bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of aerobic fitness and β1-adrenergic receptor blockade on cardiac work during dynamic exercise
Authors: Hawkins Megan N. , Barnes Quinton , Purkayastha Sushmita , Eubank Wendy , Ogoh Shigehiko , Raven Peter B.
Published: November 2008

The purpose of this investigation was to determine whether cardiovascular adaptations characteristic of long-term endurance exercise compensate more effectively during cardioselective β1-adrenergic receptor blockade-induced reductions in sympathoadrenergic-stimulated contractility. Endurance-trained (ET) athletes ( n = 8) and average-trained (AT; n = 8) subjects performed submaximal cycling exercise at moderate [45% maximum oxygen uptake (V̇o2max)] and heavy (70% V̇o2max) workloads, with and without metoprolol. Cardiac output (Q̇c), heart rate (HR), and systolic blood pressure were recorded at rest and during exercise. Cardiac work was calculated from the triple product of HR, stroke volume, and systolic blood pressure, and myocardial efficiency is represented as cardiac work for a given total body oxygen consumption. Metoprolol reduced Q̇c at 45% V̇o2max ( P = 0.004) and 70% V̇o2max ( P = 0.022) in ET subjects, but did not alter Q̇c in the AT subjects. In ET subjects at 45% V̇o2max, metoprolol-induced reductions in Q̇c were a result of decreases in HR ( P < 0.05) and the absence of a compensatory increase in stroke volume ( P > 0.05). The cardiac work and calculated cardiac efficiency were reduced with metoprolol in ET subjects at both exercise intensities and in the AT subjects during the high-intensity workload ( P < 0.01). The cardiac work and the calculated cardiac efficiency were not affected by metoprolol in the AT subjects during the 45% V̇o2max exercise. Therefore, in AT subjects, β-blockade reduced the amount of pressure generation necessary to produce the same amount of work during moderate-intensity exercise. In patients with heart disease receiving metoprolol, a decrease in the generation of cardiac pressure necessary to perform a given amount of work during mild-to-moderate exercise would prove to be beneficial.
Binaural Unmasking of Frequency-Following Responses in Rat Amygdala
Authors: Du Yi , Huang Qiang , Wu Xihong , Galbraith Gary C. , Li Liang
Published: November 2008

Survival in natural environments for small animals such as rats often depends on precise neural coding of life-threatening acoustic signals, and binaural unmasking of species-specific pain calls is especially critical. This study investigated how species-specific tail-pain chatter is represented in the rat amygdala, which receives afferents from both auditory thalamus and auditory association cortex, and whether the amygdaloid representation of the chatter can be binaurally unmasked. The results show that chatter with a fundamental frequency (F0) of 2.1 kHz was able to elicit salient phase-locked frequency-following responses (FFRs) in the lateral amygdala nucleus in anesthetized rats. FFRs to the F0 of binaurally presented chatter were sensitive to the interaural time difference (ITD), with the preference of ipsilateral-ear leading, as well as showing features of binaural inhibition. When interaurally correlated masking noises were added and ipsilateral chatter led contralateral chatter, introducing an ITD disparity between the chatter and masker significantly enhanced (unmasked) the FFRs. This binaural unmasking was further enhanced by chemically blocking excitatory glutamate receptors in the auditory association cortex. When the chatter was replaced by a harmonic tone complex with an F0 of 0.7 kHz, both the binaural-inhibition feature and the binaural unmasking were preserved only for the harmonic of 2.1 kHz but not the tone F0. These results suggest that both frequency-dependent ascending binaural modulations and cortical descending modulations of the precise auditory coding of the chatter in the amygdala are critical for processing life-threatening acoustic signals in noisy and even reverberant environments.
Sex-specific alterations in mRNA level of key lipid metabolism enzymes in skeletal muscle of overweight and obese subjects following endurance exercise
Authors: Smith Ira J. , Huffman Kim M. , Durheim Michael T. , Duscha Brian D. , Kraus William E.
Published: November 2008

Endurance exercise (EE) leads to beneficial alterations in skeletal muscle lipid metabolism in overweight and obese individuals; however, the mechanisms of these improvements are poorly understood. The primary goal of the current investigation was to test the hypothesis that long-term EE training (6 mo) leads to alterations in the mRNA abundance of key lipid metabolism enzymes in skeletal muscle of overweight and obese middle-aged women and men. A secondary aim of this study was to investigate the hypothesis that exercise-mediated adaptations in mRNA levels differ between women and men. The mRNA abundance of representative lipogenic and lipolytic genes from major lipid metabolism pathways, as well as representative lipogenic and lipolytic transcription factors, were determined by real-time PCR from skeletal muscle biopsies collected before and ∼24 h after the final bout of 6 mo of EE. Six months of EE led to increases in muscle lipoprotein lipase, peroxisome proliferator-activated receptor-γ coactivator-1α, carnitine palmitoyltransferase-1 β, diacylglycerol acyltransferase-1, and acid ceramidase mRNA in women, but not men. In contrast, in men, EE led to reductions in the mRNA content of the lipogenic factors sterol regulatory element binding protein-1c and serine palmitoyl transferase. These data suggest that EE-mediated alterations in the abundance of the lipid metabolism genes studied here are fundamentally different between overweight and obese middle-aged women and men. Future studies should determine whether these adaptations in mRNA levels translate into changes in protein function.
Sexual Function in Patients with Metastatic Midgut Carcinoid Tumours
Authors: van der Horst-Schrivers Anouk N.A. , van Ieperen Ellen , Wymenga A.N. Machteld , Boezen H. Marike , Weijmar-Schultz Willibrord C.M. , Kema Ido P. , Meijer Wim G. , de Herder Wouter W. , Willemse Pax H.B. , Links Thera P. , de Vries Elisabeth G.E.
Published: November 2008

