Anatomical organization of the memory underlying sensitization in the siphon-withdrawal reflex circuit of {\it Aplysia californica}

Previous studies have shown that short-term sensitization of the Aplysia siphon-withdrawal reflex circuit results in multiple sites of change in synaptic efficacy. In this dissertation I have used a realistic modeling approach (using an integrate-and-fire scheme), in conjunction with electrophysiological experiments, to evaluate the contribution of each site of plasticity to the sensitized response.^ This dissertation contains a detailed description of methodology for the construction of the model circuit, consisting of the LFS motor neurons and ten interneurons known to convey excitatory input to them. The model replicates closely the natural motor neuron firing response to a brief tactile stimulus.^ The various circuit elements have different roles for producing circuit output. For example, the sensory connections onto the motor neuron are important for the production of the phasic response, while the polysynaptic interneuronal connections are important for producing the tonic response.^ The multiple sites of plasticity that produce changes in circuit output also have specialized roles. Presynaptic facilitation of the sensory neuron to LFS connection enhances only the phasic component of the motor neuron firing response. The sensory neuron to interneuron connections primarily enhance the tonic component of the motor neuron firing response. Also, the L29 posttetanic potentiation and the L30 presynaptic inhibition primarily enhance the tonic component of the motor neuron firing response. Finally, the information content at the various sites of plasticity can shift with changes in stimulus intensity. This suggests that while the sites of plasticity encoding memory are fixed, the information content at these sites can be dynamic, shifting in anatomical location with changes in the intensity of the test stimulus.^ These sites of plasticity also produce specific changes in the behavioral response. Sensory-LFS plasticity selectively increases the amplitude of the behavioral response, and has no effect on the duration of the behavioral response. Interneuronal plasticity (L29 and L30) affects both the amplitude and duration of the behavioral response. Other sensory plasticity also affect both the amplitude and duration of the behavioral response, presumably by increasing the recruitment of the interneurons, which provide all of the effect on duration of the behavioral response. ^

Antibiotic resistance genes in coagulase-negative staphylococci isolated from food

Coagulase-negative staphylococci were isolated from different raw milk cheeses and raw meat products and screened for their antibiotic resistances. They were identified as Staphylococcus xylosus, S. lentus, S. caprae, S. epidemidis and S. haemolyticus. The most frequent resistances found were those to chloramphenicol, tetracycline, erythromycin and lincomycin. They have been characterized on the molecular level. The chloramphenicol resistance genes were localized in several S. xylosus and S. caprae on plasmids with sizes ranging from 3.8-kb to 4.3-kb and were identified as chloramphenicol acetyltransferase (cat). All the tetracycline resistant strains were identified as S. xylosus and harboured a 4.4-kb plasmid carrying the tetracycline efflux resistance gene (tetK). The two erythromycin/lincomycin resistant S. caprae and S. epidermidis strains did not hybridize with the MLSB resistance genes ermAM, ermA, ermB and ermC. Three erythromycin resistant Staphylococcus sp. strains harboured an erythromycin efflux resistance gene (msr) localized twice on a 18-kb plasmid and once on the chromosome. A S. haemolyticus strain showing resistance to both lincomycin and clindamycin harboured a linA gene-carrying 2.2-kb plasmid. Further resistances to gentamicin, penicillin and kanamycin were less frequently observed and yet not characterized on a molecular level.

Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial

BACKGROUND The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting. Micrometastases are dependent on angiogenesis, suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting. We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer. METHODS For this open-label, randomised phase 3 trial we recruited patients with centrally confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries. We randomly allocated patients aged 18 years or older (1:1 with block randomisation; stratified by nodal status, chemotherapy [with an anthracycline, taxane, or both], hormone receptor status [negative vs low], and type of surgery) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab (equivalent of 5 mg/kg every week for 1 year). The primary endpoint was invasive disease-free survival (IDFS). Efficacy analyses were based on the intention-to-treat population, safety analyses were done on all patients who received at least one dose of study drug, and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample. This trial is registered with ClinicalTrials.gov, number NCT00528567. FINDINGS Between Dec 3, 2007, and March 8, 2010, we randomly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy. Most patients received anthracycline-containing therapy; 1638 (63%) of the 2591 patients had node-negative disease. At the time of analysis of IDFS, median follow-up was 31·5 months (IQR 25·6-36·8) in the chemotherapy-alone group and 32·0 months (27·5-36·9) in the bevacizumab group. At the time of the primary analysis, IDFS events had been reported in 205 patients (16%) in the chemotherapy-alone group and in 188 patients (14%) in the bevacizumab group (hazard ratio [HR] in stratified log-rank analysis 0·87, 95% CI 0·72-1·07; p=0·18). 3-year IDFS was 82·7% (95% CI 80·5-85·0) with chemotherapy alone and 83·7% (81·4-86·0) with bevacizumab and chemotherapy. After 200 deaths, no difference in overall survival was noted between the groups (HR 0·84, 95% CI 0·64-1·12; p=0·23). Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR-2 might benefit from the addition of bevacizumab (Cox interaction test p=0·029). Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension (154 patients [12%] vs eight patients [1%]), severe cardiac events occurring at any point during the 18-month safety reporting period (19 [1%] vs two [<0·5%]), and treatment discontinuation (bevacizumab, chemotherapy, or both; 256 [20%] vs 30 [2%]); we recorded no increase in fatal adverse events with bevacizumab (four [<0·5%] vs three [<0·5%]). INTERPRETATION Bevacizumab cannot be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer. Further follow-up is needed to assess the potential effect of bevacizumab on overall survival.

