Knockdown of zif268 in the posterior dorsolateral striatum does not enduringly disrupt a response memory of a rewarded T-maze task

Under certain conditions pavlovian memories undergo reconsolidation, whereby the reactivated memory can be disrupted by manipulations such as knockdown of zif268. For instrumental memories, reconsolidation disruption is less well established. Our previous, preliminary data identified that there was an increase in Zif268 in the posterior dorsolateral striatum (pDLS) after expression of an instrumental habit-like ‘response’ memory, but not an instrumental goal-directed ‘place’ memory on a T-maze task. Here, the requirement for Zif268 in the reconsolidation of a response memory was tested by knockdown of Zif268, using antisense oligodeoxynucleotide infusion into the pDLS, at memory reactivation. Zif268 knockdown reduced response memory expression 72H, but not 7d later. Western blotting revealed a non-significant increase in Zif268 in the pDLS in rats using response memories, but there was no change in Zif268 expression in the hippocampus following retrieval of a place memory. Zif268 expression increased in the basolateral amygdala after memory reactivation whether a response or place strategy was used during reactivation. We propose that Zif268 expression in the basolateral amygdala may be linked to prediction error, generated by the absence of reward at reactivation. Taken together, these results suggest a complex role for Zif268 in the maintenance of instrumental memories.This work was conducted within the Behavioural and Clinical Neuroscience Institute (BCNI), a joint initiative funded by the Wellcome Trust and the UK Medical Research Council, in the Department of Psychology at the University of Cambridge. This work was funded by a UK Medical Research Council programme grant (no. G1002231) awarded to B.J.E. and A.L.M. G.H.V. was supported by a doctoral training grant from the BCNI. A.L.M. is the Ferreras-Willetts Fellow in Neuroscience at Downing College, Cambridge. E.N.C is a BBSRC Anniversary Future Leaders Fellow

Admission to acute care hospitals for adolescent substance abuse: a national descriptive analysis

BACKGROUND: Use of alcohol and illicit drugs by adolescents remains a problem in the U.S. Case identification and early treatment can occur within a broad variety of healthcare and non-healthcare settings, including acute care hospitals. The objective of this study is to describe the extent and nature of adolescent admissions to the acute inpatient setting for substance abuse (SA). We use the Agency for Healthcare Research and Quality (AHRQ) 2000 Healthcare Cost and Utilization Project Kids Inpatient Database (HCUP-KID) which includes over 2.5 million admissions for youth age 20 and under to 2,784 hospitals in 27 states in the year 2000. Specifically, this analysis estimates national number of admissions, mean total charges, and mean lengths of stay for adolescents between the ages of 12 and 17 admitted to an acute care hospital for the following diagnostic categories from the AHRQ's Clinical Classifications Software categories: "alcohol-related mental disorders" and "substance-related mental disorders". Frequency and percentage of total admissions were calculated for demographic variables of age, gender and income and for hospital characteristic variables of urban/rural designation and children's hospital designation. RESULTS: SA admissions represented 1.25 percent of adolescent admissions to acute care hospitals. Nearly 90 percent of the admission occurred in non-Children's hospitals. Most were for drug dependence (38%) or non-dependent use of alcohol or drugs (35%). Costs were highest for drug dependence admissions. Nearly half of admissions had comorbid mental health diagnoses. Higher rates of admission were seen in boys, in older adolescents, and in "self-pay" patients. Alcohol and drug rehabilitation/detoxification, alone or in combination with psychological and psychiatric evaluation and therapy, was documented for 38 percent of admissions. Over 50 percent of cases had no documentation of treatment specific to substance use behavior. CONCLUSION: General acute care hospitals have a significant and important opportunity to recognize, treat, and refer adolescents with substance abuse problems. These results suggest that inpatient facilities should develop and implement policies and processes to ensure that adolescent substance abusers admitted to their institutions receive appropriate care during the admission and appropriate referral to community care resources

The Way to a Man's Heart Is through His Stomach: What about Horses?