Background: Sexual dysfunction is a poorly studied aspect of quality of life in patients with midgut carcinoid tumours. We investigated whether carcinoid patients experience sexual problems. Methods: Patients with metastatic midgut carcinoid tumours filled in a validated questionnaire for sexual dysfunction. The prevalence of dysfunction on the subscales arousal, erection, lubrication, orgasm and dyspareunia was compared to a Dutch reference population. Plasma concentration of gonadal hormones, tryptophan and urinary 5-hydroxyindolacetic acid concentrations were measured. Results: 43 patients were studied, 27 men and 16 women. Sexual dysfunction was present in 29.6% of men and 6.3% of women. The prevalence of sexual dysfunction on the different subscales did not differ from the reference population. Patients with a sexual dysfunction had, compared to those without a sexual dysfunction, a longer duration of disease, 95.3 months (range 5.4–314.5) versus 18.6 months (range 0.6–167.9) (p = 0.024), lower plasma tryptophan concentration (±SD) of 31.5 ± 16.1 and 48.9 ± 14.5 μmol/l (p = 0.031), and more often used interferon-α, 50% of patients versus 10.5% of patients (p = 0.044). Conclusion: Patients with metastatic midgut carcinoid tumours do not experience sexual problems more often than a reference population. Male patients with sexual dysfunction are characterised by more long-standing disease and lower tryptophan concentration.
Single‐Dose Pharmacokinetic Study of Clomiphene Citrate Isomers in Anovular Patients With Polycystic Ovary Disease
Authors: Ghobadi Cyrus , Mirhosseini Nahid , Shiran Mohammad Reza , Moghadamnia Ali , Lennard Martin S. , Ledger William L. , Rostami‐Hodjegan Amin
Published: November 2008

The pharmacokinetics of the zuclomiphene (Zu) and enclomiphene (En) isomers of clomiphene citrate following a single oral dose (50 mg) were characterized for the first time in patients receiving the drug (ie, infertile women with polycystic ovary syndrome). Plasma concentrations of Zu and En were measured in 9 patients from the second day of their menstrual cycle (day 1 of dosing) up to 21 days. The mean (± coefficient of variation) of Cmax, tmax, and AUC of Zu was 15 ± 41 ng/mL, 7 ± 87 h, and 1289 ± 34 ng/mL·h (AUC0–456 h), and that of En was 15 ± 18 ng/mL, 3 ± 68 h, and 65 ± 35 ng/ml·h (AUC0–72 h), respectively. These parameters appeared to be different for Zu from those reported previously in healthy participants, except for tmax. The pharmacokinetic parameters of En in patients with polycystic ovary syndrome were not generally different from the healthy subjects. The effect of obesity on Zu kinetics was stronger than that on En. The conventional model‐dependent pharmacokinetics of clomiphene citrate isomers could not be determined due to a very flat terminal half‐life and the long‐tailed residence time, signifying the lipophilic nature and potentially extensive distribution of the compound.
Oral Hairy Leukoplakia in HIV-Negative Patients: Report of 10 Cases
Authors: Piperi Evangelia , Omlie Jessica , Koutlas Ioannis George , Pambuccian Stefan
Published: November 2008

Ten cases of oral hairy leukoplakia (OHL) in HIV- negative patients are presented. Eight of the 10 patients were on steroid treatment for chronic obstructive pulmonary disease, 1 patient was on prednisone as part of a therapeutic regimen for gastrointestinal stromal tumor, and 1 patient did not have any history of immunosuppression. There were 5 men and 5 women, ages 32-79, with mean age being 61.8 years. Nine out of 10 lesions were located unilaterally on the tongue, whereas 1 lesion was located at the junction of the hard and soft palate. All lesions were described as painless, corrugated, nonremovable white plaques (leukoplakias). Histologic features were consistent with Epstein—Barr virus—associated hyperkeratosis suggestive of OHL, and confirmatory in situ hybridization was performed in all cases. Candida hyphae and spores were present in 8 cases. Pathologists should be aware of OHL presenting not only in HIV-positive and HIV-negative organ transplant recipients but also in patients receiving steroid treatment, and more important, certain histologic features should raise suspicion for such diagnosis without prior knowledge of immunosuppression.
Phylogenetic and genomic diversity of human bacteremic Escherichia coli strains
Authors: Jaureguy Françoise , Landraud Luce , Passet Virginie , Diancourt Laure , Frapy Eric , Guigon Ghislaine , Carbonnelle Etienne , Lortholary Olivier , Clermont Olivier , Denamur Erick , Picard Bertrand , Nassif Xavier , Brisse Sylvain
Published: November 2008

Background

Extraintestinal pathogenic Escherichia coli (ExPEC) strains represent a huge public health burden. Knowledge of their clonal diversity and of the association of clones with genomic content and clinical features is a prerequisite to recognize strains with a high invasive potential. In order to provide an unbiased view of the diversity of E. coli strains responsible for bacteremia, we studied 161 consecutive isolates from patients with positive blood culture obtained during one year in two French university hospitals. We collected precise clinical information, multilocus sequence typing (MLST) data and virulence gene content for all isolates. A subset representative of the clonal diversity was subjected to comparative genomic hybridization (CGH) using 2,324 amplicons from the flexible gene pool of E. coli.

