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1.  The hippocampus, medial prefrontal cortex and selective memory retrieval: Evidence from a rodent model of the retrieval-induced forgetting effect 
Hippocampus  2014;24(9):1070-1080.
Inhibition is an important component of many cognitive functions, including memory. For example, the retrieval-induced forgetting (RIF) effect occurs when extra practice with some items from a study list inhibits the retrieval of the non-practiced items relative to a baseline condition that does not involve extra practice. Though counterintuitive, the RIF phenomenon may be important for resolving interference by inhibiting potentially competing retrieval targets. Neuroimaging studies suggest that the hippocampus and prefrontal cortex (PFC) are involved in the RIF effect, but controlled lesion studies have not yet been performed. We developed a rodent model of the RIF training procedure and trained control rats and rats with temporary inactivation of the hippocampus or mPFC. Rats were trained on a list of odor cues, presented in cups of digging medium with a buried reward, followed by additional practice trials with a subset of the cues. We then tested the rats’ memories for the cues and their association with reward by presenting them with unbaited cups containing the test odorants and measuring how long they persisted in digging. Control rats exhibited a robust RIF effect in which memory for the non-practiced odors was significantly inhibited. Thus, extra practice with some odor cues inhibited memory for the others, relative to a baseline condition that involved an identical amount of training. Inactivation of either the hippocampus or the mPFC blocked the RIF effect. We also constructed a computational model of a representational learning circuit to simulate the RIF effect. We show in this model that ‘sideband suppression’ of similar memory representations can reproduce the RIF effect and that alteration of the suppression parameters and learning rate can reproduce the lesion effects seen in our rats. Our results suggest that the RIF effect is widespread and that inhibitory processes are an important feature of memory function.
PMCID: PMC4146680  PMID: 24753146
hippocampus; prefrontal cortex; interference; retrieval inhibition
2.  The Form and Function of Hippocampal Context Representations 
Context is an essential component of learning and memory processes, and the hippocampus is critical for encoding contextual information. However, connecting hippocampal physiology with its role in context and memory has only recently become possible. It is now clear that contexts are represented by coherent ensembles of hippocampal neurons and new optogenetic stimulation studies indicate that activity in these ensembles can trigger the retrieval of context appropriate memories. We interpret these findings in light of recent evidence that the hippocampus is critically involved in using contextual information to prevent interference, and propose a theoretical framework for understanding contextual influence of memory retrieval. When a new context is encountered, a unique hippocampal ensemble is recruited to represent it. Memories for events that occur in the context become associated with the hippocampal representation. Revisiting the context causes the hippocampal context code to be re-expressed and the relevant memories are primed. As a result, retrieval of appropriate memories is enhanced and interference from memories belonging to other contexts is minimized.
PMCID: PMC3973439  PMID: 24462752
Context; Memory; Hippocampus; Interference
3.  Partial palivizumab prophylaxis and increased risk of hospitalization due to respiratory syncytial virus in a Medicaid population: a retrospective cohort analysis 
BMC Pediatrics  2014;14:261.
Infection with respiratory syncytial virus (RSV) is common among young children insured through Medicaid in the United States. Complete and timely dosing with palivizumab is associated with lower risk of RSV-related hospitalizations, but up to 60% of infants who receive palivizumab in Medicaid population do not receive full prophylaxis. The purpose of this study was to evaluate the association of partial palivizumab prophylaxis with the risk of RSV hospitalization among high-risk Medicaid-insured infants.
Claims data from 12 states during 6 RSV seasons (October 1st to April 30th in the first year of life in 2003–2009) were analyzed. Inclusion criteria were birth hospital discharge before October 1st, continuous insurance eligibility from birth through April 30th, ≥ one palivizumab administration from August 1st to end of season, and high-risk status (≤34 weeks gestational age or chronic lung disease of prematurity [CLDP] or hemodynamically significant congenital heart disease [CHD]). Fully prophylaxed infants received the first palivizumab dose by November 30th with no gaps >35 days up to the first RSV-related hospitalization or end of follow-up. All other infants were categorized as partially prophylaxed.
Of the 8,443 high-risk infants evaluated, 67% (5,615) received partial prophylaxis. Partially prophylaxed infants were more likely to have RSV-related hospitalization than fully prophylaxed infants (11.7% versus 7.9%, p< 0.001). RSV-related hospitalization rates ranged from 8.5% to 24.8% in premature, CHD, and CLDP infants with partial prophylaxis. After adjusting for potential confounders, logistic regression showed that partially prophylaxed infants had a 21% greater odds of hospitalization compared with fully prophylaxed infants (odds ratio 1.21, 95% confidence interval 1.09-1.34).
RSV-related hospitalization rates were significantly higher in high-risk Medicaid infants with partial palivizumab prophylaxis compared with fully prophylaxed infants. These findings suggest that reduced and/or delayed dosing is less effective.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2431-14-261) contains supplementary material, which is available to authorized users.
