bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomised evaluation of CollAborative care and active surveillance for Screen-Positive EldeRs with sub-threshold depression (CASPER): study protocol for a randomized controlled trial
Authors: Mitchell Natasha , Hewitt Catherine , Adamson Joy , Parrott Steve , Torgerson David , Ekers David , Holmes John , Lester Helen , McMillan Dean , Richards David , Spilsbury Karen , Godfrey Christine , Gilbody Simon
Published: October 2011

Background

Depression accounts for the greatest burden of disease among all mental health problems, and is expected to become the second-highest amongst all general health problems by 2020. By the age of 75, 1 in 7 older people meet formal diagnostic criteria for depression. Efforts to ameliorate the burden of illness and personal suffering associated with depression in older people have focussed on those with more severe depressive syndromes. Less attention has been paid to those with mild disorders/sub-threshold depressive syndromes but these patients also suffer impairments in their quality of life and level of functioning.

Methods/Design

The CASPER study has been designed to assemble an epidemiological cohort of people over 75 years of age (the CASPER cohort), from which we will identify those eligible to participate in a trial of collaborative care for sub-threshold depression (the CASPER trial).

We aim to undertake a pragmatic randomised controlled multi-centre trial evaluating the effectiveness and cost-effectiveness of collaborative care; a low intensity psychological intervention in addition to usual general practitioner care versus usual general practitioner care alone. General practitioners from practices based in the North of England will be asked to identify potentially eligible patients over the age of 75 years. Patients will be sent a letter inviting them to participate in the study.

We aim to recruit approximately 540 participants for the CASPER trial. A diagnostic interview will be carried out to ascertain trial eligibility with the major depressive episode module of the Mini International Neuropsychiatric Interview (M.I.N.I.), eligible participants randomised to either the intervention or usual care. The primary outcome will be measured with the Patient Health Questionnaire-9 (PHQ-9) and additional quality of life measures will be collected. Data will be collected at baseline, 4 and 12 months for both trial and cohort participants.

Trial Registration

ISRCTN: ISRCTN02202951
Type I vs type II spiral ganglion neurons exhibit differential survival and neuritogenesis during cochlear development
Authors: Barclay Meagan , Ryan Allen F , Housley Gary D
Published: October 2011

Background

The mechanisms that consolidate neural circuitry are a major focus of neuroscience. In the mammalian cochlea, the refinement of spiral ganglion neuron (SGN) innervation to the inner hair cells (by type I SGNs) and the outer hair cells (by type II SGNs) is accompanied by a 25% loss of SGNs.

Results

We investigated the segregation of neuronal loss in the mouse cochlea using β-tubulin and peripherin antisera to immunolabel all SGNs and selectively type II SGNs, respectively, and discovered that it is the type II SGN population that is predominately lost within the first postnatal week. Developmental neuronal loss has been attributed to the decline in neurotrophin expression by the target hair cells during this period, so we next examined survival of SGN sub-populations using tissue culture of the mid apex-mid turn region of neonatal mouse cochleae. In organotypic culture for 48 hours from postnatal day 1, endogenous trophic support from the organ of Corti proved sufficient to maintain all type II SGNs; however, a large proportion of type I SGNs were lost. Culture of the spiral ganglion as an explant, with removal of the organ of Corti, led to loss of the majority of both SGN sub-types. Brain-derived neurotrophic factor (BDNF) added as a supplement to the media rescued a significant proportion of the SGNs, particularly the type II SGNs, which also showed increased neuritogenesis. The known decline in BDNF production by the rodent sensory epithelium after birth is therefore a likely mediator of type II neuron apoptosis.

Conclusion

Our study thus indicates that BDNF supply from the organ of Corti supports consolidation of type II innervation in the neonatal mouse cochlea. In contrast, type I SGNs likely rely on additional sources for trophic support.
Fragment of tegument protein pp65 of human cytomegalovirus induces autoantibodies in BALB/c mice
Authors: Hsieh Ao-Ho , Jhou Yí-Jyun , Liang Chung-Ting , Chang Mingi , Wang Shih-Lien
Published: October 2011

Introduction

Human cytomegalovirus (HCMV) infection has been implicated in the development of autoimmunity, including systemic lupus erythematosus (SLE). Previously we reported that HCMV phosphoprotein 65 (pp65) could induce early onset of autoantibody and glomerulonephritis on lupus-prone NZB/W mice. This study further examined whether the B cell epitope(s) in pp65 is able to drive the development of autoantibody.

Methods

Sera from SLE patients or HCMVpp65-immunized mice were analyzed for anti-nuclear antibody by immunoblotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescent stain and Crithidia luciliae stain. The deposition of immunoglobulin to the kidney was also examined by immunofluorescent stain. The interactions between pp65 sub-fragment to cellular proteins were revealed by yeast two-hybrid analyses.

Results

Our results showed that most SLE patients possessed antibodies to the C-terminal half of the HCMVpp65 antigen. Of these positive sera, 73% were also positive to the pp65336-439 sub-fragment. The immunization of pp65336-439 induced formation of multiple anti-nuclear antibodies, including anti-chromatin, anti-centriole, anti-mitotic spindle type I/II (MSA I/II) and a significant elevation of anti-double-stranded DNA (anti-dsDNA) antibodies on BALB/c mice. Yeast two-hybrid analyses revealed the binding of pp65336-439 sub-fragment to cellular proteins. Immunoglobulin deposition on glomeruli was also detected on pp65336-439-immunized mice.