Results

Recombination-insensitive phylogenetic analysis of MLST data in combination with the ECOR collection revealed that bacteremic E. coli isolates were highly diverse and distributed into five major lineages, corresponding to the classical E. coli phylogroups (A+B1, B2, D and E) and group F, which comprises strains previously assigned to D. Compared to other strains of phylogenetic group B2, strains belonging to MLST-derived clonal complexes (CCs) CC1 and CC4 were associated (P < 0.05) with a urinary origin. In contrast, no CC appeared associated with severe sepsis or unfavorable outcome of the bacteremia. CGH analysis revealed genomic characteristics of the distinct CCs and identified genomic regions associated with CC1 and/or CC4.

Conclusion

Our results demonstrate that human bacteremia strains distribute over the entire span of E. coli phylogenetic diversity and that CCs represent important phylogenetic units for pathogenesis and comparative genomics.
Use of anthropometric indicators in screening for undiagnosed vertebral fractures: A cross-sectional analysis of the Fukui Osteoporosis Cohort (FOC) study
Authors: Abe Kiyoko , Tamaki Junko , Kadowaki Eiko , Sato Yuho , Morita Akemi , Komatsu Misa , Takeuchi Sayaka , Kajita Etsuko , Iki Masayuki
Published: November 2008

Background

Vertebral fractures are the most common type of osteoporotic fracture. Although often asymptomatic, each vertebral fracture increases the risk of additional fractures. Development of a safe and simple screening method is necessary to identify individuals with asymptomatic vertebral fractures.

Methods

Lateral imaging of the spine by single energy X-ray absorptiometry and vertebral morphometry were conducted in 116 Japanese women (mean age: 69.9 ± 9.3 yr). Vertebral deformities were diagnosed by the McCloskey-Kanis criteria and were used as a proxy for vertebral fractures. We evaluated whether anthropometric parameters including arm span-height difference (AHD), wall-occiput distance (WOD), and rib-pelvis distance (RPD) were related to vertebral deformities. Positive findings were defined for AHD as ≥ 4.0 cm, for WOD as ≥ 5 mm, and for RPD as ≤ two fingerbreadths. Receiver operating characteristics curves analysis was performed, and cut-off values were determined to give maximum difference between sensitivity and false-positive rate. Expected probabilities for vertebral deformities were calculated using logistic regression analysis.

Results

The mean AHD for those participants with and without vertebral deformities were 7.0 ± 4.1 cm and 4.2 ± 4.2 cm (p < 0.01), respectively. Sensitivity and specificity for use of AHD-positive, WOD-positive and RPD-positive values in predicting vertebral deformities were 0.85 (95% CI: 0.69, 1.01) and 0.52 (95% CI: 0.42, 0.62); 0.70 (95% CI: 0.50, 0.90) and 0.67 (95% CI: 0.57, 0.76); and 0.67 (95% CI: 0.47, 0.87) and 0.59 (95% CI: 0.50, 0.69), respectively. The sensitivity, specificity, and likelihood ratio for a positive result (LR) for use of combined AHD-positive and WOD-positive values were 0.65 (95% CI: 0.44, 0.86), 0.81 (95% CI: 0.73, 0.89), and 3.47 (95% CI: 3.01, 3.99), respectively. The expected probability of vertebral deformities (P) was obtained by the equation; P = 1-(exp [-1.327-0.040 × body weight +1.332 × WOD-positive + 1.623 × AHD-positive])-1. The sensitivity, specificity and LR for use of a 0.306 cut-off value for probability of vertebral fractures were 0.65 (95% CI: 0.44, 0.86), 0.87 (95% CI: 0.80, 0.93), and 4.82 (95% CI: 4.00, 5.77), respectively.

Conclusion

Both WOD and AHD effectively predicted vertebral deformities. This screening method could be used in a strategy to prevent additional vertebral fractures, even when X-ray technology is not available.
High throughput protein-protein interaction data: clues for the architecture of protein complexes
Authors: Krycer James R , Pang Chi Nam Ignatius , Wilkins Marc R
Published: November 2008

Background

High-throughput techniques are becoming widely used to study protein-protein interactions and protein complexes on a proteome-wide scale. Here we have explored the potential of these techniques to accurately determine the constituent proteins of complexes and their architecture within the complex.

Results

Two-dimensional representations of the 19S and 20S proteasome, mediator, and SAGA complexes were generated and overlaid with high quality pairwise interaction data, core-module-attachment classifications from affinity purifications of complexes and predicted domain-domain interactions. Pairwise interaction data could accurately determine the members of each complex, but was unexpectedly poor at deciphering the topology of proteins in complexes. Core and module data from affinity purification studies were less useful for accurately defining the member proteins of these complexes. However, these data gave strong information on the spatial proximity of many proteins. Predicted domain-domain interactions provided some insight into the topology of proteins within complexes, but was affected by a lack of available structural data for the co-activator complexes and the presence of shared domains in paralogous proteins.