PMCID: PMC4287588  PMID: 25308481
Prophylaxis; Respiratory syncytial virus; Palivizumab; Non-compliance
4.  HIV Migration Between Blood and Cerebrospinal Fluid or Semen Over Time 
The Journal of Infectious Diseases  2013;209(10):1642-1652.
Previous studies reported associations between neuropathogenesis and human immunodeficiency virus (HIV) compartmentalization in cerebrospinal fluid (CSF) and between sexual transmission and human immunodeficiency virus type 1 (HIV) compartmentalization in semen. It remains unclear, however, how compartmentalization dynamics change over time. To address this, we used statistical methods and Bayesian phylogenetic approaches to reconstruct temporal dynamics of HIV migration between blood and CSF and between blood and the male genital tract.
We investigated 11 HIV-infected individuals with paired semen and blood samples and 4 individuals with paired CSF and blood samples. Aligned partial HIV env sequences were analyzed by (1) phylogenetic reconstruction, using a Bayesian Markov-chain Monte Carlo approach; (2) evaluation of viral compartmentalization, using tree-based and distance-based methods; and (3) analysis of migration events, using a discrete Bayesian asymmetric phylogeographic approach of diffusion with Markov jump counts estimation. Finally, we evaluated potential correlates of viral gene flow across anatomical compartments.
We observed bidirectional replenishment of viral compartments and asynchronous peaks of viral migration from and to blood over time, suggesting that disruption of viral compartment is transient and directionally selected. These findings imply that viral subpopulations in anatomical sites are an active part of the whole viral population and that compartmental reservoirs could have implications in future eradication studies.
PMCID: PMC3997580  PMID: 24302756
Human Immunodeficiency Virus; Compartmentalization; Migration; Cerebrospinal Fluid; Semen; Coalescence
5.  Shallow Encoding and Forgetting Are Associated with Dependence in Instrumental Activities of Daily Living Among Older Adults Living with HIV Infection 
Aging and HIV are both risk factors for memory deficits and declines in real-world functioning. However, we know little about the profile of memory deficits driving instrumental activities of daily living (IADL) declines across the lifespan in HIV. This study examined 145 younger (<50 years) and 119 older (≥50 years) adults with HIV who completed the California Verbal Learning Test-Second Edition (CVLT-II), the Wechsler Memory Scale-Third Edition Logical Memory subtest (WMS-III LM), and a modified Lawton and Brody ADL questionnaire. No memory predictors of IADL dependence emerged in the younger cohort. In the older group, IADL dependence was uniquely associated with worse performance on all primary CVLT-II variables, as well as elevated recency effects. Poorer immediate and delayed recall of the WMS-III LM was also associated with IADL dependence, although recognition was intact. Findings suggest older HIV-infected adults with shallow encoding and forgetting are at risk for IADL dependence.
PMCID: PMC4000232  PMID: 24695591
Aging; Disability; Everyday functioning; Learning and memory
6.  Measuring Vaccine Confidence: Introducing a Global Vaccine Confidence Index 
PLoS Currents  2015;7:ecurrents.outbreaks.ce0f6177bc97332602a8e3fe7d7f7cc4.
Background. Public confidence in vaccination is vital to the success of immunisation programmes worldwide. Understanding the dynamics of vaccine confidence is therefore of great importance for global public health. Few published studies permit global comparisons of vaccination sentiments and behaviours against a common metric. This article presents the findings of a multi-country survey of confidence in vaccines and immunisation programmes in Georgia, India, Nigeria, Pakistan, and the United Kingdom (UK) – these being the first results of a larger project to map vaccine confidence globally. Methods. Data were collected from a sample of the general population and from those with children under 5 years old against a core set of confidence questions. All surveys were conducted in the relevant local-language in Georgia, India, Nigeria, Pakistan, and the UK. We examine confidence in immunisation programmes as compared to confidence in other government health services, the relationships between confidence in the system and levels of vaccine hesitancy, reasons for vaccine hesitancy, ultimate vaccination decisions, and their variation based on country contexts and demographic factors. Results. The numbers of respondents by country were: Georgia (n=1000); India (n=1259); Pakistan (n=2609); UK (n=2055); Nigerian households (n=12554); and Nigerian health providers (n=1272). The UK respondents with children under five years of age were more likely to hesitate to vaccinate, compared to other countries. Confidence in immunisation programmes was more closely associated with confidence in the broader health system in the UK (Spearman’s ρ=0.5990), compared to Nigeria (ρ=0.5477), Pakistan (ρ=0.4491), and India (ρ=0.4240), all of which ranked confidence in immunisation programmes higher than confidence in the broader health system. Georgia had the highest rate of vaccine refusals (6 %) among those who reported initial hesitation. In all other countries surveyed most respondents who reported hesitating to vaccinate went on to receive the vaccine except in Kano state, Nigeria, where the percentage of those who ultimately refused vaccination after initially hesitating was as high as 76%) Reported reasons for hesitancy in all countries were classified under the domains of “confidence,” “convenience,” or “complacency,” and confidence issues were found to be the primary driver of hesitancy in all countries surveyed.