Conclusions

Our data suggested that HCMVpp65336-439 sub-fragment may induce cross-reactive antibodies to several nuclear antigens, which could contribute to the development of autoimmunity in genetic-suspected individuals.
Long-Term Reactions to Genetic Testing forBRCA1andBRCA2Mutations: Does Time Heal Women's Concerns?
Authors: Halbert Chanita Hughes , Stopfer Jill E. , McDonald Jasmine , Weathers Benita , Collier Aliya , Troxel Andrea B. , Domchek Susan
Published: October 2011

Purpose

Short-term reactions to BRCA1 and BRCA2 (BRCA1/2) genetic test results have been described in several reports, but the long-terms effects of testing have not been examined extensively.

Methods

We conducted an observational study to characterize the long-term impact of genetic testing for BRCA1/2 mutations in 167 women who had received genetic test results at least 4 years ago. We also evaluated the relationship between genetic testing–specific reactions and breast and ovarian cancer screening to determine the behavioral significance of adverse reactions.

Results

Seventy-four percent of women were not experiencing any distress regarding their test result, 41% were not experiencing any uncertainty, and 51% had a score for positive experiences that was suggestive of low levels of adverse reactions in terms of family support and communication. Mutation carriers (odds ratio, 3.96; 95% CI, 1.44 to 10.89; P = .01) were most likely to experience distress. Only less time since disclosure was related significantly to experiencing uncertainty (odds ratio, 0.62; 95% CI, 0.44 to 0.88; P = .008). In terms of cancer screening, 81% of women had a mammogram during the year before study enrollment, 25% had magnetic resonance imaging (MRI), 20% had a transvaginal ultrasound, and 20% had a CA-125. Experiencing distress was associated significantly with having a CA-125 (χ2= 3.89, P = .05), and uncertainty was associated with having an MRI (χ2= 8.90, P = .003).

Conclusion

Our findings show that women are not likely to experience genetic testing concerns several years after receiving BRCA1/2 test results; distress and uncertainty are not likely to have adverse effects on screening among women at risk for hereditary disease.
Eight Cycles of Escalated-Dose BEACOPP Compared With Four Cycles of Escalated-Dose BEACOPP Followed by Four Cycles of Baseline-Dose BEACOPP With or Without Radiotherapy in Patients With Advanced-Stage Hodgkin's Lymphoma: Final Analysis of the HD12 Trial of the German Hodgkin Study Group
Authors: Borchmann Peter , Haverkamp Heinz , Diehl Volker , Cerny Thomas , Markova Jana , Ho Anthony D. , Eich Hans-Theodor , Mueller-Hermelink Hans Konrad , Kanz Lothar , Greil Richard , Rank Andreas , Paulus Ursula , Smardova Lenka , Huber Christoph , Dörken Bernd , Nerl Christoph , Krause Stefan W. , Mueller Rolf-Peter , Fuchs Michael , Engert Andreas
Published: October 2011

Purpose

Eight cycles of BEACOPPescalated (escalated dose of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by radiotherapy (RT) to initial bulk or residual tumor mass is the German Hodgkin Study Group standard of care for advanced-stage Hodgkin's lymphoma (HL). However, treatment-related toxicity is a concern, and the role of RT in this setting is unclear. The HD12 study thus aimed to reduce toxicity while maintaining efficacy.

Patients and Methods

In this prospectively randomized multicenter trial, eight cycles of BEACOPPescalated was compared with four cycles of BEACOPPescalated followed by four cycles of the baseline dose of BEACOPP (BEACOPPbaseline; 4 + 4), and RT with no RT in the case of initial bulk or residual disease. The study was designed to exclude a difference in 5-year freedom from treatment failure (FFTF) rate of 6%.

Results

Between January 1999 and January 2003, 1,670 patients age 16 to 65 years were enrolled onto the HD12 study. At 5 years, FFTF was 86.4% in the BEACOPPescalated arm and 84.8% in the 4 + 4 arm (difference, −1.6%; 95% CI, −5.2% to 1.9%), and overall survival was 92% versus 90.3% (difference, −1.7%; 95% CI, −4.6% to 1.1%). Deaths related to acute toxicity of chemotherapy were observed in 2.9% of patients (BEACOPPescalated, n = 19; 4 + 4, n = 27). FFTF was inferior without RT (90.4% v 87%; difference, −3.4%; 95% CI, −6.6% to −0.1%), particularly in patients who had residual disease after chemotherapy (difference, −5.8%; 95% CI, −10.7% to −1.0%), but not in patients with bulk in complete response after chemotherapy (difference, −1.1%; 95% CI, −6.2% to 4%).

Conclusion

The reduction of BEACOPP to the 4 + 4 regimen did not substantially reduce severe toxicity but might decrease efficacy. Our results do not support the omission of consolidation RT for patients with residual disease. Alternative strategies for improving the risk-to-benefit ratio for patients with advanced HL are needed.
RIBBON-2: A Randomized, Double-Blind, Placebo-Controlled, Phase III Trial Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy for Second-Line Treatment of Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer
Authors: Brufsky Adam M. , Hurvitz Sara , Perez Edith , Swamy Raji , Valero Vicente , O'Neill Vincent , Rugo Hope S.
Published: October 2011

Purpose

This phase III study compared the efficacy and safety of bevacizumab combined with standard chemotherapy regimens versus chemotherapy alone as second-line treatment of patients with human epidermal growth factor receptor 2 (HER2) –negative metastatic breast cancer.