Conclusion

The constituent proteins of complexes are likely to be determined with accuracy by combining data from high-throughput techniques. The topology of some proteins in the complexes will be able to be clearly inferred. We finally suggest strategies that can be employed to use high throughput interaction data to define the membership and understand the architecture of proteins in novel complexes.
Functional insight into Maelstrom in the germline piRNA pathway: a unique domain homologous to the DnaQ-H 3'–5' exonuclease, its lineage-specific expansion/loss and evolutionarily active site switch
Authors: Zhang Dapeng , Xiong Huiling , Shan Jufang , Xia Xuhua , Trudeau Vance L
Published: November 2008

Maelstrom (MAEL) plays a crucial role in a recently-discovered piRNA pathway; however its specific function remains unknown. Here a novel MAEL-specific domain characterized by a set of conserved residues (Glu-His-His-Cys-His-Cys, EHHCHC) was identified in a broad range of species including vertebrates, sea squirts, insects, nematodes, and protists. It exhibits ancient lineage-specific expansions in several species, however, appears to be lost in all examined teleost fish species. Functional involvement of MAEL domains in DNA- and RNA-related processes was further revealed by its association with HMG, SR-25-like and HDAC_interact domains. A distant similarity to the DnaQ-H 3'–5' exonuclease family with the RNase H fold was discovered based on the evidence that all MAEL domains adopt the canonical RNase H fold; and several protist MAEL domains contain the conserved 3'–5' exonuclease active site residues (Asp-Glu-Asp-His-Asp, DEDHD). This evolutionary link together with structural examinations leads to a hypothesis that MAEL domains may have a potential nuclease activity or RNA-binding ability that may be implicated in piRNA biogenesis. The observed transition of two sets of characteristic residues between the ancestral DnaQ-H and the descendent MAEL domains may suggest a new mode for protein function evolution called "active site switch", in which the protist MAEL homologues are the likely evolutionary intermediates due to harboring the specific characteristics of both 3'–5' exonuclease and MAEL domains.

Reviewers

This article was reviewed by L Aravind, Wing-Cheong Wong and Frank Eisenhaber. For the full reviews, please go to the Reviewers' Comments section.
Cost Effectiveness of Intraperitoneal Compared With Intravenous Chemotherapy for Women With Optimally Resected Stage III Ovarian Cancer: A Gynecologic Oncology Group Study
Authors: Havrilesky Laura J. , Alvarez Secord Angeles , Darcy Kathleen M. , Armstrong Deborah K. , Kulasingam Shalini
Published: November 2008

Purpose

To determine the cost effectiveness of intraperitoneal versus intravenous regimens for adjuvant treatment of optimally resected stage III ovarian cancer.

Patients and Methods

A decision model was developed to compare the cost effectiveness at 7-, 11.5-, and 35-year horizons of intravenous carboplatin and paclitaxel (IV-CARBO/PAC), intravenous cisplatin and paclitaxel (IV-CIS/PAC), or intravenous paclitaxel followed by intraperitoneal cisplatin and paclitaxel (IP-CIS/PAC). Survival data were from women participating in representative Gynecologic Oncology Group (GOG) protocols. Medicare reimbursement rates and the Agency for Healthcare Research and Quality Database were used to estimate costs for treatment regimens and grade 3 to 4 adverse effects, respectively.

Results

Median predicted survival was 66, 57, 51, and 48 months for IP-CIS/PAC, IV-CARBO/PAC, IV-CIS/PAC (GOG 172), or IV-CIS/PAC (GOG 158), respectively. Across a range of analyses, IV-CIS/PAC was more costly and had lower life expectancy than IV-CARBO/PAC. Compared with IV-CARBO/PAC, IP-CIS/PAC had an incremental cost-effectiveness ratio (ICER) of $180,022 per quality-adjusted life year (QALY) saved at a 7-year time horizon, $71,835/QALY at 11.5 years, and $32,053/QALY over a lifetime. Extending the survival advantage of IP-CIS/PAC over 11.5 years and a lifetime results in ICERs of $26,249 and $23,973, respectively. Assuming IP-CIS/PAC and IV-CIS/PAC were equally effective when administered on an outpatient basis, the ICER of IP-CIS/PAC compared with IV-CARBO/PAC was $26,311.

Conclusion

Inpatient IP-CIS/PAC, while not cost effective compared with IV-CARBO/PAC at 7 years, becomes cost effective if a longer time horizon is modeled and/or a survival benefit can be assumed to persist longer than currently available data. Outpatient IP-CIS/PAC may also be cost effective compared with IV-CARBO/PAC if proven as effective as inpatient IP-CIS/PAC.
Pharmacodynamic-Guided Modified Continuous Reassessment Method–Based, Dose-Finding Study of Rapamycin in Adult Patients With Solid Tumors
Authors: Jimeno Antonio , Rudek Michelle A. , Kulesza Peter , Ma Wen Wee , Wheelhouse Jenna , Howard Anna , Khan Yasmin , Zhao Ming , Jacene Heather , Messersmith Wells A. , Laheru Daniel , Donehower Ross C. , Garrett-Mayer Elizabeth , Baker Sharyn D. , Hidalgo Manuel
Published: November 2008

Purpose

Pharmacodynamic studies are frequently incorporated into phase I trials, but it is uncommon that they guide dose selection. We conducted a dose selection study with daily rapamycin (sirolimus) in patients with solid tumors employing a modified continuous reassessment method (mCRM) using real-time pharmacodynamic data as primary dose-estimation parameter.

Patients and Methods

We adapted the mCRM logit function from its classic toxicity-based input data to a pharmacodynamic-based input. The pharmacodynamic end point was skin phospho-P70 change after 28 days. Pharmacodynamic effect was defined as at least 80% inhibition from baseline. The first two dose levels (2 and 3 mg) were evaluated before implementing the mCRM, and the data used to estimate the next dose level based on statistical modeling. Toxicity-based boundaries limited the escalation steps. Other correlates analyzed were positron emission tomography (PET) and computed tomography, pharmacokinetics, phospho-P70 in peripheral-blood mononuclear cells, and tumor biopsies in patients at the maximum-tolerated dose (MTD).