Raw as Archival Still Image Format: A Consideration

Source materials like fine art, over-sized, fragile maps, and delicate artifacts have traditionally been digitally converted through the use of controlled lighting and high resolution scanners and camera backs. In addition the capture of items such as general and special collections bound monographs has recently grown both through consortial efforts like the Internet Archive's Open Content Alliance and locally at the individual institution level. These projects, in turn, have introduced increasingly higher resolution consumer-grade digital single lens reflex cameras or "DSLRs" as a significant part of the general cultural heritage digital conversion workflow. Central to the authors' discussion is the fact that both camera backs and DSLRs commonly share the ability to capture native raw file formats. Because these formats include such advantages as access to an image's raw mosaic sensor data within their architecture, many institutions choose raw for initial capture due to its high bit-level and unprocessed nature. However to date these same raw formats, so important to many at the point of capture, have yet to be considered "archival" within most published still imaging standards, if they are considered at all. Throughout many workflows raw files are deleted and thrown away after more traditionally "archival" uncompressed TIFF or JPEG 2000 files have been derived downstream from their raw source formats [1][2]. As a result, the authors examine the nature of raw anew and consider the basic questions, Should raw files be retained? What might their role be? Might they in fact form a new archival format space? Included in the discussion is a survey of assorted raw file types and their attributes. Also addressed are various sustainability issues as they pertain to archival formats with a special emphasis on both raw's positive and negative characteristics as they apply to archival practices. Current common archival workflows versus possible raw-based ones are investigated as well. These comparisons are noted in the context of each approach's differing levels of usable captured image data, various preservation virtues, and the divergent ideas of strictly fixed renditions versus the potential for improved renditions over time. Special attention is given to the DNG raw format through a detailed inspection of a number of its various structural components and the roles that they play in the format's latest specification. Finally an evaluation is drawn of both proprietary raw formats in general and DNG in particular as possible alternative archival formats for still imaging.

Elderly age is not a negative predictive factor for virological response to therapy with pegylated interferon-α and ribavirin in chronic hepatitis C virus patients

BACKGROUND & AIMS: Age is frequently discussed as negative host factor to achieve a sustained virological response (SVR) to antiviral therapy of chronic hepatitis C. However, elderly patients often show advanced fibrosis/cirrhosis as known negative predictive factor. The aim of this study was to assess age as an independent predictive factor during antiviral therapy. METHODS: Overall, 516 hepatitis C patients were treated with pegylated interferon-α and ribavirin, thereof 66 patients ≥60 years. We analysed the impact of host factors (age, gender, fibrosis, haemoglobin, previous hepatitis C treatment) and viral factors (genotype, viral load) on SVR per therapy course by performing a generalized estimating equations (GEE) regression modelling, a matched pair analysis and a classification tree analysis. RESULTS: Overall, SVR per therapy course was 42.9 and 26.1%, respectively, in young and elderly patients with hepatitis C virus (HCV) genotypes 1/4/6. The corresponding figures for HCV genotypes 2/3 were 74.4 and 84%. In the GEE model, age had no significant influence on achieving SVR. In matched pair analysis, SVR was not different in young and elderly patients (54.2 and 55.9% respectively; P = 0.795 in binominal test). In classification tree analysis, age was not a relevant splitting variable. CONCLUSIONS: Age is not a significant predictive factor for achieving SVR, when relevant confounders are taken into account. As life expectancy in Western Europe at age 60 is more than 20 years, it is reasonable to treat chronic hepatitis C in selected elderly patients with relevant fibrosis or cirrhosis but without major concomitant diseases, as SVR improves survival and reduces carcinogenesis.

Negative bias of processing ambiguously cued emotional stimuli.