Patients and Methods

Patients were randomly assigned 2:1 to chemotherapy + bevacizumab or to chemotherapy + placebo. Before random assignment, investigators chose capecitabine, a taxane (paclitaxel, nab-paclitaxel, or docetaxel), gemcitabine, or vinorelbine. Dosing for bevacizumab or placebo was 15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks, depending on chemotherapy regimen. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, PFS by chemotherapy cohort, objective response rate (ORR), duration of objective response, 1-year survival rate, and safety.

Results

RIBBON-2 enrolled 684 patients (225, chemotherapy + placebo; 459, chemotherapy + bevacizumab). The combination of bevacizumab with chemotherapy demonstrated a statistically significant benefit. Median PFS increased from 5.1 to 7.2 months (stratified hazard ratio for PFS, 0.78; 95% CI, 0.64 to 0.93; P = .0072). The 10% improvement in ORR between the placebo- and bevacizumab-containing arms (39.5% v 29.6%; P = .0193), although not statistically significant, was consistent with previous trials. There was no statistically significant difference in overall survival. The most common grade ≥ 3 adverse events (AEs) related to bevacizumab treatment were hypertension (9.0%) and proteinuria (3.1%). There was an increased number of AEs leading to study discontinuation in the chemotherapy + bevacizumab arm compared with the chemotherapy + placebo arm (13.3% v 7.2%).

Conclusion

The combination of bevacizumab with commonly used chemotherapies improved PFS in the second-line treatment of patients with HER2-negative metastatic breast cancer, with a safety profile comparable with that in prior phase III studies.
Sensitive Detection of BCR-ABL1 Mutations in Patients With Chronic Myeloid Leukemia After Imatinib Resistance Is Predictive of Outcome During Subsequent Therapy
Authors: Parker Wendy T. , Lawrence Rebecca M. , Ho Musei , Irwin Darryl L. , Scott Hamish S. , Hughes Timothy P. , Branford Susan
Published: October 2011

Purpose

BCR-ABL1 mutation analysis is recommended to facilitate selection of appropriate therapy for patients with chronic myeloid leukemia after treatment with imatinib has failed, since some frequently occurring mutations confer clinical resistance to nilotinib and/or dasatinib. However, mutations could be present below the detection limit of conventional direct sequencing. We developed a sensitive, multiplexed mass spectrometry assay (detection limit, 0.05% to 0.5%) to determine the impact of low-level mutations after imatinib treatment has failed.

Patients and Methods

Mutation status was assessed in 220 patients treated with nilotinib or dasatinib after they experienced resistance to imatinib.

Results

Mutations were detected by sequencing in 128 patients before commencing nilotinib or dasatinib therapy (switchover). In 64 patients, 132 additional low-level mutations were detected by mass spectrometry alone (50 of 132 mutations were resistant to nilotinib and/or dasatinib). When patients received the inhibitor for which the mutation confers resistance, 84% of the low-level resistant mutations rapidly became dominant clones detectable by sequencing, including 11 of 12 T315I mutations. Subsequent complete cytogenetic response rates were lower for patients with resistant mutations at switchover detected by sequencing (0%) or mass spectrometry alone (16%) compared with patients with other mutations or no mutations (41% and 49%, respectively; P < .001). Failure-free survival among the 100 patients with chronic phase chronic myeloid leukemia when resistant mutations were detected at switchover by sequencing or mass spectrometry alone was 0% and 0% compared with 51% and 45% for patients with other mutations or no mutations (P = .003).

Conclusion

Detection of low-level mutations after imatinib resistance offers critical information to guide subsequent therapy selection. If an inappropriate kinase inhibitor is selected, there is a high risk of treatment failure with clonal expansion of the resistant mutant.
Randomized, Placebo-Controlled Phase III Study of Docetaxel Plus Carboplatin With Celecoxib and Cyclooxygenase-2 Expression As a Biomarker for Patients With Advanced Non–Small-Cell Lung Cancer: The NVALT-4 Study
Authors: Groen Harry J.M. , Sietsma Hannie , Vincent Andrew , Hochstenbag Monique M.H. , van Putten John W.G. , van den Berg Anke , Dalesio Otilia , Biesma Bonne , Smit Hans J.M. , Termeer Ariën , Hiltermann T. Jeroen N. , van den Borne Ben E.E.M. , Schramel Franz M.N.H.
Published: October 2011

Purpose

Cyclooxygenase-2 (COX-2) protein expression in patients with non–small-cell lung cancer (NSCLC) may be not only a prognostic marker but also predictive for COX-2 inhibition. We hypothesized that COX-2 expression is associated with shorter survival and that celecoxib, being a potent COX-2 inhibitor, increases tumor response and survival.

Patients and Methods

A phase III study was performed in patients with stage IIIb/IV NSCLC who had pathologic confirmation, no prior chemotherapy, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function. Treatment consisted of docetaxel and carboplatin every 3 weeks for five cycles. Patients were randomly assigned to receive celecoxib 400 mg or placebo twice daily. COX-2 expression on tumor cells was detected by immunohistochemistry. Primary end point was overall survival (OS).