Results

Twenty-one patients were enrolled at doses between 2 and 9 mg. Pharmacodynamic effect occurred across dose levels, and toxicity boundaries ultimately drove dose selection. The MTD of daily oral rapamycin was 6 mg. Toxicities in at least 20% were hyperglycemia, hyperlipidemia, elevated transaminases, anemia, leucopenia, neutropenia, and mucositis. Pharmacokinetics were consistent with prior data, and exposure increased with dose. No objective responses occurred, but five previously progressing patients received at least 12 cycles. PET showed generalized stable or decreased glucose uptake unrelated to antitumor effect.

Conclusion

mCRM-based dose escalation using real-time pharmacodynamic assessment was feasible. However, the selected pharmacodynamic end point did not correlate with dose. Toxicity ultimately drove dose selection. Rapamycin is a well-tolerated and active oral anticancer agent.
Screening for Neurocognitive Impairment in Pediatric Cancer Long-Term Survivors
Authors: Krull Kevin R. , Okcu M. Fatih , Potter Brian , Jain Neelam , Dreyer ZoAnn , Kamdar Kala , Brouwers Pim
Published: November 2008

Purpose

Recent studies suggest that up to 40% of childhood cancer survivors may experience neurocognitive problems, a finding that has led the Children's Oncology Group to recommend regular evaluation. However, for a variety of reasons, including costs, time restraints, health insurance, and access to professional resources, these guidelines are often difficult to implement. We report reliability and validity data on a brief neurocognitive screening method that could be used to routinely screen patients in need of comprehensive follow-up.

Patients and Methods

Two hundred forty consecutive patients were screened during their annual visits to a long-term survivor clinic using standard neurocognitive measures and brief parent rating. From this total, 48 patients had a second screening, and 52 patients had a comprehensive follow-up evaluation. Test-retest reliability and predictive and discriminative validity were examined.

Results

Good test-retest reliability was demonstrated, with an overall r = 0.72 and all individual subtest correlations greater than r = 0.40. Although means tended to improve from first to second testing, no significant changes were detected (all P > .10). The screen accurately predicted global intellect (F6,45 = 11.81, P < .0001), reading skills (F6,45 = 4.74, P < .001), and mathematics (F6,45 = 3.35, P < .008). Parent rating was a marginal indicator of global intellect only.

Conclusion

The brief neurocognitive screening was a better predictor of child functioning than specific parent rating. This brief measure, which can be completed in 30 minutes, is a practical and reliable method to identify cancer survivors in need of further neurocognitive follow-up.
Controlling Prescription Drug Costs: Regulation and the Role of Interest Groups in Medicare and the Veterans Health Administration
Authors: Frakt Austin B. , Pizer Steven D. , Hendricks Ann M.
Published: November 2008

Medicare and the Veterans Health Administration (VA) both finance large outpatient prescription drug programs, though in very different ways. In the ongoing debate on how to control Medicare spending, some suggest that Medicare should negotiate directly with drug manufacturers, as the VA does. In this article we relate the role of interest groups to policy differences between Medicare and the VA and, in doing so, explain why such a large change to the Medicare drug program is unlikely. We argue that key policy differences are attributable to stable differences in interest group involvement. While this stability makes major changes in Medicare unlikely, it suggests the possibility of leveraging VA drug purchasing to achieve savings in Medicare. This could be done through a VA-administered drug-only benefit for Medicare-enrolled veterans. Such a partnership could incorporate key elements of both programs: capacity to accept large numbers of enrollees (like Medicare) and leverage to negotiate prescription drug prices (like the VA). Moreover, it could be implemented at no cost to the VA while achieving savings for Medicare and beneficiaries.
Distinct roles of class IA PI3K isoforms in primary and immortalised macrophages
Authors: Papakonstanti Evangelia A. , Zwaenepoel Olivier , Bilancio Antonio , Burns Emily , Nock Gemma E. , Houseman Benjamin , Shokat Kevan , Ridley Anne J. , Vanhaesebroeck Bart
Published: November 2008

The class IA isoforms of phosphoinositide 3-kinase (p110α, p110β and p110δ) often have non-redundant functions in a given cell type. However, for reasons that are unclear, the role of a specific PI3K isoform can vary between cell types. Here, we compare the relative contributions of PI3K isoforms in primary and immortalised macrophages. In primary macrophages stimulated with the tyrosine kinase ligand colony-stimulating factor 1 (CSF1), all class IA PI3K isoforms participate in the regulation of Rac1, whereas p110δ selectively controls the activities of Akt, RhoA and PTEN, in addition to controlling proliferation and chemotaxis. The prominent role of p110δ in these cells correlates with it being the main PI3K isoform that is recruited to the activated CSF1 receptor (CSF1R). In immortalised BAC1.2F5 macrophages, however, the CSF1R also engages p110α, which takes up a more prominent role in CSF1R signalling, in processes including Akt phosphorylation and regulation of DNA synthesis. Cell migration, however, remains dependent mainly on p110δ. In other immortalised macrophage cell lines, such as IC-21 and J774.2, p110α also becomes more prominently involved in CSF1-induced Akt phosphorylation, at the expense of p110δ.These data show that PI3K isoforms can be differentially regulated in distinct cellular contexts, with the dominant role of the p110δ isoform in Akt phosphorylation and proliferation being lost upon cell immortalisation. These findings suggest that p110δ-selective PI3K inhibitors may be more effective in inflammation than in cancer.
The ubiquitin-like modifier FAT10 interacts with HDAC6 and localizes to aggresomes under proteasome inhibition
Authors: Kalveram Birte , Schmidtke Gunter , Groettrup Marcus
Published: November 2008