Daily we cope with upcoming potentially disadvantageous events. Therefore, it makes sense to be prepared for the worst case. Such a 'pessimistic' bias is reflected in brain activation during emotion processing. Healthy individuals underwent functional neuroimaging while viewing emotional stimuli that were earlier cued ambiguously or unambiguously concerning their emotional valence. Presentation of ambiguously announced pleasant pictures compared with unambiguously announced pleasant pictures resulted in increased activity in the ventrolateral prefrontal, premotor and temporal cortex, and in the caudate nucleus. This was not the case for the respective negative conditions. This indicates that pleasant stimuli after ambiguous cueing provided 'unexpected' emotional input, resulting in the adaptation of brain activity. It strengthens the hypothesis of a 'pessimistic' bias of brain activation toward ambiguous emotional events.

Accuracy of the withdrawal reflex for localization of the site of cervical disk herniation in dogs: 35 cases (2004-2007)

OBJECTIVE To evaluate the accuracy of neurologic examination versus magnetic resonance imaging (MRI) in localization of cervical disk herniation and evaluate the usefulness of withdrawal reflex testing in dogs. DESIGN Retrospective case series. ANIMALS 35 client-owned dogs with a single-level cervical disk herniation as determined via MRI. PROCEDURES 1 of 2 board-certified neurologists performed a complete neurologic examination in each dog. Clinical signs of a cervical lesion included evidence of neck pain and tetraparesis. The withdrawal reflex was used for neuroanatomic localization (C1-C5 or C6-T2). Agreement between results of neurologic and MRI examinations was determined. RESULTS Agreement between neurologic and MRI diagnoses was 65.8%. In 11 dogs in which the lesion was clinically localized to the C6-T2 segment on the basis of a decreased withdrawal reflex in the forelimbs, MRI revealed an isolated C1-C5 disk lesion. In 1 dog, in which the lesion was suspected to be at the C1-C5 level, MRI revealed a C6-T2 lesion. Cranial cervical lesions were significantly associated with an incorrect neurologic diagnosis regarding site of the lesion. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that the withdrawal reflex in dogs with cervical disk herniation is not reliable for determining the affected site and that a decreased withdrawal reflex does not always indicate a lesion from C6 to T2.

Negative density dependence of seed dispersal and seedling recruitment in a Neotropical palm

Negative density dependence (NDD) of recruitment is pervasive in tropical tree species. We tested the hypotheses that seed dispersal is NDD, due to intraspecific competition for dispersers, and that this contributes to NDD of recruitment. We compared dispersal in the palm Attalea butyracea across a wide range of population density on Barro Colorado Island in Panama and assessed its consequences for seed distributions. We found that frugivore visitation, seed removal and dispersal distance all declined with population density of A. butyracea, demonstrating NDD of seed dispersal due to competition for dispersers. Furthermore, as population density increased, the distances of seeds from the nearest adult decreased, conspecific seed crowding increased and seedling recruitment success decreased, all patterns expected under poorer dispersal. Unexpectedly, however, our analyses showed that NDD of dispersal did not contribute substantially to these changes in the quality of the seed distribution; patterns with population density were dominated by effects due solely to increasing adult and seed density.

Detection of RTX toxin genes in gram-negative bacteria with a set of specific probes

The family of RTX (RTX representing repeats in the structural toxin) toxins is composed of several protein toxins with a characteristic nonapeptide glycine-rich repeat motif. Most of its members were shown to have cytolytic activity. By comparing the genetic relationships of the RTX toxin genes we established a set of 10 gene probes to be used for screening as-yet-unknown RTX toxin genes in bacterial species. The probes include parts of apxIA, apxIIA, and apxIIIA from Actinobacillus pleuropneumoniae, cyaA from Bordetella pertusis, frpA from Neisseria meningitidis, prtC from Erwinia chrysanthemi, hlyA and elyA from Escherichia coli, aaltA from Actinobacillus actinomycetemcomitans and lktA from Pasteurella haemolytica. A panel of pathogenic and nonpathogenic gram-negative bacteria were investigated for the presence of RTX toxin genes. The probes detected all known genes for RTX toxins. Moreover, we found potential RTX toxin genes in several pathogenic bacterial species for which no such toxins are known yet. This indicates that RTX or RTX-like toxins are widely distributed among pathogenic gram-negative bacteria. The probes generated by PCR and the hybridization method were optimized to allow broad-range screening for RTX toxin genes in one step. This included the binding of unlabelled probes to a nylon filter and subsequent hybridization of the filter with labelled genomic DNA of the strain to be tested. The method constitutes a powerful tool for the assessment of the potential pathogenicity of poorly characterized strains intended to be used in biotechnological applications. Moreover, it is useful for the detection of already-known or new RTX toxin genes in bacteria of medical importance.