PMCID: PMC4353663  PMID: 25789200
vaccine hesitancy
7.  Cues, context, and long-term memory: the role of the retrosplenial cortex in spatial cognition 
Spatial navigation requires memory representations of landmarks and other navigation cues. The retrosplenial cortex (RSC) is anatomically positioned between limbic areas important for memory formation, such as the hippocampus (HPC) and the anterior thalamus, and cortical regions along the dorsal stream known to contribute importantly to long-term spatial representation, such as the posterior parietal cortex. Damage to the RSC severely impairs allocentric representations of the environment, including the ability to derive navigational information from landmarks. The specific deficits seen in tests of human and rodent navigation suggest that the RSC supports allocentric representation by processing the stable features of the environment and the spatial relationships among them. In addition to spatial cognition, the RSC plays a key role in contextual and episodic memory. The RSC also contributes importantly to the acquisition and consolidation of long-term spatial and contextual memory through its interactions with the HPC. Within this framework, the RSC plays a dual role as part of the feedforward network providing sensory and mnemonic input to the HPC and as a target of the hippocampal-dependent systems consolidation of long-term memory.
PMCID: PMC4122222  PMID: 25140141
retrosplenial cortex; hippocampus; context; navigation; long-term memory; learning; allocentric; consolidation
8.  A Structurally Variable Hinged Tetrahedron Framework from DNA Origami 
Journal of Nucleic Acids  2011;2011:360954.
Nanometer-sized polyhedral wire-frame objects hold a wide range of potential applications both as structural scaffolds as well as a basis for synthetic nanocontainers. The utilization of DNA as basic building blocks for such structures allows the exploitation of bottom-up self-assembly in order to achieve molecular programmability through the pairing of complementary bases. In this work, we report on a hollow but rigid tetrahedron framework of 75 nm strut length constructed with the DNA origami method. Flexible hinges at each of their four joints provide a means for structural variability of the object. Through the opening of gaps along the struts, four variants can be created as confirmed by both gel electrophoresis and direct imaging techniques. The intrinsic site addressability provided by this technique allows the unique targeted attachment of dye and/or linker molecules at any point on the structure's surface, which we prove through the superresolution fluorescence microscopy technique DNA PAINT.
PMCID: PMC3176657  PMID: 21941629
9.  The Anterior Thalamus is Critical for Overcoming Interference in a Context-Dependent Odor Discrimination Task 
Behavioral neuroscience  2012;126(5):710-719.
The anterior thalamus (AT) is anatomically interconnected with the hippocampus and other structures known to be involved in memory, and the AT is involved in many of the same learning and memory functions as the hippocampus. For example, like the hippocampus, the AT is involved in spatial cognition and episodic memory. The hippocampus also has a well-documented role in contextual memory processes, but it is not known whether the AT is similarly involved in contextual memory. In the present study, we assessed the role of the AT in contextual memory processes by temporarily inactivating the AT and training rats on a recently developed context-based olfactory list learning task, which was designed to assess the use of contextual information to resolve interference. Rats were trained on one list of odor discrimination problems, followed by training on a second list in either the same context or a different context. In order to induce interference, some of the odors appeared on both lists with their predictive value reversed. Control rats that learned the two lists in different contexts performed significantly better than rats that learned the two lists in the same context. However, AT lesions completely abolished this contextual learning advantage, a result that is very similar to the effects of hippocampal inactivation. These findings demonstrate that the AT, like the hippocampus, is involved in contextual memory and suggest that the hippocampus and AT are part of a functional circuit involved in contextual memory.
PMCID: PMC3464499  PMID: 23025833
anterior thalamus; learning; memory; interference; context
10.  The Beneficial Effects of n-3 Polyunsaturated Fatty Acids on Diet Induced Obesity and Impaired Glucose Control Do Not Require Gpr120 
PLoS ONE  2014;9(12):e114942.