During misfolded-protein stress, the cytoplasmic protein histone deacetylase 6 (HDAC6) functions as a linker between the dynein motor and polyubiquitin to mediate the transport of polyubiquitylated cargo to the aggresome. Here, we identify a new binding partner of HDAC6, the ubiquitin-like modifier FAT10 (also known as UBD), which is cytokine-inducible and – similar to ubiquitin – serves as a signal for proteasomal degradation. In vivo, the two proteins only interacted under conditions of proteasome impairment. The binding of HDAC6 to FAT10 was mediated by two separate domains: the C-terminal ubiquitin-binding zinc-finger (BUZ domain) of HDAC6 and its first catalytic domain, even though catalytic activity of HDAC6 was not required for this interaction. Both endogenous and ectopically expressed FAT10 as well as the model conjugate FAT10-GFP localized to the aggresome in a microtubule-dependent manner. Furthermore, FAT10-containing as well as ubiquitin-containing aggresomes were reduced in both size and number in HDAC6-deficient fibroblasts. We conclude that, if FAT10 fails to subject its target proteins to proteasomal degradation, an alternative route is taken to ensure their sequestration and possibly also their subsequent removal by transporting them to the aggresome via the association with HDAC6.
Comparative study of welding residual stresses in carbon and stainless steel butt welds
Authors: Lee C-H , Chang K-H , Lee C-Y
Published: November 2008

With the increased use of stainless steels in construction, it has become of critical importance to estimate the magnitude and distribution of welding residual stresses in a welded structure made of stainless steels. Simulation tools based on the finite element (FE) method are very useful to predict welding-induced residual stresses. Welding residual stresses in carbon steel welds have been thoroughly investigated through numerous FE models. In the case of stainless steel welds, a large number of FE simulations focusing on welding residual stresses have been performed; however, most of them have been confined to circumferential welding with the emphasis on pressurized pipe components, whereas few analyses have been carried out on a conventional structural member such as a butt-welded plate. Stainless steel has material stress—strain characteristics and thermal properties that differ from those of carbon steel; both properties influence the formation of welding residual stresses. This suggests that established FE models for predicting welding residual stresses in carbon steel welds may not be appropriate for stainless steel welds. Three-dimensional FE simulation of welding residual stresses in stainless steel butt welds has therefore been carried out. The thermomechanical FE model and the simulation methodology used are detailed and the results are discussed. In addition, welding residual stresses in carbon steel butt welds are examined for comparison.
Investigation into the influences of the power circuit on the micro-electrochemical discharge machining process
Authors: Sarkar B R , Doloi B , Bhattacharyya B
Published: November 2008

The electrochemical discharge machining (ECDM) process has become a promising area in the field of non-conventional machining processes, as it has a great potential to machine electrically non-conducting materials such as glass and ceramics. However, when it is applied as a micromachining process, its performance characteristics are influenced by various control factors such as the applied voltage, electrolyte concentration, and interelectrode gap, the characteristics of the power circuit, etc., as a result of variation in the sparking intensity. The objective of the present research work is to find out the most suitable power circuit for the ECDM process during its application in the microdrilling of glass. The influences of various power circuit configurations on the material removal rate (MRR), the tool wear rate (TWR), the radial overcut (ROC), and the heat-affected zone (HAZ) have been investigated using an NaOH salt solution as electrolyte. The individual effects of the inductance L, resistance R, and capacitance C of the power circuit on machining performance have been studied experimentally in order to find their optimal values. Experiments have been carried out to search for the pairwise effect of power circuit variables by considering their optimal values according to a Taguchi L9 orthogonal array. Maximum MRR and minimum TWR can be achieved at LC/60V/20 wt %/20 mm and RL/50 V/30 wt %/40 mm respectively. Minimum ROC and minimum HAZ thickness have been obtained at RC/50 V/10 wt %/40 mm. Thus, from the point of view of the accuracy and quality of the machined hole, an RC circuit has been found to be most suitable for the micromachining of electrically non-conducting materials by the electrochemical discharge machining process.
The ethics of egg donation in the over fifties
Authors: Smajdor Anna
Published: November 2008

It has been conclusively demonstrated that postmenopausal women can gestate and give birth to children. However, to do so, they require donated oocytes, which are in short supply. In this paper, I explore a number of arguments for limiting access to donated oocytes to women of normal reproductive age. I consider the idea that older women have already had their chance to reproduce, and have chosen to forego it. I also consider the question of whether younger women have a more compelling clinical need, and ask whether the risks involved in postmenopausal motherhood are excessive. I argue that many of the concerns about postmenopausal motherhood are based on unjustified assumptions. Postmenopausal women are treated very differently to men of similar ages in the context of reproduction. I question whether this constitutes unjust discrimination or whether it reflects intrinsic differences between women's and men's reproductive capacities, and parental roles. In either case, women are often at a disadvantage and are subject to heavy social pressure in their reproductive choices. I conclude that there are no compelling reasons for a systematic ban on the use of donated oocytes in postmenopausal women. However, the procurement of oocytes for use in any woman raises some series ethical issues, and as new technologies and research avenues proliferate, pressure on this resource is likely to increase.
Pre-Entry Knowledge, Learning, and the Survival of New Firms
Authors: Dencker John C. , Gruber Marc , Shah Sonali K.
Published: November 2008