International audienceBACKGROUND: How do we bond to one another? While in some species, like humans, physical contact plays a role in the process of attachment, it has been suggested that tactile contact's value may greatly differ according to the species considered. Nevertheless, grooming is often considered as a pleasurable experience for domestic animals, even though scientific data is lacking. On another hand, food seems to be involved in the creation of most relationships in a variety of species. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we used the horse training context to test the effects of food versus grooming during repeated human-horse interactions. The results reveal that food certainly holds a key role in the attachment process, while tactile contact was here clearly insufficient for bonding to occur. CONCLUSION/SIGNIFICANCE: This study raises important questions on the way tactile contact is perceived, and shows that large inter-species differences are to be expected

Rapid Global Expansion of Invertebrate Fisheries: Trends, Drivers, and Ecosystem Effects

BACKGROUND: Worldwide, finfish fisheries are receiving increasing assessment and regulation, slowly leading to more sustainable exploitation and rebuilding. In their wake, invertebrate fisheries are rapidly expanding with little scientific scrutiny despite increasing socio-economic importance. METHODS AND FINDINGS: We provide the first global evaluation of the trends, drivers, and population and ecosystem consequences of invertebrate fisheries based on a global catch database in combination with taxa-specific reviews. We also develop new methodologies to quantify temporal and spatial trends in resource status and fishery development. Since 1950, global invertebrate catches have increased 6-fold with 1.5 times more countries fishing and double the taxa reported. By 2004, 34% of invertebrate fisheries were over-exploited, collapsed, or closed. New fisheries have developed increasingly rapidly, with a decrease of 6 years (3 years) in time to peak from the 1950s to 1990s. Moreover, some fisheries have expanded further and further away from their driving market, encompassing a global fishery by the 1990s. 71% of taxa (53% of catches) are harvested with habitat-destructive gear, and many provide important ecosystem functions including habitat, filtration, and grazing. CONCLUSIONS: Our findings suggest that invertebrate species, which form an important component of the basis of marine food webs, are increasingly exploited with limited stock and ecosystem-impact assessments, and enhanced management attention is needed to avoid negative consequences for ocean ecosystems and human well-being

Predicting Weight Outcomes in Preadolescence: The Role of Toddlers? Self-regulation Skills and the Temperament Dimension of Pleasure

Objective To investigate the role of toddlers? self-regulation skills and temperament in predicting weight outcomes in preadolescence. Method Participants for this study included 195 children (114 girls) obtained from three different cohorts participating in a larger ongoing longitudinal study. At 2 years of age, participants participated in several laboratory tasks designed to assess their self-regulation abilities, including emotion regulation, sustained attention, and delay of gratification, while parents filled out a temperament questionnaire to assess toddlers? pleasure expression. Height and weight measures were collected when children were 4, 5, 7, and 10 years of age. Children also filled out a body image and eating questionnaire at the 10 year visit. Results Self-regulation skills in toddlers were associated with both BMI development, pediatric obesity, and body image/eating concerns. The temperament dimension of pleasure was also associated with BMI development and pediatric obesity but not body image/eating concerns. Conclusion Self-regulation difficulties across domains as well as temperament based pleasure in toddlers represented significant individual risk factors for the development of pediatric obesity eight years later. Early self-regulation difficulties also contributed to body image and eating concerns that typically accompanied overweight children. The mechanisms by which early self-regulation skills and temperament based pleasure may contribute to the development of pediatric obesity and associated weight concerns are discussed

Timing Constraints of In Vivo Gag Mutations during Primary HIV-1 Subtype C Infection

Background: Aiming to answer the broad question “When does mutation occur?” this study examined the time of appearance, dominance, and completeness of in vivo Gag mutations in primary HIV-1 subtype C infection. Methods: A primary HIV-1C infection cohort comprised of 8 acutely and 34 recently infected subjects were followed frequently up to 500 days post-seroconversion (p/s). Gag mutations were analyzed by employing single-genome amplification and direct sequencing. Gag mutations were determined in relation to the estimated time of seroconversion. Time of appearance, dominance, and completeness was compared for different types of in vivo Gag mutations. Results: Reverse mutations to the wild type appeared at a median (IQR) of 62 (44;139) days p/s, while escape mutations from the wild type appeared at 234 (169;326) days p/s (p<0.001). Within the subset of mutations that became dominant, reverse and escape mutations appeared at 54 (30;78) days p/s and 104 (47;198) days p/s, respectively (p<0.001). Among the mutations that reached completeness, reverse and escape mutations appeared at 54 (30;78) days p/s and 90 (44;196) days p/s, respectively (p = 0.006). Time of dominance for reverse mutations to and escape mutations from the wild type was 58 (44;105) days p/s and 219 (90;326) days p/s, respectively (p<0.001). Time of completeness for reverse and escape mutations was 152 (100;176) days p/s and 243 (101;370) days p/s, respectively (p = 0.001). Fitting a Cox proportional hazards model with frailties confirmed a significantly earlier time of appearance (hazard ratio (HR): 2.6; 95% CI: 2.3–3.0), dominance (4.8 (3.4–6.8)), and completeness (3.6 (2.3–5.5)) of reverse mutations to the wild type Gag than escape mutations from the wild type. Some complex mutational pathways in Gag included sequential series of reversions and escapes. Conclusions: The study identified the timing of different types of in vivo Gag mutations in primary HIV-1 subtype C infection in relation to the estimated time of seroconversion. Overall, the in vivo reverse mutations to the wild type occurred significantly earlier than escape mutations from the wild type. This shorter time to incidence of reverse mutations remained in the subsets of in vivo Gag mutations that reached dominance or completeness

