Septal lesions impair the acquisition of a cued place navigation task: attentional or memory deficit?

These experiments were designed to analyze how medial septal lesions reducing the cholinergic innervation in the hippocampus might affect place learning. Rats with quisqualic lesions of the medial septal area (MS) were trained in a water maze and on a homing table where the escape position was located at a spatially fixed position and further indicated by a salient cue suspended above it. The lesioned rats were significantly impaired in reaching the cued escape platform during training. In addition rats, did not show any discrimination of the training sector during a probe trial in which no platform or cue was present. This impairment remained significant during further training in the absence of the cue. When the cued escape platform was located at an unpredictable spatial location, the MS-lesioned rats showed no deficit and spent more time under the cue than control rats during the probe trial. On the homing board, with a salient object in close proximity to the escape hole, the MS rats showed no deficit in escape latencies, although a significant reduction in spatial memory was observed. However, this was overcome by additional training in the absence of the cue. Under these conditions, rats with septal lesions were prone to develop a pure guidance strategy, whereas normal rats combined a guidance strategy with a memory of the escape position relative to more distant landmarks. The presence of a salient cue appeared to decrease attention to environmental landmarks, thus reducing spatial memory. These data confirm the general hypothesis that MS lesions reduce the capacity to rely on a representation of the relation between several landmarks with different salience.

Concurrent or sequential adjuvant letrozole and radiotherapy after conservative surgery for early-stage breast cancer (CO-HO-RT): a phase 2 randomised trial.

BACKGROUND: Letrozole radiosensitises breast cancer cells in vitro. In clinical settings, no data exist for the combination of letrozole and radiotherapy. We assessed concurrent and sequential radiotherapy and letrozole in the adjuvant setting. METHODS: This phase 2 randomised trial was undertaken in two centres in France and one in Switzerland between Jan 12, 2005, and Feb 21, 2007. 150 postmenopausal women with early-stage breast cancer were randomly assigned after conserving surgery to either concurrent radiotherapy and letrozole (n=75) or sequential radiotherapy and letrozole (n=75). Randomisation was open label with a minimisation technique, stratified by investigational centres, chemotherapy (yes vs no), radiation boost (yes vs no), and value of radiation-induced lymphocyte apoptosis (< or = 16% vs >16%). Whole breast was irradiated to a total dose of 50 Gy in 25 fractions over 5 weeks. In the case of supraclavicular and internal mammary node irradiation, the dose was 44-50 Gy. Letrozole was administered orally once daily at a dose of 2.5 mg for 5 years (beginning 3 weeks pre-radiotherapy in the concomitant group, and 3 weeks post-radiotherapy in the sequential group). The primary endpoint was the occurrence of acute (during and within 6 weeks of radiotherapy) and late (within 2 years) radiation-induced grade 2 or worse toxic effects of the skin. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00208273. FINDINGS: All patients were analysed apart from one in the concurrent group who withdrew consent before any treatment. During radiotherapy and within the first 12 weeks after radiotherapy, 31 patients in the concurrent group and 31 in the sequential group had any grade 2 or worse skin-related toxicity. The most common skin-related adverse event was dermatitis: four patients in the concurrent group and six in the sequential group had grade 3 acute skin dermatitis during radiotherapy. At a median follow-up of 26 months (range 3-40), two patients in each group had grade 2 or worse late effects (both radiation-induced subcutaneous fibrosis). INTERPRETATION: Letrozole can be safely delivered shortly after surgery and concomitantly with radiotherapy. Long-term follow-up is needed to investigate cardiac side-effects and cancer-specific outcomes. FUNDING: Novartis Oncology France.

Quality of Learners' Time and Learning Performance Beyond Quantitative Time-on-Task

Peer-reviewed

JPEG standard uniform quantization error modeling with applications to sequential and progressive operation modes

In this paper we propose a method for computing JPEG quantization matrices for a given mean square error or PSNR. Then, we employ our method to compute JPEG standard progressive operation mode definition scripts using a quantization approach. Therefore, it is no longer necessary to use a trial and error procedure to obtain a desired PSNR and/or definition script, reducing cost. Firstly, we establish a relationship between a Laplacian source and its uniform quantization error. We apply this model to the coefficients obtained in the discrete cosine transform stage of the JPEG standard. Then, an image may be compressed using the JPEG standard under a global MSE (or PSNR) constraint and a set of local constraints determined by the JPEG standard and visual criteria. Secondly, we study the JPEG standard progressive operation mode from a quantization based approach. A relationship between the measured image quality at a given stage of the coding process and a quantization matrix is found. Thus, the definition script construction problem can be reduced to a quantization problem. Simulations show that our method generates better quantization matrices than the classical method based on scaling the JPEG default quantization matrix. The estimation of PSNR has usually an error smaller than 1 dB. This figure decreases for high PSNR values. Definition scripts may be generated avoiding an excessive number of stages and removing small stages that do not contribute during the decoding process with a noticeable image quality improvement.