New firms are endowed with knowledge and experience at birth through the human capital of their founder(s). Existing empirical research suggests that this pre-entry knowledge and experience will influence the firm's chances of survival; however, the mechanisms underlying this relationship have yet to be investigated. We seek to better understand and unpack this relationship. Specifically, we study the extent to which a founder's pre-entry knowledge of the business activity and pre-entry management experience influence the effectiveness of two subsequent learning activities—namely, early-stage business planning and product-line change. Our findings suggest that pre-entry knowledge and management experience increase firm survival through moderating the effects of these subsequent learning activities. We also find that learning activities are not always beneficial; in our sample, early-stage business planning is associated with decreased firm survival, and product line change is associated with increased firm survival. We examine these patterns using survey data collected from 436 individuals in the Munich region who founded their own firms as an alternative to continued unemployment. Our results have theoretical implications for the entrepreneurship, evolutionary economics, and organizational learning literatures.
Risk of Hepatotoxicity Associated with the Use of Telithromycin: A Signal Detection Using Data Mining Algorithms
Authors: Chen Yan , Guo Jeff J , Healy Daniel P , Lin Xiaodong , Patel Nick C
Published: November 2008

Background:

With the exception of case reports, limited data are available regarding the risk of hepatotoxicity associated with the use of telithromycin.

Objective:

To detect the safety signal regarding the reporting of hepatotoxicity associated with the use of telithromycin using 4 commonly employed data mining algorithms (DMAs).

Methods:

Based on the Adverse Events Reporting System (AERS) database of the Food and Drug Administration, 4 DMAs, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the Gamma Poisson Shrinker (GPS), were applied to examine the association between the reporting of hepatotoxicity and the use of telithromycin. The study period was from the first quarter of 2004 to the second quarter of 2006. The reporting of hepatotoxicity was identified using the preferred terms indexed in the Medical Dictionary for Regulatory Activities. The drug name was used to identify reports regarding the use of telithromycin.

Results:

A total of 226 reports describing hepatotoxicity associated with the use of telithromycin were recorded in the AERS. A safety problem of telithromycin associated with increased reporting of hepatotoxicity was clearly detected by 4 algorithms as early as 2005, signaling the problem in the first quarter by the ROR and the IC, in the second quarter by the PRR, and in the fourth quarter by the GPS.

Conclusions:

A safety signal was indicated by the 4 DMAs suggesting an association between the reporting of hepatotoxicity and the use of telithromycin. Given the wide use of telithromycin and serious consequences of hepatotoxicity, clinicians should be cautious when selecting telithromycin for treatment of an infection. In addition, further observational studies are required to evaluate the utility of signal detection systems for early recognition of serious, life-threatening, low-frequency drug-induced adverse events.
Renewed Cocaine Exposure Produces Transient Alterations in Nucleus Accumbens AMPA Receptor-Mediated Behavior
Authors: Bachtell Ryan K. , Self David W.
Published: November 2008

Withdrawal from repeated cocaine is associated with increased synaptic and extrasynaptic AMPA receptor (AMPAR) expression in nucleus accumbens (NAc) neurons and enhanced behavioral sensitivity to AMPAR stimulation. Recent studies found that increased membrane expression of AMPARs is reversed or normalized on cocaine reexposure in withdrawal, but the mechanism for this AMPAR plasticity and the behavioral implications are unknown. Here, we examine the effects of renewed cocaine exposure during withdrawal on enhanced NAc AMPAR sensitivity and investigate the underlying mechanisms. Cocaine reexposure transiently reversed enhanced NAc AMPAR-mediated locomotion 1 d later, while enhancing cocaine-induced locomotion. Reversal in AMPAR sensitivity was prohibited by NAc AMPAR blockade with CNQX during cocaine reexposure and mimicked by intra-NAc infusions of AMPA, suggesting that cocaine-induced glutamate stimulation of NAc AMPARs is necessary for reversing AMPAR responsiveness. Similarly, systemic treatment with the dopamine D1-like agonist SKF 81297 [(±)-6-chloro-7,8-dihydroxy-l-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide] reversed AMPAR responsiveness in cocaine withdrawal, but the effect was prevented by local NAc AMPAR blockade in the NAc, and not local D1-like receptor blockade, suggesting a role for glutamate afferents in the reversal of enhanced AMPAR sensitivity. Together, these findings suggest that cocaine-induced glutamate release in sensitized animals is responsible for dynamic alterations in AMPAR function that contribute to enhanced cocaine sensitivity.
The Role of Neuropeptide Y in the Expression and Extinction of Fear-Potentiated Startle
Authors: Gutman Alisa R. , Yang Yong , Ressler Kerry J. , Davis Michael
Published: November 2008

Neuropeptides are a promising target for novel treatments for anxiety and other psychiatric disorders and neuropeptide Y (NPY) has emerged as a key component of anxiolytic circuits in the brain. For this reason, we have evaluated the role of NPY in the expression and extinction of conditioned fear. We found that intracerebroventricular administration of NPY inhibits both baseline acoustic startle and the expression of fear-potentiated startle. Infusion of NPY (10 pmol/side) into the basolateral, but not the medial, nucleus of the amygdala reproduced the intracerebroventricular effect. Central administration of NPY (10 μg) also enhanced within-session extinction of fear-potentiated startle. This finding, coupled with the growing body of literature correlating NPY with resilience in humans, led us to the hypothesis that NPY may enhance the extinction of conditioned fear. When NPY (10 μg) is administered intracerebroventricularly before extinction training, extinction retention for both the contextual and cued components of conditioned fear is enhanced when tested 48 h later off drug. Additionally, we found that intra-basolateral amygdala administration of the NPY Y1receptor antagonist BIBO 3304 (200 pmol/side) before extinction training led to a profound deficit in extinction retention. This is the first evidence that NPY facilitates and an NPY antagonist blocks the extinction of conditioned fear. We believe that the role of NPY in the extinction of conditioned fear may, at least in part, explain the mechanism underlying the association between NPY and psychobiological resilience in humans.
Postnatal Differentiation of Basket Cells from Slow to Fast Signaling Devices
Authors: Doischer Daniel , Aurel Hosp Jonas , Yanagawa Yuchio , Obata Kunihiko , Jonas Peter , Vida Imre , Bartos Marlene
Published: November 2008