GPR120 (Ffar4) has been postulated to represent an important receptor mediating the improved metabolic profile seen upon ingestion of a diet enriched in polyunsaturated fatty acids (PUFAs). GPR120 is highly expressed in the digestive system, adipose tissue, lung and macrophages and also present in the endocrine pancreas. A new Gpr120 deficient mouse model on pure C57bl/6N background was developed to investigate the importance of the receptor for long-term feeding with a diet enriched with fish oil. Male Gpr120 deficient mice were fed two different high fat diets (HFDs) for 18 weeks. The diets contained lipids that were mainly saturated (SAT) or mainly n-3 polyunsaturated fatty acids (PUFA). Body composition, as well as glucose, lipid and energy metabolism, was studied. As expected, wild type mice fed the PUFA HFD gained less body weight and had lower body fat mass, hepatic lipid levels, plasma cholesterol and insulin levels and better glucose tolerance as compared to those fed the SAT HFD. Gpr120 deficient mice showed a similar improvement on the PUFA HFD as was observed for wild type mice. If anything, the Gpr120 deficient mice responded better to the PUFA HFD as compared to wild type mice with respect to liver fat content, plasma glucose levels and islet morphology. Gpr120 deficient animals were found to have similar energy, glucose and lipid metabolism when fed HFD PUFA compared to wild type mice. Therefore, GPR120 appears to be dispensable for the improved metabolic profile associated with intake of a diet enriched in n-3 PUFA fatty acids.
PMCID: PMC4277291  PMID: 25541716
11.  A Comparison of the Effects of Temporary Hippocampal Lesions on Single and Dual Context Versions of the Olfactory Sequence Memory Task 
Behavioral neuroscience  2012;126(4):588-592.
In recent years, many animal models of memory have focused on one or more of the various components of episodic memory. For example, the odor sequence memory task requires subjects to remember individual items and events (the odors) and the temporal aspects of the experience (the sequence of odor presentation). The well-known spatial context coding function of the hippocampus, as exemplified by place cell firing, may reflect the ‘where’ component of episodic memory. In the present study, we added a contextual component to the odor sequence memory task by training rats to choose the earlier odor in one context and the later odor in another context and we compared the effects of temporary hippocampal lesions on performance of the original single context task and the new dual context task. Temporary lesions significantly impaired the single context task, although performance remained significantly above chance levels. In contrast, performance dropped all the way to chance when temporary lesions were used in the dual context task. These results demonstrate that rats can learn a dual context version of the odor sequence learning task which requires the use of contextual information along with the requirement to remember the ‘what’ and ‘when’ components of the odor sequence. Moreover, the additional requirement of context-dependent expression of the ‘what-when’ memory made the task fully dependent on the hippocampus. Moreover, the addition of the contextual component made the task fully dependent on the hippocampus.
PMCID: PMC3477488  PMID: 22687149
hippocampus; episodic memory; what-where-when; context; sequence memory
12.  Retrospective Analysis of Long-Term Adherence to and Persistence with DPP-4 Inhibitors in US Adults with Type 2 Diabetes Mellitus 
Advances in Therapy  2014;31:1287-1305.
Patients with type 2 diabetes mellitus (T2DM) must remain adherent and persistent on antidiabetic medications to optimize clinical benefits. This analysis compared adherence and persistence among adults initiating dipeptidyl peptidase-4 inhibitors (DPP-4is), sulfonylureas (SUs), and thiazolidinediones (TZDs) and between patients initiating saxagliptin or sitagliptin, two DPP-4is.
This retrospective cohort study utilized the US MarketScan® (Truven Health Analytics, Ann Arbor, MI, USA) Commercial and Medicare Supplemental health insurance claims databases. Adults aged ≥18 years with T2DM who initiated a DPP-4i, SU, or TZD from January 1, 2009 to January 31, 2012 were included. Patients must have been continuously enrolled for ≥1 year prior to and ≥1 year following initiation. Adherence was measured using proportion of days covered (PDC), with PDC ≥ 0.80 considered adherent. Persistence was measured as time to discontinuation, defined as last day with drug prior to a 60+ days gap in therapy. Multivariable logistic regression and Cox proportional hazards models compared the outcomes between cohorts, controlling for baseline differences.
The sample included 238,372 patients (61,399 DPP-4i, 134,961 SU, 42,012 TZD). During 1-year follow-up, 47.3% of DPP-4i initiators, 41.2% of SU initiators, and 36.7% of TZD initiators were adherent. Adjusted odds of adherence were significantly greater among DPP-4i initiators than SU (adjusted odds ratio [AOR] = 1.678, P < 0.001) and TZD initiators (AOR = 1.605, P < 0.001). During 1-year follow-up, 55.0% of DPP-4i initiators, 47.8% of SU initiators, and 42.9% of TZD initiators did not discontinue therapy. Adjusted hazards of discontinuation were significantly greater for SU (adjusted hazard ratio [AHR] = 1.390, P < 0.001) and TZD initiators (AHR = 1.402, P < 0.001) compared with DPP-4i initiators. Saxagliptin initiators had significantly better adherence (AOR = 1.213, P < 0.001) compared with sitagliptin initiators, and sitagliptin initiators had significantly greater hazard of discontinuation (AHR = 1.159, P < 0.001). Results were similar over a 2-year follow-up.