Concurrent or Sequential Adjuvant Letrozole and Radiotherapy after Conservative Surgery for Early-stage Breast Cancer: Long-term Results of the Cohort Phase 2 Randomized Trial

Purpose/Objective(s): Letrozole radiosensitizes breast cancer cells in vitro. In clinical settings, no data exist for the combination of letrozole and radiotherapy. We assessed concurrent and sequential radiotherapy and letrozole in the adjuvant setting.Materials/Methods: The present study is registered with ClinicalTrials.gov, number NCT00208273. This Phase 2 randomized trial was undertaken in two centers in France and one in Switzerland between January 12, 2005, and February 21, 2007. One hundred fifty postmenopausal women with early-stage breast cancer were randomly assigned after conserving surgery to either concurrent radiotherapy and letrozole (n = 75) or sequential radiotherapy and letrozole (n = 75). Randomization was open label with a minimization technique, stratified by investigational centers, chemotherapy (yes vs. no), radiation boost (yes vs. no), and value of radiation-induced lymphocyte apoptosis (#16% vs. .16%). The whole breast was irradiated to a total dose of 50 Gy in 25 fractions over 5 weeks. In the case of supraclavicular and internal mammary node irradiation, the dose was 44 - 50 Gy. Letrozole was administered orally once daily at a dose of 2 - 5 mg for 5 years (beginning 3 weeks pre-radiotherapy in the concomitant group, and 3 weeks postradiotherapy in the sequential group). The primary endpoint was the occurrence of acute (during and within 6 weeks of radiotherapy) and late (within 2 years) radiation-induced Grade 2 or worse toxic effects of the skin and lung (functional pulmonary test and lung CT-scan). Analyses were by intention-to-treat. The long-term follow-up after 2 years was only performed in Montpellier (n = 121) and evaluated skin toxicity (clinical examination every 6 months), lung fibrosis (one CT-scan yearly), cosmetic outcome.Results: All patients were analyzed apart from 1 in the concurrent group who withdrew consent before any treatment.Within the first 2 years (n = 149), no lung toxicity was identified by CT scan and no modification from baseline was noted by the lung diffusion capacity test. Two patients in each group had Grade 2 or worse late effects (both radiation-induced subcutaneous fibrosis [RISF]). After 2 years (n = 121), and with a median follow-up of 50 months (38-62), 2 patients (1 in each arm) presented a Grade 3 RISF. No lung toxicity was identified by CT scan. Cosmetic results (photographies) and quality of life was good to excellent. All patients who had Grade 3 subcutaneous fibrosis had an RILA value of 16% or less, irrespective of the sequence with letrozole.Conclusions:With long-term follow-up, letrozole can be safely delivered shortly after surgery and concomitantly with radiotherapy.

Effects of preset sequential administrations of sunitinib and everolimus on tumour differentiation in Caki-1 renal cell carcinoma.

BACKGROUND: Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are both approved for advanced renal cell carcinoma (RCC) as first-line and second-line therapy, respectively. In the clinics, sunitinib treatment is limited by the emergence of acquired resistance, leading to a switch to second-line treatment at progression, often based on everolimus. No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression. Such strategy is expected to delay the emergence of acquired resistance and improve tumour control. The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus. METHODS: In human Caki-1 RCC xenograft model, sunitinib was alternated with everolimus every week, every 2 weeks, or every 3 weeks. Effects on necrosis, hypoxia, angiogenesis, and EMT status were assessed by immunohisochemistry and immunofluorescence. RESULTS: Sunitinib and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies. In each group of treatment, tumour growth control was associated with inhibition of mTOR pathway and changes from a mesenchymal towards an epithelial phenotype, with a decrease in vimentin and an increase in E-cadherin expression. The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects, leading to tumour necrosis. CONCLUSIONS: In summary, our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent.

