Evidence for a compulsive-like behavior in rats exposed to alternate access to highly preferred palatable food.

Converging evidence suggests that recurrent excessive calorie restriction causes binge eating by promoting behavioral disinhibition and overeating. This interpretation suggests that cognitive adaptations may surpass physiological regulations of metabolic needs after recurrent cycles of dieting and binging. Intermittent access to palatable food has long been studied in rats, but the consequences of such diet cycling procedures on the cognitive control of food seeking remain unclear. Female Wistar rats were divided in two groups matched for food intake and body weight. One group received standard chow pellets 7 days/week, whereas the second group was given chow pellets for 5 days and palatable food for 2 days over seven consecutive weeks. Rats were also trained for operant conditioning. Intermittent access to palatable food elicited binging behavior and reduced intake of normal food. Rats with intermittent access to palatable food failed to exhibit anxiety-like behaviors in the elevated plus maze, but displayed reduced locomotor activity in the open field and developed a blunted corticosterone response following an acute stress across the diet procedure. Trained under a progressive ratio schedule, both groups exhibited the same motivation for sweetened food pellets. However, in contrast to controls, rats with a history of dieting and binging exhibited a persistent compulsive-like behavior when access to preferred pellets was paired with mild electrical foot shock punishments. These results highlight the intricate development of anxiety-like disorders and cognitive deficits leading to a loss of control over preferred food intake after repetitive cycles of intermittent access to palatable food.

A low-dose stimulation protocol using highly purified follicle-stimulating hormone can lead to high pregnancy rates in in vitro fertilization patients with polycystic ovaries who are at risk of a high ovarian response to gonadotropins.

OBJECTIVE: To study the benefits of a low-dose stimulation (LDS) protocol with purified urinary follicle-stimulating hormone in patients with polycystic ovaries who have presented previously with a very high ovarian response to a standard hMG stimulation. DESIGN: Cohort study. SETTING: Fertility center in a university hospital. PATIENT(S): Sixty-one patients involved in an IVF/ICSI program from January 1995 to December 1996. INTERVENTION(S): The patients were first stimulated with a standard protocol using hMG and presented with a very high ovarian response. These patients were then stimulated a second time using a low-dose protocol. Cryopreserved embryos were transferred in later artificial or natural cycles until to December 1999. MAIN OUTCOME MEASURE(S): Number of gonadotropin ampules; estradiol level on the day of ovulation induction; follicles, oocytes, and cryopreserved zygotes; fertilization, implantation, and pregnancy rates; and number of ovarian hyperstimulation syndromes (OHSS). RESULT(S): The number of ampules used, the estradiol level reached, and the number of oocytes obtained were significantly lower under the LDS than the standard protocol. High implantation (21.8%) and clinical pregnancy (38.4%) rates were obtained after LDS. The cumulated deliveries per cycle started and per patient were, respectively, 41.6% and 52.5%. Five patients suffered OHSS with the standard protocol, and none with the LDS. CONCLUSION(S): The LDS protocol offers a safe and efficient treatment for patients who present with echographic polycystic ovaries and are at risk of an excessive ovarian response to standard IVF stimulation protocols.

Gene loss and evolutionary rates following whole-genome duplication in teleost fishes.

Teleost fishes provide the first unambiguous support for ancient whole-genome duplication in an animal lineage. Studies in yeast or plants have shown that the effects of such duplications can be mediated by a complex pattern of gene retention and changes in evolutionary pressure. To explore such patterns in fishes, we have determined by phylogenetic analysis the evolutionary origin of 675 Tetraodon duplicated genes assigned to chromosomes, using additional data from other species of actinopterygian fishes. The subset of genes, which was retained in double after the genome duplication, is enriched in development, signaling, behavior, and regulation functional categories. The evolutionary rate of duplicate fish genes appears to be determined by 3 forces: 1) fish proteins evolve faster than mammalian orthologs; 2) the genes kept in double after genome duplication represent the subset under strongest purifying selection; and 3) following duplication, there is an asymmetric acceleration of evolutionary rate in one of the paralogs. These results show that similar mechanisms are at work in fishes as in yeast or plants and provide a framework for future investigation of the consequences of duplication in fishes and other animals.

Is adjuvant chemotherapy of benefit for postmenopausal women who receive endocrine treatment for highly endocrine-responsive, node-positive breast cancer? International Breast Cancer Study Group Trials VII and 12-93.