US adults with T2DM who initiated DPP-4i therapy, particularly saxagliptin, had significantly better adherence and persistence compared with patients who initiated SUs or TZDs.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-014-0171-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4271133  PMID: 25504156
Adherence; Dipeptidyl peptidase-4 inhibitors; Persistence; Type 2 diabetes mellitus
13.  Open versus laparoscopic right hemicolectomy in the elderly population 
AIM: To compare short term outcomes of elective laparoscopic and open right hemicolectomy (RH) in an elderly population.
METHODS: All patients over the age of 70 undergoing elective RH at Ninewells Hospital and Perth Royal Infirmary between January 2006 and May 2011 were included in our analysis. Operative details, hospital length of stay, morbidity and mortality was collected by way of proforma from a dedicated prospective database. An extracorporeal anastomosis was performed routinely in the laparoscopic group. The primary endpoints for analysis were morbidity and mortality. Our secondary endpoints were operative duration, length of hospital stay and discharge destination.
RESULTS: Two hundred and six patients were included in our analysis. One hundred and twenty-five patients underwent an open resection and 81 patients had a laparoscopic resection. The mean operating time was significantly longer in the laparoscopic group (139 ±
36 min vs 197 ± 53 min, P = 0.001). The mean length of hospital stay was similar in both groups (11.2 ± 7.8 d vs 9.6 ± 10.7 d, P = 0.28). The incidence of post-operative morbidities was 27% in the open group and 38% in the laparoscopic group (P = 0.12). Overall in-hospital mortality was 0.8% in open procedures vs 1% in laparoscopic.
CONCLUSION: Laparoscopic RH was associated with a significantly longer operative time compared to open RH. In our study, laparoscopic RH was not associated with reduced post-operative morbidity or significantly shorter length of hospital stay.
PMCID: PMC3692954  PMID: 23805362
Right hemicolectomy; Elderly; Laparoscopy; Open
14.  The Role of Adult Hippocampal Neurogenesis in Reducing Interference 
Behavioral neuroscience  2012;126(3):381-391.
Adult neurogenesis in the hippocampal dentate gyrus plays an important role in learning and memory. However, the precise contribution of the new neurons to hippocampal function remains controversial. Emerging evidence suggests that neurogenesis is important for pattern separation and for mitigating interference when similar items must be learned at different times. In the present study, we directly test this prediction using a recently developed olfactory memory task that has those specific features. In this task, rats learn two highly interfering lists of odor pairs, one after the other in either the same or in different contexts. Consistent with our hypothesis, focal cranial irradiation, resulting in selective reduction of neurogenesis within the dentate gyrus, significantly impaired the ability to overcome interference during learning of the second list. The ability to learn a single odor list was unimpaired. We also show that irradiation had no effect on learning in a hippocampal dependent spatial alternation task. Although both tasks involved learning interfering responses, the time course for learning the interfering items differed. Learning the interfering odor lists took place sequentially, over the course of several sessions, whereas learning the interfering spatial locations took place concurrently, within each session. Thus, the gradual addition of new neurons may have provided a pattern separation mechanism for the olfactory task but not for the maze task. These findings demonstrate a role for neurogenesis in resolving interference and they are consistent with models suggesting a critical role for neurogenesis in pattern separation.
PMCID: PMC3477487  PMID: 22642883
hippocampus; memory interference; adult neurogenesis; learning and memory; dentate gyrus
15.  Complimentary Roles of the Hippocampus and Retrosplenial Cortex in Behavioral Context Discrimination 
Hippocampus  2011;22(5):1121-1133.
Complex cognitive functions, such as learning and memory, arise from the interaction of multiple brain regions that comprise functional circuits and different components of these circuits make unique contributions to learning. The hippocampus and the retrosplenial cortex (RSC) are anatomically interconnected and both regions are involved in learning and memory. Previous studies indicate that the hippocampus exhibits unique firing patterns for different contexts and that RSC neurons selectively respond to cues that predict reinforcement or the need for a behavioral response, suggesting a hippocampal role in encoding contexts and an RSC role in encoding behaviorally significant cues. To test this, we simultaneously recorded hippocampal and RSC neuronal activity as rats learned to discriminate two behavioral contexts. The rats learned to approach the east arm of a plus maze for reward during the first half of each session and to approach the west arm during the second half. The ‘go east’ and ‘go west’ conditions constitute distinct behavioral contexts, which were cued by the reward location. Neurons in both regions developed highly context-specific responses as subjects learned to discriminate the contexts, but the response patterns differed in the two brain regions. Consistent with a context processing role, hippocampal neurons developed context specific responses to a variety of task stimuli and events. In contrast, RSC neurons only developed context specific responses to the reward location, which served as the context identifying cue. These results suggest that the hippocampus and RSC play distinct, but complimentary roles in mediating context appropriate memories and behaviors.