Results

From July 2003 to December 2007, 561 patients were randomly assigned. Toxicity was mild, and no increase in cardiovascular events was observed. Tumor response was 38% in the celecoxib arm and 30% in the placebo arm (P = .08). Median progression-free survival was 4.5 months (95% CI, 4.0 to 4.8) for the celecoxib arm and 4.0 months (95% CI, 3.6 to 4.9) for the placebo arm (hazard ratio [HR], 0.8; 95% CI, 0.6 to 1.1; P = .25). Median OS was 8.2 months (95% CI, 7.5 to 8.8) for both treatment arms (HR, 0.9; 95% CI, 0.6 to 1.2; P = .32). COX-2 expression did not independently predict survival. Benefit from celecoxib, restricted to patients with low COX-2 expression, was not significant when adjusted for prognostic factors.

Conclusion

In advanced NSCLC, celecoxib does not improve survival. In this study, COX-2 expression was not a prognostic biomarker and had no predictive value when celecoxib was added to chemotherapy.
Endocrine Characterization of the Designer Steroid Methyl-1-Testosterone: Investigations on Tissue-Specific Anabolic-Androgenic Potency, Side Effects, and Metabolism
Authors: Parr Maria K. , Blatt Christina , Zierau Oliver , Hess Cornelius , Gütschow Michael , Fusshöller Gregor , Opfermann Georg , Schänzer Wilhelm , Diel Patrick
Published: October 2011

Various products containing rarely characterized anabolic steroids are nowadays marketed as dietary supplements. Herein, the designer steroid methyl-1-testosterone (M1T) (17β-hydroxy-17α-methyl-5α-androst-1-en-3-one) was identified, and its biological activity, potential adverse effects, and metabolism were investigated. The affinity of M1T toward the androgen receptor (AR) was tested in vitro using a yeast AR transactivation assay. Its tissue-specific androgenic and anabolic potency and potential adverse effects were studied in a Hershberger assay (sc or oral), and tissue weights and selected molecular markers were investigated. Determination of M1T and its metabolites was performed by gas chromatography mass spectrometry. In the yeast AR transactivation assay, M1T was characterized as potent androgen. In rats, M1T dose-dependently stimulated prostate and levator ani muscle weight after sc administration. Oral administration had no effect but stimulated proliferation in the prostate and modulated IGF-I and AR expression in the gastrocnemius muscle in a dose-dependent manner. Analysis of tyrosine aminotransferase expression provided evidence for a strong activity of M1T in the liver (much higher after oral administration). In rat urine, 17α-methyl-5α-androstane-3α,17β-diol, M1T, and a hydroxylated metabolite were identified. In humans, M1T was confirmed in urine in addition to its main metabolites 17α-methyl-5α-androst-1-ene-3α,17β-diol and 17α-methyl-5α-androstane-3α,17β-diol. Additionally, the corresponding 17-epimers as well as 17β-hydroxymethyl-17α-methyl-18-nor-5α-androsta-1,13-dien-3-one and its 17-epimer were detected, and their elimination kinetics was monitored. It was demonstrated that M1T is a potent androgenic and anabolic steroid after oral and sc administration. Obviously, this substance shows no selective AR modulator characteristics and might exhibit liver toxicity, especially after oral administration.
Na(+)/H(+) Exchanger Regulatory Factor 1 (NHERF1) Is Required for the Estradiol-Dependent Increase of Phosphatase and Tensin Homolog (PTEN) Protein Expression
Authors: Yang Longyan , Wang Ying , Chen Peng , Hu Jia , Xiong Ying , Feng Duiping , Liu Hua , Zhang Hong , Yang Hui , He Junqi
Published: October 2011

Expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) can be induced by estrogens at the posttranscriptional level. However, the molecular mechanism of the process is unclear. In this study, we found that the C terminus (CT) of PTEN is indispensable for 17-β-estradiol (E2)-increased PTEN expression. Therefore, we screened for PTEN-CT-associated proteins using a glutathione-S-transferase pull-down approach in combination with mass spectrometry-based proteomic analyses. Our experiments led to the identification of Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) as a major PTEN-CT binding partner. The first postsynaptic density protein-95/Discslarge/zonula occludens-1 homology domain of NHERF1 and the last four amino acids of PTEN were found to be key determinants of this interaction. By associating with PTEN, NHERF1 could enhance PTEN protein expression by retention of PTEN turnover, as demonstrated by NHERF1 overexpression and small interfering RNA-mediated knockdown experiments, respectively. Furthermore, NHERF1 inhibited ubiquitination of the PTEN protein upon competition with binding of PTEN to neural precursor cell expressed, developmentally down-regulated 4, an ubiquitin E3 ligase. E2 strongly induced the expression of NHERF1 and PTEN only in estrogen receptor (ER)-positive cells but not in ER-negative cells. ICI182780, an ER-specific inhibitor, decreased the expression of both NHERF1 and PTEN, and ICI182780 pretreatment also retarded E2-increased PTEN expression in ER-MDA-MB-231 cells. In both ER-MDA-MB-231 and MCF-7 cells, E2 failed to increase PTEN expression when NHERF1 was knocked down. Taken together, these are the first results that present a possible mechanism for E2-increased PTEN expression. In this process, E2 first induces NHERF1 expression by activating the ER. Upon competition with neural precursor cell expressed, developmentally down-regulated 4, NHERF1 then interacts with PTEN to inhibit PTEN degradation, through an ubiquitination-dependent pathway. This in turn leads to the increase of PTEN expression at the protein level.
Elevated GH/IGF-I, Due to Somatotrope-Specific Loss of Both IGF-I and Insulin Receptors, Alters Glucose Homeostasis and Insulin Sensitivity in a Diet-Dependent Manner
Authors: Gahete Manuel D. , Córdoba-Chacón José , Anadumaka Chike V. , Lin Qing , Brüning Jens C. , Kahn C. Ronald , Luque Raúl M. , Kineman Rhonda D.
Published: October 2011