To compare the efficacy of chemoendocrine treatment with that of endocrine treatment (ET) alone for postmenopausal women with highly endocrine responsive breast cancer. In the International Breast Cancer Study Group (IBCSG) Trials VII and 12-93, postmenopausal women with node-positive, estrogen receptor (ER)-positive or ER-negative, operable breast cancer were randomized to receive either chemotherapy or endocrine therapy or combined chemoendocrine treatment. Results were analyzed overall in the cohort of 893 patients with endocrine-responsive disease, and according to prospectively defined categories of ER, age and nodal status. STEPP analyses assessed chemotherapy effect. The median follow-up was 13 years. Adding chemotherapy reduced the relative risk of a disease-free survival event by 19% (P = 0.02) compared with ET alone. STEPP analyses showed little effect of chemotherapy for tumors with high levels of ER expression (P = 0.07), or for the cohort with one positive node (P = 0.03). Chemotherapy significantly improves disease-free survival for postmenopausal women with endocrine-responsive breast cancer, but the magnitude of the effect is substantially attenuated if ER levels are high.

The activation process of the alpha1B-adrenergic receptor: potential role of protonation and hydrophobicity of a highly conserved aspartate.

In this study, a quantitative approach was used to investigate the role of D142, which belongs to the highly conserved E/DRY sequence, in the activation process of the alpha1B-adrenergic receptor (alpha1B-AR). Experimental and computer-simulated mutagenesis were performed by substituting all possible natural amino acids at the D142 site. The resulting congeneric set of proteins together with the finding that all the receptor mutants show various levels of constitutive (agonist-independent) activity enabled us to quantitatively analyze the relationships between structural/dynamic features and the extent of constitutive activity. Our results suggest that the hydrophobic/hydrophilic character of D142, which could be regulated by protonation/deprotonation of this residue, is an important modulator of the transition between the inactive (R) and active (R*) state of the alpha1B-AR. Our study represents an example of quantitative structure-activity relationship analysis of the activation process of a G protein-coupled receptor.

Mineralogical, K-Ar, stable and Sr isotope systematics of K-white micas during very low-grade metamorphism of limestones (Helvetic nappes, Western Switzerland)

Mineralogical, K-Ar, Rb-Sr and stable isotope analyses have been carried out on K-white micas from Helvetic Malm limestones in order to examine their evolution during very low- to low-grade Alpine metamorphism, associated with intense ductile deformation. Metamorphic temperatures were estimated al approximately 300-degrees-C from stable isotopes (quartz-calcite thermometry), occurrence of chloritoid, and `'epizonal'' illite crystallinity index. K-white micas consist of variable mixtures of 2M, phengite and muscovite, as revealed by detailed X-ray diffraction analyses using peak decomposition of the (060, 331) spectra. K-Ar apparent ages display a strong grain-size dependence in which mainly fine-grained size fractions (< 2 mum) record Alpine ages (37-15 Ma). However, these ages provide a relative rather than an absolute chronology of the diachronous Alpine metamorphic evolution of the Helvetic nappes. The resetting of the K-Ar isotopic system of K-white micas to Alpine metamorphic conditions reflects an apparent combination of crystallization/recrystallization and radiogenic Ar-40 diffusion loss. The oxygen isotope compositions of micas (+ 15 to + 22 parts per thousand) are intermediate between detrital and O-18-enriched values expected for micas neoformed within an abundant marine carbonate matrix. No isotopic equilibrium has been reached between calcite and micas. The variable depletion of hydrogen isotope compositions (- 126 to - 82 parts per thousand) is influenced by the interaction with organic matter under closed-system conditions. Organic matter, if not removed, may also represent a serious source of error in K-Ar age determination, by introducing radiogenic Ar-40 contamination. Sr-87/Sr-86 isotope ratios of micas range from 0.70879 to 0.70902 with one outlier at 0.71794. The low values reflect Sr exchange with calcite occurring during crystallization/recrystallization of micas under closed-system conditions.

Combination of MRI and dynamic FET PET for initial glioma grading.