PMCID: PMC3166541  PMID: 21630374
hippocampus; retrosplenial cortex; cingulate cortex; context; place cell
16.  Hippocampal Context Processing is Critical for Interference Free Recall of Odor Memories in Rats 
Hippocampus  2011;22(4):906-913.
Interference is a critical problem for memory systems and a primary cause of retrieval failure. One strategy for minimizing interference is to associate the items to be remembered with the context in which they were learned. For example, human subjects who learn two lists of words in separate contexts experience less interference and better recall than subjects who learn both lists in the same context. The hippocampus has long been known to be involved in processing contextual information and recent studies have shown that hippocampal neurons exhibit context-unique firing patterns that could serve as a neural representation of the context. These observations suggest that hippocampal context processing may play a critical role in overcoming interference. To test this hypothesis, we adapted the context based list learning procedure for use with rats. Control rats and rats given temporary lesions of the hippocampus were trained on two lists of eight odor pairs, either in the same context or in different contexts. In order to induce interference, some of the odors appeared on both lists with their predictive value reversed. As with human subjects, rats that learned the two lists in different contexts performed significantly better than rats that learned the lists in the same context. However, hippocampal lesions completely abolished this contextual learning advantage. We also trained rats on a low interference version of the task by using lists that did not contain any common items. Interestingly, rats with hippocampal lesions were entirely unimpaired when the learning situation did not involve high levels of interference. These findings are consistent with the idea that the hippocampus encodes contexts and further suggest that hippocampal context coding is beneficial because it provides a means of overcoming interference.
PMCID: PMC3151480  PMID: 21542056
hippocampus; context; interference
17.  Hippocampal Episode Fields Develop with Learning 
Hippocampus  2010;21(11):1240-1249.
Several recent studies have shown that hippocampal neurons fire during the delay period in between trials and that these firing patterns differ when different behaviors are required, suggesting that the neuronal responses may be involved in maintaining the memories needed for the upcoming trial. In particular, one study found that hippocampal neurons reliably fired at particular times, referred to as ‘episode fields’ (EFs), during the delay period of a spatial alternation task (Pastalkova et al, 2008, Science 321:1322-7). The firing of these neurons resulted in distinct sequential firing patterns on left and right turn trials, and these firing patterns could be used to predict the upcoming behavioral response. In the present study, we examined neuronal firing during the delay period of a hippocampal dependent plus maze task which involved learning to approach two different reward locations (east and west) and we examined the development of these firing patterns with learning. As in the previous study, hippocampal neurons exhibited discrete periods of elevated firing during the delay (EFs) and the firing patterns were distinct on the east and west trials. Moreover, these firing patterns emerged and began to differentiate the east and west conditions during the first training session and continued to develop as the rats learned the task. The finding of similar firing patterns in different tasks suggests that the EFs are a robust phenomenon, which may occur whenever subjects must maintain distinct memory representations during a delay period. Additionally, in the previous study (Pastalkova et al, 2008), the distinct firing patterns could have been due to the differing goal locations, behavioral responses (left or right turns) or trajectories. In the present study, neuronal firing varied with the goal location regardless of the trajectories or responses, suggesting that the firing patterns encode the behavioral context rather than specific behaviors.
PMCID: PMC2970708  PMID: 20665593
hippocampus; delay; context; place cell; episode field
18.  Mechanism of gate opening in the 20S proteasome by the proteasomal ATPases 
Molecular cell  2008;30(3):360-368.
Substrates enter the cylindrical 20S proteasome through a gated channel that is regulated by the ATPases in the 19S regulatory particle in eukaryotes or the homologous PAN ATPase complex in archaea. These ATPases contain a conserved C-terminal hydrophobic-tyrosine-X (HbYX) motif that triggers gate opening upon ATP binding. Using electron cryomicroscopy, we identified the sites in the archaeal 20S where PAN’s C-terminal residues bind and determined the structures of the gate in its closed and open forms. Peptides containing the HbYX motif bind to 20S in the pockets between neighboring α-subunits where they interact with conserved residues required for gate opening. This interaction induces a rotation in the α-subunits and displacement of a reverse turn loop that stabilizes the open-gate conformation. This mechanism differs from that of PA26/28, which lacks the HbYX motif and does not cause α-subunit rotation. These findings demonstrated how the ATPases C-termini functions to facilitate substrate entry.
PMCID: PMC4141531  PMID: 18471981
Proteasome; proteasomal ATPase; Electron cryomicroscopy; protein degradation; AAA ATPases
19.  GPR120 (FFAR4) is preferentially expressed in pancreatic delta cells and regulates somatostatin secretion from murine islets of Langerhans 
Diabetologia  2014;57(6):1182-1191.