High Viral Fitness during Acute HIV-1 Infection

Several clinical studies have shown that, relative to disease progression, HIV-1 isolates that are less fit are also less pathogenic. The aim of the present study was to investigate the relationship between viral fitness and control of viral load (VL) in acute and early HIV-1 infection. Samples were obtained from subjects participating in two clinical studies. In the PULSE study, antiretroviral therapy (ART) was initiated before, or no later than six months following seroconversion. Subjects then underwent multiple structured treatment interruptions (STIs). The PHAEDRA study enrolled and monitored a cohort of individuals with documented evidence of primary infection. The subset chosen were individuals identified no later than 12 months following seroconversion to HIV-1, who were not receiving ART. The relative fitness of primary isolates obtained from study participants was investigated ex vivo. Viral DNA production was quantified using a novel real time PCR assay. Following intermittent ART, the fitness of isolates obtained from 5 of 6 PULSE subjects decreased over time. In contrast, in the absence of ART the fitness of paired isolates obtained from 7 of 9 PHAEDRA subjects increased over time. However, viral fitness did not correlate with plasma VL. Most unexpected was the high relative fitness of isolates obtained at Baseline from PULSE subjects, before initiating ART. It is widely thought that the fitness of strains present during the acute phase is low relative to strains present during chronic HIV-1 infection, due to the bottleneck imposed upon transmission. The results of this study provide evidence that the relative fitness of strains present during acute HIV-1 infection may be higher than previously thought. Furthermore, that viral fitness may represent an important clinical parameter to be considered when deciding whether to initiate ART during early HIV-1 infection

The potential of optical proteomic technologies to individualize prognosis and guide rational treatment for cancer patients

Genomics and proteomics will improve outcome prediction in cancer and have great potential to help in the discovery of unknown mechanisms of metastasis, ripe for therapeutic exploitation. Current methods of prognosis estimation rely on clinical data, anatomical staging and histopathological features. It is hoped that translational genomic and proteomic research will discriminate more accurately than is possible at present between patients with a good prognosis and those who carry a high risk of recurrence. Rational treatments, targeted to the specific molecular pathways of an individual’s high-risk tumor, are at the core of tailored therapy. The aim of targeted oncology is to select the right patient for the right drug at precisely the right point in their cancer journey. Optical proteomics uses advanced optical imaging technologies to quantify the activity states of and associations between signaling proteins by measuring energy transfer between fluorophores attached to specific proteins. Förster resonance energy transfer (FRET) and fluorescence lifetime imaging microscopy (FLIM) assays are suitable for use in cell line models of cancer, fresh human tissues and formalin-fixed paraffin-embedded tissue (FFPE). In animal models, dynamic deep tissue FLIM/FRET imaging of cancer cells in vivo is now also feasible. Analysis of protein expression and post-translational modifications such as phosphorylation and ubiquitination can be performed in cell lines and are remarkably efficiently in cancer tissue samples using tissue microarrays (TMAs). FRET assays can be performed to quantify protein-protein interactions within FFPE tissue, far beyond the spatial resolution conventionally associated with light or confocal laser microscopy. Multivariate optical parameters can be correlated with disease relapse for individual patients. FRET-FLIM assays allow rapid screening of target modifiers using high content drug screens. Specific protein-protein interactions conferring a poor prognosis identified by high content tissue screening will be perturbed with targeted therapeutics. Future targeted drugs will be identified using high content/throughput drug screens that are based on multivariate proteomic assays. Response to therapy at a molecular level can be monitored using these assays while the patient receives treatment: utilizing re-biopsy tumor tissue samples in the neoadjuvant setting or by examining surrogate tissues. These technologies will prove to be both prognostic of risk for individuals when applied to tumor tissue at first diagnosis and predictive of response to specifically selected targeted anticancer drugs. Advanced optical assays have great potential to be translated into real-life benefit for cancer patients