A unique mouse model was developed with elevated endogenous GH (2- to 3-fold) and IGF-I (1.2- to 1.4-fold), due to somatotrope-specific Cre-mediated inactivation of IGF-I receptor (IgfIr) and insulin receptor (Insr) genes (IgfIr,InsrrGHpCre, referred to as HiGH mice). We demonstrate that the metabolic phenotype of HiGH mice is diet dependent and differs from that observed in other mouse models of GH excess due to ectopic heterologous transgene expression or pituitary tumor formation. Elevated endogenous GH promotes lean mass and whole-body lipid oxidation but has minimal effects on adiposity, even in response to diet-induced obesity. When caloric intake is moderated, elevated GH improves glucose clearance, despite low/normal insulin sensitivity, which may be explained in part by enhanced IGF-I and insulin output. However, when caloric intake is in excess, elevated GH promotes hepatic lipid accumulation, insulin resistance, hyperglycemia, and ketosis. The HiGH mouse model represents a useful tool to study the role endogenous circulating GH levels play in regulating health and disease.
Low metabolism in a tropical bat from lowland Panama measured using heart rate telemetry: an unexpected life in the slow lane
Authors: Dechmann Dina K. N. , Ehret Severin , Gaub Aline , Kranstauber Bart , Wikelski Martin
Published: October 2011

Animals must optimize their daily energy budgets, particularly if energy expenditures are as high as they are in flying animals. However, energy budgets of free-ranging tropical animals are poorly known. Newly miniaturized heart rate transmitters enabled this to be addressed this in the small, energetically limited, neotropical bat Molossus molossus. High-resolution 48 h energy budgets showed that this species significantly lowers its metabolism on a daily basis, even though ambient temperatures remain high. Mean roosting heart rate was 144 beats min–1, much lower than expected for a 10 g bat. Low roosting heart rates combined with short nightly foraging times (37 min night–1) resulted in an estimated energy consumption of 4.08 kJ day–1, less than one-quarter of the predicted field metabolic rate. Our results indicate that future research may reveal this as a more common pattern than currently assumed in tropical animals, which may have implications in the context of the effect of even small temperature changes on tropical species.
Vocal control by the common marmoset in the presence of interfering noise
Authors: Roy Sabyasachi , Miller Cory T. , Gottsch Dane , Wang Xiaoqin
Published: October 2011

The natural environment is inherently noisy with acoustic interferences. It is, therefore, beneficial for a species to modify its vocal production to effectively communicate in the presence of interfering noises. Non-human primates have been traditionally considered to possess limited voluntary vocal control, but little is known about their ability to modify vocal behavior when encountering interfering noises. Here we tested the ability of the common marmoset (Callithrix jacchus) to control the initiation of vocalizations and maintain vocal interactions between pairs in an acoustic environment in which the length and predictability (periodic or random aperiodic occurrences) of interfering noise bursts were varied. Despite the presence of interfering noise, the marmosets continued to engage in antiphonal calling behavior. Results showed that the overwhelming majority of calls were initiated during silence gaps even when the length of the silence gap following each noise burst was unpredictable. During the periodic noise conditions, as the length of the silence gap decreased, the latency between the end of noise burst and call onset decreased significantly. In contrast, when presented with aperiodic noise bursts, the marmosets chose to call predominantly during long (4 and 8 s) over short (2 s) silence gaps. In the 8 s periodic noise conditions, a marmoset pair either initiated both calls of an antiphonal exchange within the same silence gap or exchanged calls in two consecutive silence gaps. Our findings provide compelling evidence that common marmosets are capable of modifying their vocal production according to the dynamics of their acoustic environment during vocal communication.
Identification and functional characterization of an ovarian aquaporin from the cockroachBlattella germanicaL. (Dictyoptera, Blattellidae)
Authors: Herraiz Alba , Chauvigné François , Cerdà Joan , Bellés Xavier , Piulachs Maria-Dolors
Published: October 2011

Aquaporins (AQPs) are membrane proteins that form water channels, allowing rapid movement of water across cell membranes. AQPs have been reported in species of all life kingdoms and in almost all tissues, but little is known about them in insects. Our purpose was to explore the occurrence of AQPs in the ovary of the phylogenetically basal insect Blattella germanica (L.) and to study their possible role in fluid homeostasis during oogenesis. We isolated an ovarian AQP from B. germanica (BgAQP) that has a deduced amino acid sequence showing six potential transmembrane domains, two NPA motifs and an ar/R constriction region, which are typical features of the AQP family. Phylogenetic analyses indicated that BgAQP belongs to the PRIP group of insect AQPs, previously suggested to be water specific. However, ectopic expression of BgAQP in Xenopus laevis oocytes demonstrated that this AQP transports water and modest amounts of urea, but not glycerol, which suggests that the PRIP group of insect AQPs may have heterogeneous solute preferences. BgAQP was shown to be highly expressed in the ovary, followed by the fat body and muscle tissues, but water stress did not significantly modify the ovarian expression levels. RNA interference (RNAi) reduced BgAQP mRNA levels in the ovary but the oocytes developed normally. The absence of an apparent ovarian phenotype after BgAQP RNAi suggests that other functionally redundant AQPs that were not silenced in our experiments might exist in the ovary of B. germanica.
Spring phenology does not affect timing of reproduction in the great tit (Parus major)
Authors: Schaper Sonja V. , Rueda Carolina , Sharp Peter J. , Dawson Alistair , Visser Marcel E.
Published: October 2011