Gamma frequency (30–100 Hz) oscillations in the mature cortex underlie higher cognitive functions. Fast signaling in GABAergic interneuron networks plays a key role in the generation of these oscillations. During development of the rodent brain, gamma activity appears at the end of the first postnatal week, but frequency and synchrony reach adult levels only by the fourth week. However, the mechanisms underlying the maturation of gamma activity are unclear. Here we demonstrate that hippocampal basket cells (BCs), the proposed cellular substrate of gamma oscillations, undergo marked changes in their morphological, intrinsic, and synaptic properties between postnatal day 6 (P6) and P25. During maturation, action potential duration, propagation time, duration of the release period, and decay time constant of IPSCs decreases by ∼30–60%. Thus, postnatal development converts BCs from slow into fast signaling devices. Computational analysis reveals that BC networks with young intrinsic and synaptic properties as well as reduced connectivity generate oscillations with moderate coherence in the lower gamma frequency range. In contrast, BC networks with mature properties and increased connectivity generate highly coherent activity in the upper gamma frequency band. Thus, late postnatal maturation of BCs enhances coherence in neuronal networks and will thereby contribute to the development of cognitive brain functions.
Glutamatergic Transmission Is Sustained at a Later Period of Development of Medial Nucleus of the Trapezoid Body–Lateral Superior Olive Synapses in Circling Mice
Authors: Hong Sung Hwa , Kim Myeung Ju , Ahn Seung Cheol
Published: November 2008

Synaptic transmission between the medial nucleus of the trapezoid body (MNTB) and the lateral superior olive (LSO) was investigated in circling mice, an animal model for inherited deafness, using the voltage-clamp technique. In postnatal day 9 (P9)∼P11 homozygous (cir/cir) circling mice, perfusion with 10 μmdl-APV and 10 μmCNQX reduced the 10 min average of postsynaptic currents (PSCs) to 8.8 ± 3.0% compared with controls (n= 6). In heterozygous (+/cir) mice in the same age range, the 10 min PSCs average was reduced to 87.5 ± 3.7% compared with controls (n= 7). In P0∼P2 homozygous (cir/cir) and heterozygous (+/cir) mice, the 10 min PSCs averages were 11.0 ± 2.6% (n= 9) and 84.1 ± 4.6% (n= 11), respectively. The effects of a glutamate antagonist mixture were almost the same in single fiber stimulation of P9∼P11 mice, reducing mean PSCs to 5.2 ± 3.1% (homozygous (cir/cir) mice,n= 8) and 78.3 ± 4.3% (heterozygous (+/cir) mice,n= 12). Immunohistochemical study revealed that glycine receptor (GlyR) immunoreactivity in heterozygous (+/cir) mice was more prominent than in homozygous (cir/cir) mice, while immunoreactivities of NR1 and NR2A-type NMDAR of P16 homozygous (cir/cir) mice were more prominent than in heterozygous (+/cir) mice of the same age. No significant difference was found in the immunoreactivity of NR2B-type NMDAR. These results indicate that glutamatergic transmission is sustained at a later period of developing MNTB–LSO synapses in homozygous (cir/cir) mice.
Modeling a Negative Response Bias in the Human Amygdala by Noradrenergic–Glucocorticoid Interactions
Authors: Kukolja Juraj , Schläpfer Thomas E. , Keysers Christian , Klingmüller Dietrich , Maier Wolfgang , Fink Gereon R. , Hurlemann René
Published: November 2008

An emerging theme in the neuroscience of emotion is the question of how acute stress shapes, and distorts, social-emotional behavior. The prevailing neurocircuitry models of social-emotional behavior emphasize the central role of the amygdala. Acute stress leads to increased central levels of norepinephrine (NE) and cortisol (CORT), and evidence suggests that these endogenous neuromodulators synergistically influence amygdala responses to social-emotional stimuli. We therefore hypothesized that amygdala responses to emotional facial expressions would be susceptible to pharmacologically induced increases in central NE and CORT levels. To specifically test this hypothesis, we measured amygdala activation to emotional faces using functional magnetic resonance imaging in 62 healthy subjects under four pharmacological conditions: (1) single oral dose of placebo, (2) 4 mg of the selective NE-reuptake inhibitor reboxetine (RBX), (3) 30 mg of hydrocortisone, or (4) both drugs in combination. We found that a decrease in amygdala activation to positive facial emotion was coupled with an increase in amygdala activation to negative facial emotion in the RBX-CORT combined challenge condition. In conclusion, a pharmacologically induced elevation of central NE and CORT levels in healthy subjects created a negative response bias in the amygdala that did not exist at baseline. Our results implicate a causative role of NE–CORT interactions in the emergence of a negative bias of cognitive and emotional functions which is germane in stress-related affective spectrum disorders.