once per week or more [odds ratio (95% confidence interval) 1.51 (1.01–2.29]. By individual metabolic abnormality, drinking in excess of the dietary guidelines was associated with an increased risk of impaired fasting glucose/diabetes mellitus, hypertriglyceridemia, abdominal obesity, and high blood pressure.

Conclusion: Public health messages should emphasize the potential cardiometabolic risk associated with drinking in excess of national guidelines and binge drinking.
Mitochondrial Function in Skeletal Muscle Is Normal and Unrelated to Insulin Action in Young Men Born with Low Birth Weight
Authors: Brøns Charlotte , Jensen Christine B. , Storgaard Heidi , Alibegovic Amra , Jacobsen Stine , Nilsson Emma , Astrup Arne , Quistorff Bjørn , Vaag Allan
Published: July 2008

Objective: Low birth weight (LBW) is an independent risk factor of insulin resistance and type 2 diabetes. Recent studies suggest that mitochondrial dysfunction and impaired expression of genes involved in oxidative phosphorylation (OXPHOS) may play a key role in the pathogenesis of insulin resistance in aging and type 2 diabetes. The aim of this study was to determine whether LBW in humans is associated with mitochondrial dysfunction in skeletal muscle.

Methods: Mitochondrial capacity for ATP synthesis was assessed by 31phosphorus magnetic resonance spectroscopy in forearm and leg muscles in 20 young, lean men with LBW and 26 matched controls. On a separate day, a hyperinsulinemic euglycemic clamp with excision of muscle biopsies and dual-energy x-ray absorptiometry scanning was performed. Muscle gene expression of selected OXPHOS genes was determined by quantitative real-time PCR.

Results: The LBW subjects displayed a variety of metabolic and prediabetic abnormalities, including elevated fasting blood glucose and plasma insulin levels, reduced insulin-stimulated glycolytic flux, and hepatic insulin resistance. Nevertheless, in vivo mitochondrial function was normal in LBW subjects, as was the expression of OXPHOS genes.

Conclusions: These data support and expand previous findings of abnormal glucose metabolism in young men with LBW. In addition, we found that the young, healthy men with LBW exhibited hepatic insulin resistance. However, the study does not support the hypothesis that muscle mitochondrial dysfunction per se is the underlying key metabolic defect that explains or precedes whole body insulin resistance in LBW subjects at risk for developing type 2 diabetes.
Slk19-dependent mid-anaphase pause in kinesin-5-mutated cells
Authors: Movshovich Natalia , Fridman Vladimir , Gerson-Gurwitz Adina , Shumacher Inbal , Gertsberg Irena , Fich Alexander , Hoyt M. Andrew , Katz Benjamin , Gheber Larisa
Published: July 2008

We examined spindle elongation in anaphase in Saccharomyces cerevisiae cells mutated for the kinesin-5 motor proteins Cin8 and Kip1. Cells were deleted for KIP1 and/or expressed one of two motor-domain Cin8 mutants (Cin8-F467A or Cin8-R196K, which differ in their ability to bind microtubules in vitro, with Cin8-F467A having the weakest ability). We found that, in kinesin-5-mutated cells, predominantly in kip1Δ cin8-F467A cells, anaphase spindle elongation was frequently interrupted after the fast phase, resulting in a mid-anaphase pause. Expression of kinesin-5 mutants also caused an asymmetric midzone location and enlarged midzone size, suggesting that proper organization of the midzone is required for continuous spindle elongation. We also examined the effects of components of the FEAR pathway, which is involved in the early-anaphase activation of Cdc14 regulatory phosphatase, on anaphase spindle elongation in kip1Δ cin8-F467A cells. Deletion of SLK19, but not SPO12, eliminated the mid-anaphase pause, caused premature anaphase onset and defects in DNA division during anaphase, and reduced viability in these cells. Finally, overriding of the pre-anaphase checkpoint by overexpression of Cdc20 also eliminated the mid-anaphase pause and caused DNA deformation during anaphase in kip1Δ cin8-F467A cells. We propose that transient activation of the pre-anaphase checkpoint in kinesin-5-mutated cells induces a Slk19-dependent mid-anaphase pause, which might be important for proper DNA segregation.
aPKC enables development of zonula adherens by antagonizing centripetal contraction of the circumferential actomyosin cables
Authors: Kishikawa Masaru , Suzuki Atsushi , Ohno Shigeo
Published: July 2008

Atypical protein kinase C (aPKC) generally plays crucial roles in the establishment of cell polarity in various biological contexts. In mammalian epithelial cells, aPKC essentially works towards the transition of primordial spot-like adherens junctions (AJs) into continuous belt-like AJs, also called zonula adherens, lined with perijunctional actin belts. To reveal the mechanism underlying this aPKC function, we investigated the functional relationship between aPKC and myosin II, the essential role of which in epithelial-junction development was recently demonstrated. Despite its deleterious effects on junction formation, overexpression of a dominant-negative mutant of aPKC (aPKCλ kn) did not interfere with the initial phase of myosin-II activation triggered by the formation of Ca2+-switch-induced cell-cell contacts. Furthermore, cells overexpressing aPKCλ kn exhibited myosin-II-dependent asymmetric organization of F-actin along the apicobasal axis, suggesting that aPKC contributes to junction development without affecting the centripetal contraction of the circumferential actomyosin cables. Time-lapse analyses using GFP-actin directly revealed that the circumferential actomyosin cables were centrifugally expanded and developed into perijunctional actin belts during epithelial polarization, and that aPKCλ kn specifically compromised this process. Taken together, we conclude that aPKC is required for antagonizing the myosin-II-driven centripetal contraction of the circumferential actin cables, thereby efficiently coupling the myosin-II activity with junction development and cell polarization. The present results provide novel insights into not only the site of action of aPKC kinase activity but also the role of actomyosin contraction in epithelial polarization.
Laminin α5 influences the architecture of the mouse small intestine mucosa
Authors: Mahoney Zhen X. , Stappenbeck Thaddeus S. , Miner Jeffrey H.
Published: July 2008

The mammalian intestine displays two distinct patterns of mucosal organization. The small intestine contains mucosal epithelial invaginations (the crypts of Lieberkühn) that are continuous with evaginations (villi) into the lumen. The colon also contains crypts of Lieberkühn, but its epithelial surface is lined by flat surface cuffs. The epithelial cells of both organs communicate with the underlying mesenchyme through a basement membrane that is composed of a variety of extracellular matrix proteins, including members of the laminin family. The basement membranes of the small intestine and colon contain distinct laminin subtypes; notably, the villus basement membrane is rich in laminin α5. Here, we show that the diminution of laminin α5 in a mouse model led to a compensatory deposition of colonic laminins, which resulted in a transformation from a small intestinal to a colonic mucosal architecture. The alteration in mucosal architecture was associated with reduced levels of nuclear p27Kip1 – a cell-cycle regulator – and altered intestinal epithelial cell proliferation, migration and differentiation. Our results suggest that laminin α5 has a crucial role in establishing and maintaining the specific mucosal pattern of the mouse small intestine.