Many seasonal breeders adjust the timing of reproduction in response to year-to-year variations in supplementary environmental cues, amongst which ambient temperature is thought to be most influential. However, it is possible that for species such as the great tit (Parus major L.), phenological cues from sprouting vegetation and the consequent abundance of invertebrate prey, although dependent on temperature, may provide supplementary environmental cues per se. This hypothesis was investigated in breeding pairs of great tits kept in outdoor aviaries. In spring, experimental pairs were provided with access to leafing birch branches and caterpillars as a visual food cue, while control pairs were provided with non-leafing branches. Observations were made on the onset of laying and on concentrations of plasma luteinizing hormone (LH) at regular intervals to monitor changes in reproductive function. The onset of egg laying was not advanced by the presence of leafing branches and caterpillars. LH concentrations increased during the course of the study, but phenological cues did not affect plasma LH levels in females and males. Early spring vegetation, such as the leafing of birch branches, and the appearance of caterpillar prey do not appear to play a significant role in fine-tuning the onset of egg laying in great tits.
Increased plant volatile production affects oviposition, but not larval development, in the moth Helicoverpa armigera
Authors: McCallum Emily J. , Cunningham John Paul , Lücker Joost , Zalucki Myron P. , De Voss James J. , Botella José R.
Published: October 2011

It is well established that herbivorous insects respond to changes in plant odour production, but little attention has been given to whether these responses relate to direct fitness costs of plant volatile production on insect growth and survival. Here, we use transgenic Nicotiana tabacum (tobacco) plants that produce relatively large amounts of the volatile (S)-linalool to study whether the responses of egg-laying herbivorous insects to linalool production relate directly to the growth and survival of offspring. In choice tests, fewer eggs were laid on transgenic plants compared with non-transformed controls, indicating that increased linalool emissions have a deterrent effect on Helicoverpa armigera oviposition. Larval survival and larval mass after feeding on transgenic leaves, however, was comparable to non-transformed controls. (S)-linalool, whether in volatile or sequestered form, does not appear to have a direct effect on offspring fitness in this moth. We discuss how the ecology of this polyphagous moth species may necessitate a high tolerance for certain volatiles and their related non-volatile compounds, and suggest that responses by adult female H. armigera moths towards increased linalool production may be context specific and relate to other indirect effects on fitness.
From population-level effects to individual response: modelling temperature dependence in Gammarus pulex
Authors: Moenickes Sylvia , Schneider Anne-Kathrin , Mühle Lesley , Rohe Lena , Richter Otto , Suhling Frank
Published: October 2011

Population-level effects of global warming result from concurrent direct and indirect processes. They are typically described by physiologically structured population models (PSPMs). Therefore, inverse modelling offers a tool to identify parameters of individual physiological processes through population-level data analysis, e.g. the temperature dependence of growth from size–frequency data of a field population. Here, we make use of experiments under laboratory conditions, in mesocosms and field monitoring to determine the temperature dependence of growth and mortality of Gammarus pulex. We found an optimum temperature for growth of approximately 17°C and a related temperature coefficient, Q10, of 1.5°C–1, irrespective of whether we classically fitted individual growth curves or applied inverse modelling based on PSPMs to laboratory data. From a comparison of underlying data sets we conclude that applying inverse modelling techniques to population-level data results in meaningful response parameters for physiological processes if additional temperature-driven effects, including within-population interaction, can be excluded or determined independently. If this is not the case, parameter estimates describe a cumulative response, e.g. comprising temperature-dependent resource dynamics. Finally, fluctuating temperatures in natural habitats increased the uncertainty in parameter values. Here, PSPM should be applied for virtual monitoring in order to determine a sampling scheme that comprises important dates to reduce parameter uncertainty.
Impact of a Multidisciplinary Team Review of Potential Outpatient Parenteral Antimicrobial Therapy Prior to Discharge from an Academic Medical Center
Authors: Heintz Brett H , Halilovic Jenana , Christensen Cinda L
Published: October 2011

Background::

Outpatient parenteral antimicrobial therapy (OPAT) is frequently prescribed at hospital discharge, often without infectious diseases (ID) clinician oversight. We developed a multidisciplinary team, including an ID pharmacist, to review OPAT care plans at hospital discharge to improve safety, clinical efficacy, practicality, and appropriateness of the proposed antimicrobial regimen.

Objective:

To evaluate the impact of the OPAT team on regimen safety, efficacy, and complexity; calculate the economic benefits of the service by avoiding hospital discharge delay, central venous catheter placement, or need for OPAT; and evaluate the discharge environment among OPAT referrals.

Methods:

In an observational design, we analyzed the impact of an OPAT team from July 2009 through June 2010 at a large academic tertiary care hospital. All patients with plans for continued parenteral therapy after discharge referred to the OPAT team were included in the analysis. Patients were excluded if OPAT was cancelled prior to processing of the referral.

Results:

During the 1-year study period. 569 of 644 consecutive referrals to the OPAT team met inclusion criteria, resulting in 494 OPAT courses. Interventions by an ID pharmacist were made for safety (56%), regimen complexity (41%), and efficacy (29%). Lack of formal ID physician consultation resulted in more interventions for safety (64% vs 48%, p < 0.001) and efficacy (36% vs 21%, p < 0.001). Discharge delays were avoided for 35 referrals, resulting in 228 hospital days avoided and approximately $366,000 in hospital bed cost savings. Use of OPAT was avoided in 75 referrals (13.2%), preventing central venous catheter placement in 48 patients (8.4%), resulting in an additional $58,080 in cost savings.