The NEFA-responsive G-protein coupled receptor 120 (GPR120) has been implicated in the regulation of inflammation, in the control of incretin secretion and as a predisposing factor influencing the development of type 2 diabetes by regulation of islet cell apoptosis. However, there is still considerable controversy about the tissue distribution of GPR120 and, in particular, it remains unclear which islet cell types express this molecule. In the present study, we have addressed this issue by constructing a Gpr120-knockout/β-galactosidase (LacZ) knock-in (KO/KI) mouse to examine the distribution and functional role of GPR120 in the endocrine pancreas.
A KO/KI mouse was generated in which exon 1 of the Gpr120 gene (also known as Ffar4) was replaced in frame by LacZ, thereby allowing for regulated expression of β-galactosidase under the control of the endogenous GPR120 promoter. The distribution of GPR120 was inferred from expression studies detecting β-galactosidase activity and protein production. Islet hormone secretion was measured from isolated mouse islets treated with selective GPR120 agonists.
β-galactosidase activity was detected as a surrogate for GPR120 expression exclusively in a small population of islet endocrine cells located peripherally within the islet mantle. Immunofluorescence analysis revealed co-localisation with somatostatin suggesting that GPR120 is preferentially produced in islet delta cells. In confirmation of this, glucose-induced somatostatin secretion was inhibited by a range of selective GPR120 agonists. This response was lost in GPR120-knockout mice.
The results imply that GPR120 is selectively present within the delta cells of murine islets and that it regulates somatostatin secretion.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-014-3213-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC4018485  PMID: 24663807
Endocrine pancreas; FFAR4; GPR120; Insulin secretion; n-3 fatty acids; n-6 fatty acids; NEFA; Pertussis toxin
20.  Predictors of Initiating Rapid-Acting Insulin Analog Using Vial/Syringe, Prefilled Pen, and Reusable Pen Devices in Patients with Type 2 Diabetes 
Limited data are available on the predictors of insulin delivery device choice. This study assessed the patient- and health-care-system-related factors that predict the initiation of one rapid-acting insulin analog (RAIA) delivery system over another.
A retrospective analysis using a claims database (January 1, 2007, through March 31, 2009) was conducted. Patients were required to be diagnosed with type 2 diabetes mellitus, and have ≥12 months of continuous eligibility prior to their first prescription of a RAIA on or after January 1, 2008. The three cohorts in the study were vial/syringe (n = 6820), prefilled pen (n = 5840), and reusable pen (n = 2052). Multiple factors were examined using stepwise logistic regression.
Factors that increased the likelihood of initiating RAIA using prefilled pen versus vial/syringe included endocrinologist visit [odds ratio (OR) = 3.13, 95% confidence interval (CI) = 2.56, 3.82], prior basal insulin use with pen (OR = 4.85, 95% CI = 4.21, 5.59), and use of ≥1 oral antihyperglycemic agents (OR = 1.32, 95% CI = 1.20, 1.45). Factors that decreased the likelihood included inpatient admission (OR = 0.76, 95% CI = 0.70, 0.83), nursing home visit (OR = 0.22, 95% CI = 0.18, 0.27), and obesity (OR = 0.67, 95% CI = 0.53, 0.83). There were fewer differences between prefilled and reusable pen initiators. Factors that increased the likelihood of initiating with prefilled versus reusable pen included endocrinologist visit (OR = 1.87, CI = 1.50, 2.34) and inpatient admission (OR = 1.46, 95% CI = 1.30, 1.64).
Significant differences in predictors were observed between prefilled pen and vial/syringe initiators. The differences were fewer between prefilled and reusable pen initiators. These differences should be taken into consideration when evaluating outcomes associated with specific insulin delivery systems.
PMCID: PMC2901030  PMID: 20513319
insulin; pen device; type 2 diabetes mellitus; vial
21.  The inpatient experience and predictors of length of stay for patients hospitalized with systolic heart failure: comparison by commercial, Medicaid, and Medicare payer type 
Journal of medical economics  2012;16(1):43-54.
Descriptions of the inpatient experience for patients hospitalized with systolic heart failure (HF) are limited and lack a cross-sectional representation of the US population. While length of stay (LOS) is a primary determinant of resource use and post-discharge events, few models exist for estimating LOS.
Research design and methods
MarketScan® administrative claims data from 1/1/2005–6/30/2008 were used to select hospitalized patients aged ≥18 years with discharge diagnoses for both HF (primary diagnosis) and systolic HF (any diagnostic position) without prior HF hospitalization or undergoing transplantation.
Among 17,597 patients with systolic HF; 4109 had commercial; 2118 had Medicaid; and 11,370 had Medicare payer type. Medicaid patients had longer mean LOS (7.1 days) than commercial (6.3 days) or Medicare (6.7 days). In-hospital mortality was highest for patients with Medicaid (2.4%), followed by Medicare (1.3%) and commercial (0.6%). Commercial patients were more likely to receive inpatient procedures. Renal failure, pressure ulcer, malnutrition, a non-circulatory index admission DRG, receipt of a coronary artery bypass procedure or cardiac catheterization, or need for mechanical ventilation during the index admission were associated with increased LOS; receipt of a pacemaker device at index was associated with shorter LOS.