AIM: MRI and PET with 18F-fluoro-ethyl-tyrosine (FET) have been increasingly used to evaluate patients with gliomas. Our purpose was to assess the additive value of MR spectroscopy (MRS), diffusion imaging and dynamic FET-PET for glioma grading. PATIENTS, METHODS: 38 patients (42 ± 15 aged, F/M: 0.46) with untreated histologically proven brain gliomas were included. All underwent conventional MRI, MRS, diffusion sequences, and FET-PET within 3±4 weeks. Performances of tumour FET time-activity-curve, early-to-middle SUVmax ratio, choline / creatine ratio and ADC histogram distribution pattern for gliomas grading were assessed, as compared to histology. Combination of these parameters and respective odds were also evaluated. RESULTS: Tumour time-activity-curve reached the best accuracy (67%) when taken alone to distinguish between low and high-grade gliomas, followed by ADC histogram analysis (65%). Combination of time-activity-curve and ADC histogram analysis improved the sensitivity from 67% to 86% and the specificity from 63-67% to 100% (p < 0.008). On multivariate logistic regression analysis, negative slope of the tumour FET time-activity-curve however remains the best predictor of high-grade glioma (odds 7.6, SE 6.8, p = 0.022). CONCLUSION: Combination of dynamic FET-PET and diffusion MRI reached good performance for gliomas grading. The use of FET-PET/MR may be highly relevant in the initial assessment of primary brain tumours.

Ecology and evolution of social-organization: insights from fire ants and other highly eusocial insects

Social organisms exhibit conspicuous intraspecific variation in all facets of their social organization. A prominent example of such variation in the highly eusocial Hymenoptera is differences in the number of reproductive queens per colony, Differences in queen number in ants are associated with differences in a host of reproductive and social traits, including queen phenotype and breeding strategy, mode of colony reproduction, and pattern of sex allocation. We examine the causes and consequences of changes in colony queen number and associated traits using the fire ant Solenopsis invicta as a principal model. Ecological constraints on mode of colony founding may act as important selective forces causing the evolution of queen number in this and many other ants, with social organization generally perpetuated across generations by means of the social environment molding appropriate queen phenotypes and reproductive strategies. Shifts in colony queen number have profound effects on genetic structure within nests and may also influence genetic structure at higher levels (aggregations of nests or local demes) because of the association of queen number with particular mating and dispersal habits. Divergence of breeding habits between populations with different social organizations has the potential to promote genetic differentiation between these social variants. Thus, evolution of social organization can be important in generating intrinsic selective regimes that channel subsequent social evolution and in initiating the development of significant population genetic structure, including barriers to gene flow important in cladogenesis.

The unfolded protein response: integrating stress signals through the stress sensor IRE1α.

Stress induced by accumulation of unfolded proteins at the endoplasmic reticulum (ER) is a classic feature of secretory cells and is observed in many tissues in human diseases including cancer, diabetes, obesity, and neurodegeneration. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that transmits information about the protein folding status at the ER to the nucleus and cytosol to restore ER homeostasis. Inositol-requiring transmembrane kinase/endonuclease-1 (IRE1α), the most conserved UPR stress sensor, functions as an endoribonuclease that processes the mRNA of the transcription factor X-box binding protein-1 (XBP1). IRE1α signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. Here we provide an overview of the signaling and regulatory mechanisms underlying IRE1α function and discuss the emerging role of the UPR in adaptation to protein folding stress in specialized secretory cells and in pathological conditions associated with alterations in ER homeostasis.

Restoration of anti-tetanus toxoid responses in patients initiating highly active antiretroviral therapy with or without a boost immunization: an INITIO substudy.

INITIO is an open-labelled randomized trial evaluating first-line therapeutic strategies for human immunodeficiency virus-1 (HIV-1) infection. In an immunology substudy a tetanus toxoid booster (TTB) immunization was planned for 24 weeks after initiation of highly active antiretroviral therapy (HAART). All patients had received tetanus toxoid immunization in childhood. Generation of proliferative responses to tetanus toxoid was compared in two groups of patients, those receiving a protease inhibitor (PI)-sparing regimen (n = 21) and those receiving a PI-containing (n = 54) regimen. Fifty-two participants received a TTB immunization [PI-sparing (n = 15), PI-containing (n = 37)] and 23 participants did not [PI-sparing (n = 6) or PI-containing (n = 17)]. Cellular responses to tetanus antigen were monitored by lymphoproliferation at time of immunization and every 24 weeks to week 156. Proportions with a positive response (defined as stimulation index > or = 3 and Delta counts per minute > or = 3000) were compared at weeks 96 and 156. All analyses were intent-to-treat. Fifty-two participants had a TTB immunization at median 25 weeks; 23 patients did not. At weeks 96 and 156 there was no evidence of a difference in tetanus-specific responses, between those with or without TTB immunization (P = 0.2, P = 0.4). There was no difference in the proportion with response between those with PI-sparing or PI-containing regimens at both time-points (P = 0.8, P = 0.7). The proliferative response to tetanus toxoid was unaffected by initial HAART regimen. Anti-tetanus responses appear to reconstitute eventually in most patients over 156 weeks when treated successfully with HAART, irrespective of whether or not a TTB immunization has been administered.