Conclusions:

The OPAT team optimized safety, efficacy, and convenience of OPAT while providing substantial cost savings. Further studies are needed to confirm the program's cost-effectiveness.
Moxifloxacin as an Alternative or Additive Therapy for Treatment of Pulmonary Tuberculosis
Authors: Fouad Mohamed , Gallagher Jason C
Published: October 2011

Objective:

To evaluate clinical studies on the role of moxifloxacin in the treatment of pulmonary tuberculosis (TB).

Data Sources:

A literature search was conducted using MEDLINE (1960-July 2011). Key search terms were moxifloxacin, BAY 12-8039, fluoroquinolones, and TB. References of review articles and of a Cochrane Review were also evaluated.

Study Selection and Data Extraction:

All articles published in English were evaluated. Prospective studies that evaluated the use of moxifloxacin in addition to or in substitution for first-line TB therapies were reviewed and included. Case series and retrospective studies were excluded.

Data Synthesis:

Four 8-week clinical trials were included. All had comparator regimens containing standard doses of rifampin, isoniazid, ethambutol, and pyrazinamide. Two evaluated the substitution of moxifloxacin for ethambutol, 1 evaluated the substitution of moxifloxacin for isoniazid, and 1 studied the addition of moxifloxacin to a standard regimen. The dose of moxifloxacin was 400 mg daily in all studies, but dosing frequency differed from 3 to 7 days per week. All used culture conversion at 8 weeks as the primary end point, although they coliected cultures at different times. Only 1 study found a significant difference in time to culture conversion at 8 weeks. One study found no significant difference at any point during the study. The other 2 studies found a significant difference in time to culture conversion at 4 and 6 weeks. In all trials, moxifloxacin was well tolerated, with nausea being the only significant adverse effect reported compared to the other arms of the studies.

Conclusions:

Although it cannot be stated definitively, available evidence suggests that moxifloxacin appears to be as effective as ethambutol and is possibly as effective as isoniazid In the treatment of pulmonary TB. Given the generally poor second-line options for the treatment of TB, moxifloxacin Is an attractive option as an alternative drug in TB treatment.
Classical Conditioning Analog Enhanced Acetylcholine Responses But Reduced Excitability of an Identified Neuron
Authors: Lorenzetti Fred D. , Baxter Douglas A. , Byrne John H.
Published: October 2011

Although classical and operant conditioning are operationally distinct, it is unclear whether these two forms of learning are mechanistically distinct or similar. Feeding behavior ofAplysiaprovides a useful model system for addressing this issue. Both classical and operant appetitive behavioral training enhance feeding, and neuronal correlates have been identified. Behavioral training was replicated byin vitroanalogs that use isolated ganglia. Moreover, a single-cell analog of operant conditioning was developed using neuron B51, a cell important for the expression of the conditioned behavior. Here, a single-cell analog of classical conditioning was developed. Acetylcholine (ACh) mediated the conditioned stimulus (CS)-elicited excitation of B51 in ganglia and mimicked the CS in the single-cell analog of classical conditioning. Pairing ACh with dopamine, which mediates the unconditioned stimulus in ganglia, decreased the excitability of B51, and increased the CS-elicited excitation of B51, similar to results following bothin vivoandin vitroclassical training. Finally, a D1dopamine receptor (D1R) agonist failed to support classical conditioning in the cellular analog, whereas D1R mediates reinforcement in operant conditioning.
Action Potential Generation at an Axon Initial Segment-Like Process in the Axonless Retinal AII Amacrine Cell
Authors: Wu Chaowen , Ivanova Elena , Cui Jinjuan , Lu Qi , Pan Zhuo-Hua
Published: October 2011

In axon-bearing neurons, action potentials conventionally initiate at the axon initial segment (AIS) and are important for neuron excitability and cell-to-cell communication. However in axonless neurons, spike origin has remained unclear. Here we report in the axonless, spiking AII amacrine cell of the mouse retina a dendritic process sharing organizational and functional similarities with the AIS. This process was revealed through viral-mediated expression of channelrhodopsin-2-GFP with the AIS-targeting motif of sodium channels (NavII-III). The AII processes showed clustering of voltage-gated Na+channel 1.1 (Nav1.1) as well as AIS markers ankyrin-G and neurofascin. Furthermore, NavII-III targeting disrupted Nav1.1 clustering in the AII process, which drastically decreased Na+current and abolished the ability of the AII amacrine cell to generate spiking. Our findings indicate that, despite lacking an axon, spiking in the axonless neuron can originate at a specialized AIS-like process.
The Residence Time of GABAARs at Inhibitory Synapses Is Determined by Direct Binding of the Receptor α1 Subunit to Gephyrin
Authors: Mukherjee Jayanta , Kretschmannova Karla , Gouzer Geraldine , Maric Hans-Michael , Ramsden Sarah , Tretter Verena , Harvey Kirsten , Davies Paul A. , Triller Antoine , Schindelin Hermann , Moss Stephen J.
Published: October 2011