Can resistance to trastuzumab be reversed by endocrine therapy? Combination of trastuzumab and letrozole after resistance to sequential trastuzumab and aromatase inhibitor monotherapies in patients with ER-positive, HER-2 positive, advanced breast cancer: a proof-of-concept trial (SAKK 23/03)

Introduction: Trastuzumab (T) is a cornerstone in the treatment of patients with HER2-overexpressing advanced breast cancer and development of resistance to T is a major therapeutic problem. HER-2 is part of a highly interactive signaling network that may impair efficacy of endocrine therapy. A sequential treatment design was chosen in this trial to ensure complete resistance to single agent therapy before receiving both a non-steroidal aromatase inhibitor (AI) and T. Any kind of clinical activity with combined treatment of AI and T after progression of single agent treatments could indicate restoration of sensitivity as a consequence of cross-talking and networking between both pathways. Methods: Key eligibility criteria included postmenopausal patients (pts.) with advanced, measurable, HER-2 positive (assessed by FISH, ratio (≥2)), HR positive disease and progression on prior treatment with a non-steroidal AI, e.g. letrozole or anastrozole, either in an adjuvant or advanced setting. Pts. received standard dose T monotherapy either weekly or three-weekly in step 1 and upon disease progression, continued T in combination with letrozole in step 2. The primary endpoint was clinical benefit response (CBR: CR, PR or SD for at least 24 weeks (+/- 1 week) according to RECIST) in step 2. Results: Thirteen pts. were enrolled in five centers in Switzerland. In step 1, six pts. (46%) achieved CBR. Median time to progression (TTP) was 161 days (Range: 50 - 627). Based on data collected until the end of May 2010, CBR was observed in seven out of the eleven evaluable pts. (64%) in step 2, including one pt. with partial response. Four of the seven pts. within step 2 that achieved CBR also had CBR in step 1. Seven out of eleven pts. have documented tumor progression during step 2 treatment. Median TTP for all eleven pts. was 184 days (range 61 - 471). Mean time on study treatment (TTP in step 1 plus TTP in step 2) for pts. reaching step 2 was 380 days (range 174 - 864). Adverse events were generally mild. Conclusion: Results of this proof-of-principle trial suggest that complete resistance to both AI and T can be overcome in a proportion of pts. by combined treatment of AI and T, as all pts. served as their own control. Our results appear promising for a new treatment strategy which offers a chemotherapy-free and well-tolerated option for at least a subset of the pts. with HR positive, HER-2 positive breast cancer. Further trials will need to corroborate this finding.

Therapeutisches Drug-Monitoring in der Psychiatrie : Kurze Zusammenfassung des neuen Konsensuspapiers der Arbeitsgruppe TDM der AGNP [Therapeutic drug monitoring in psychiatry : A brief summary of the new consensus paper by the task force on TDM of the AGNP].

In October 2011 the Task Force Therapeutic Drug Monitoring of the Association for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) published an update (Pharmacopsychiatry 2011, 44: 195-235) of the first version of the consensus paper on therapeutic drug monitoring (TDM) published in 2004. This article summarizes the essential statements to make them accessible to a wider readership in German speaking countries.

Task Support in Scenario Process: Case LUT 2016

This thesis attempts to find whether scenario planning supports the organizational strategy as a method for addressing uncertainty. The main issues are why, what and how scenario planning fits in organizational strategy and how the process could be supported to make it more effective. The study follows the constructive approach. It starts with examination of competitive advantage and the way that an organization develops strategy and how it addresses the uncertainty in its operational environment. Based on the conducted literature review, scenario methods would seem to provide versatile platform for addressing future uncertainties. The construction is formed by examining the scenario methods and presenting suitable support methods, which results in forming of the theoretical proposition for supporter scenario process. The theoretical framework is tested in laboratory conditions, and the results from the test sessions are used a basis for scenario stories. The process of forming the scenarios and the results are illustrated and presented for scrutiny

Adaptive changes in a radial maze task: Efficient selection of baited arms with reduced foraging in senescent hooded rats

Qualitative differences in strategy selection during foraging in a partially baited maze were assessed in young and old rats. The baited and non-baited arms were at a fixed position in space and marked by a specific olfactory cue. The senescent rats did more re-entries during the first four-trial block but were more rapid than the young rats in selecting the reinforced arms during the first visits. Dissociation between the olfactory spatial cue reference by rotating the maze revealed that only few old subjects relied on olfactory cues to select the baited arms and the remainder relied mainly on the visuo-spatial cues.

A Sequential Allocation Problem: The Asymptotic Distribution of Resources

In this paper we consider a sequential allocation problem with n individuals. The first individual can consume any amount of some endowment leaving the remaining for the second individual, and so on. Motivated by the limitations associated with the cooperative or non-cooperative solutions we propose a new approach. We establish some axioms that should be satisfied, representativeness, impartiality, etc. The result is a unique asymptotic allocation rule. It is shown for n = 2; 3; 4; and a claim is made for general n. We show that it satisfies a set of desirable properties. Key words: Sequential allocation rule, River sharing problem, Cooperative and non-cooperative games, Dictator and ultimatum games. JEL classification: C79, D63, D74.