Cetuximab In Combination With Docetaxel In Patients (Pts) With Metastatic Castration Resistant (Mcrpc) And Docetaxel-Refractory Prostate Cancer: Final Analysis Of The Multicenter Phase Ii Trial Sakk 08/07

There is no registered treatment (ttr) for pts with mCRPC who have progressive disease during or shortly after docetaxel (doc). EGFR overexpression increases in prostate cancer during the course of the disease. We investigated efficacy and safety of the combination of the monoclonal EGFR antibody cetuximab (cet) and doc in pts with mCRPC who are doc-refractory. Methods: Pts with mCRPC progressing during or < 90 days after at least 12 weeks of doc were included. Ttr consisted of the same doc regimen as prior to progression (35mg/m2 d1,8,15 q4w or 75mg/m2 q3w) in combination with cet (400mg/m2 d1, then 250mg/m2 weekly). Primary endpoint was progression free survival (PFS) at 12 weeks defined as absence of PSA progression or progression of metastases (mets). Secondary endpoints included toxicity, PFS at 24 weeks, PSA response, response of measureable disease and overall survival. 35 pts were needed in a Simon's two stage optimal design with a power of 90% and a significance level of 5% in order to test PFS rate at 12 weeks of £10% vs ?30%. Results: 35 evaluable pts were enrolled at 15 Swiss centers between 7/08 and 9/09. Median follow up was 14.8 months. Confirmed PFS at 12 weeks was 34% (95%CI 19-52%), PFS at 24 weeks was 20% and overall survival was 12.0 months (95%CI 7.1 -15.6). 20% (7/35) had a confirmed decline in PSA ? 50% and 31% (11/35) had a confirmed PSA decline ? 30%. Of pts with measurable disease (n=24) PR, SD and PD at week 12 was 4%, 54% and 25%, respectively (17% not evaluable). 3/9 (33%) pts with PDduring last doc ttr before inclusion reached the primary endpoint compared to 7/18 (39%) with PR or SD to last doc. 54% of evaluable pts experienced grade 3 and 6% grade 4 toxicity. Discussion: The result of the primary endpoint was promising in this first trial to test cet in combination with doc in pts with docetaxel-refractory mCRPC. Because this goal was achieved in such a highly pretreated pts population it appears that inhibition of the EGFR pathway may play a more important and persistent role in the treatment of prostate cancer than perceived so far. Further research is therefore warranted. Disclosure: R. Cathomas: - Membership on advisory board for sanofi aventis (suisse) and Merck. S. Gillessen: - Membership in advisory board for Sanofi Aventis. All other authors have declared no conflicts of interest.

Closed and open grade I and II tibial shaft fractures treated by reamed intramedullary nailing.

OBJECTIVE: To evaluate the results of closed and open grade I and II tibial shaft fractures treated by reamed nail and unreamed nailing. SUBJECTS AND METHODS: Between 1997 and 2000, 119 patients with tibial shaft fractures were treated with reamed tibial nails. Postoperatively 96 patients (70 closed and 26 grade I and II open fractures) were followed clinically and radiologically for up to 18 months. The nail was inserted either by patellar tendon splitting or by nonsplitting technique. The nail was inserted after overreaming by 1.5 mm. Postoperatively, patients with isolated tibial fracture were mobilized by permitting partial weight bearing on the injured leg for 6 weeks. Patients with associated ankle fractures were allowed to walk with a Sarmiento cast. RESULTS: Postoperatively, 6 (6.3%) patients developed a compartment syndrome after surgery. In 48 (50%) cases, dynamization of the nail was carried out after a mean period of 12 weeks for delayed union. Overall, a 90.6% union was obtained at a mean of 24 weeks without difference between closed or open fractures. Two (2.1%) patients with an open grade II fracture developed a deep infection requiring treatment. A 9.4% rate of malunion was observed. Eight (8.3%) patients developed screw failure without clinical consequences. At the last follow-up, 52% of patients with patellar tendon splitting had anterior knee pain, compared to those (14%) who did not have tendon splitting. CONCLUSION: Reamed intramedullary nail is a suitable implant in treating closed as well as grade I and II open tibial shaft fractures.