The majority of fast synaptic inhibition in the brain is mediated by benzodiazepine-sensitive α1-subunit-containing GABA type A receptors (GABAARs); however, our knowledge of the mechanisms neurons use to regulate their synaptic accumulation is rudimentary. Using immunoprecipitation, we demonstrate that GABAARs and gephyrin are intimately associated at inhibitory synapses in cultured rat neurons.In vitrowe reveal that the E-domain of gephyrin directly binds to the α1 subunit with an affinity of ∼20 μm, mediated by residues 360–375 within the intracellular domain of this receptor subunit. Mutating residues 360–375 decreases both the accumulation of α1-containing GABAARs at gephyrin-positive inhibitory synapses in hippocampal neurons and the amplitude of mIPSCs. We also demonstrate that the affinity of gephyrin for the α1 subunit is modulated by Thr375, a putative phosphorylation site. Mutation of Thr375 to a phosphomimetic, negatively charged amino acid decreases both the affinity of the α1 subunit for gephyrin, and therefore receptor accumulation at synapses, and the amplitude of mIPSCs. Finally, single-particle tracking reveals that gephyrin reduces the diffusion of α1-subunit-containing GABAARs specifically at inhibitory synapses, thereby increasing their confinement at these structures. Our results suggest that the direct binding of gephyrin to residues 360–375 of the α1 subunit and its modulation are likely to be important determinants for the stabilization of GABAARs at synaptic sites, thereby modulating the strength of synaptic inhibition.
A Perimotor Framework Reveals Functional Segmentation in the Motoneuronal Network Controlling Locomotion inCaenorhabditis elegans
Authors: Haspel Gal , O'Donovan Michael J.
Published: October 2011

The neuronal connectivity dataset of the nematodeCaenorhabditis elegansattracts wide attention from computational neuroscientists and experimentalists. However, the dataset is incomplete. The ventral and dorsal nerve cords of a single nematode were reconstructed halfway along the body and the posterior data are missing, leaving 21 of 75 motoneurons of the locomotor network with partial or no connectivity data. Using a new framework for network analysis, the perimotor space, we identified rules of connectivity that allowed us to approximate the missing data by extrapolation. Motoneurons were mapped into perimotor space in which each motoneuron is located according to the muscle cells it innervates. In this framework, a pattern of iterative connections emerges which includes most (0.90) of the connections. We identified a repeating unit consisting of 12 motoneurons and 12 muscle cells. The cell bodies of the motoneurons of such a unit are not necessarily anatomical neighbors and there is no obvious anatomical segmentation. A connectivity model, composed of six repeating units, is a description of the network that is both simplified (modular and without noniterative connections) and more complete (includes the posterior part) than the original dataset. The perimotor framework of observed connectivity and the segmented connectivity model give insights and advance the study of the neuronal infrastructure underlying locomotion inC. elegans. Furthermore, we suggest that the tools used herein may be useful to interpret, simplify, and represent connectivity data of other motor systems.
Comparing Apples and Oranges: Using Reward-Specific and Reward-General Subjective Value Representation in the Brain
Authors: Levy Dino J. , Glimcher Paul W.
Published: October 2011

The ability of human subjects to choose between disparate kinds of rewards suggests that the neural circuits for valuing different reward types must converge. Economic theory suggests that these convergence points represent the subjective values (SVs) of different reward types on a common scale for comparison. To examine these hypotheses and to map the neural circuits for reward valuation we had food and water-deprived subjects make risky choices for money, food, and water both in and out of a brain scanner. We found that risk preferences across reward types were highly correlated; the level of risk aversion an individual showed when choosing among monetary lotteries predicted their risk aversion toward food and water. We also found that partially distinct neural networks represent the SVs of monetary and food rewards and that these distinct networks showed specific convergence points. The hypothalamic region mainly represented the SV for food, and the posterior cingulate cortex mainly represented the SV for money. In both the ventromedial prefrontal cortex (vmPFC) and striatum there was a common area representing the SV of both reward types, but only the vmPFC significantly represented the SVs of money and food on a common scale appropriate for choice in our data set. A correlation analysis demonstrated interactions across money and food valuation areas and the common areas in the vmPFC and striatum. This may suggest that partially distinct valuation networks for different reward types converge on a unified valuation network, which enables a direct comparison between different reward types and hence guides valuation and choice.
Explaining Left Lateralization for Words in the Ventral Occipitotemporal Cortex
Authors: Seghier Mohamed L. , Price Cathy J.
Published: October 2011

Reading is a uniquely human task and therefore any sign of neuronal activation that is specific to reading is of considerable interest. One intriguing observation is that ventral occipitotemporal (vOT) activation is more strongly left lateralized for written words than other visual stimuli. This has contributed to claims that left vOT plays a special role in reading. Here, we investigated whether left lateralized vOT responses for words were the consequence of visual feature processing, visual word form selectivity, or higher level language processing. Using fMRI in 82 skilled readers, our paradigm compared activation and lateralization for words and nonlinguistic stimuli during different tasks. We found that increased left lateralization for words relative to pictures was the consequence of reduced activation in right vOT rather than increased activation in left vOT. We also found that the determinants of lateralization varied with the subregion of vOT tested. In posterior vOT, lateralization depended on the spatial frequency of the visual inputs. In anterior vOT, lateralization depended on the semantic demands of the task. In middle vOT, lateralization depended on a combination of visual expertise in the right hemisphere and semantics in the left hemisphere. These results have implications for interpreting left lateralized vOT activation during reading. Specifically, left lateralized activation in vOT does not necessarily indicate an increase in left vOT processing but is instead a consequence of decreased right vOT function. Moreover, the determinants of lateralization include both visual and semantic factors depending on the subregion tested.