Selection of patients with systolic HF is limited by completeness and accuracy of medical coding, and results may not be generalizable to patients with diastolic HF or to international populations.
Inpatient care, LOS, and in-hospital survival differ by payer among patients hospitalized with systolic HF, although co-morbidity and inpatient procedures consistently influence LOS across payer types. These findings may refine risk stratification, allowing for targeted intensive inpatient management and/or aggressive transitional care to improve outcomes and increase the efficiency of care.
PMCID: PMC3893694  PMID: 22954063
Heart failure; Systolic; Hospitalization; Length of stay; Payer
22.  Rates and Predictors of 30-Day Readmission Among Commercially Insured and Medicaid-Enrolled Patients Hospitalized With Systolic Heart Failure 
Circulation. Heart failure  2012;5(6):10.1161/CIRCHEARTFAILURE.112.967356.
Heart failure (HF) readmission rates are primarily derived from Medicare enrollees. Given increasing public scrutiny of HF readmissions, understanding the rate and predictors in populations covered by other payers is also important, particularly among patients with systolic dysfunction, for whom most HF-specific therapies are targeted.
Methods and Results
MarketScan Commercial and Medicaid Administrative Claims Databases were used to identify all first hospitalizations with an International Classification of Diseases-9 discharge diagnosis code for HF (primary position) and systolic HF (any position) between January 1, 2005, and June 30, 2008. Among 4584 unique systolic HF index admissions (mean age 55 years), 30-day crude readmission rates were higher for Medicaid than commercially insured patients: all-cause 17.4% versus 11.8%; HF-related 6.7% versus 4.0%, respectively. In unadjusted analysis, higher comorbidity and prior healthcare utilization predicted readmission; age, sex, and plan type did not. After adjustment for case mix, the odds of all-cause and HF-related readmission were 32% and 68% higher, respectively, among Medicaid than commercially insured patients (P<0.02 for both). No significant differences in readmission rates were seen for managed care versus fee-for-service or capitated versus noncapitated plan types.
Compared with commonly cited Medicare HF readmission rates of 20% to 25%, Medicaid patients with systolic HF had lower 30-day readmission rates, and commercially insured patients had even lower rates. Even after adjustment for case mix, Medicaid patients were more likely to be readmitted than commercially insured patients, suggesting that more attention should be focused on readmissions among socioeconomically disadvantaged populations.
PMCID: PMC3873644  PMID: 23072736
heart failure; systolic; hospitalization; readmission; payer
23.  Strengthening research capacity through the medical education partnership initiative: the Mozambique experience 
Since Mozambique’s independence, the major emphasis of its higher educational institutions has been on didactic education. Because of fiscal and human resource constraints, basic and applied research activities have been relatively modest in scope, and priorities have often been set primarily by external collaborators. These factors have compromised the scope and the relevance of locally conducted research and have limited the impact of Mozambique’s universities as major catalysts for national development.
Case description
We developed a multi-institutional partnership to undertake a comprehensive analysis of the research environment at Mozambique’s major public universities to identify factors that have served as barriers to the development of a robust research enterprise. Based on this analysis, we developed a multifaceted plan to reduce the impact of these barriers and to enhance research capacity within Mozambique.
On the basis of our needs assessment, we have implemented a number of major initiatives within participating institutions to facilitate basic and applied research activities. These have included specialized training programmes, a reorganization of the research administration infrastructure, the development of multiple collaborative research projects that have emphasized local research priorities and a substantial investment in bioinformatics. We have established a research support centre that provides grant development and management services to Mozambique’s public universities and have developed an independent Institutional Review Board for the review of research involving human research subjects. Multiple research projects involving both communicable and non-communicable diseases have been developed and substantial external research support has been obtained to undertake these projects. A sizable investment in biomedical informatics has enhanced both connectivity and access to digital reference material. Active engagement with relevant entities within the Government of Mozambique has aligned institutional development with national priorities.
Although multiple challenges remain, over the past 3 years significant progress has been made towards establishing conditions within which a broad range of basic, translational and clinical and public health research can be undertaken. Ongoing development of this research enterprise will enhance capacity to address critical locally relevant research questions and will leverage resources to accelerate the development of Mozambique’s national universities.
PMCID: PMC3895849  PMID: 24304706
Research; Research capacity building in Mozambique; MEPI Mozambique
24.  The cytoprotective effects of oleoylethanolamide in insulin-secreting cells do not require activation of GPR119 
British Journal of Pharmacology  2012;165(8):2758-2770.
β-cells express a range of fatty acid-responsive G protein-coupled receptors, including GPR119, which regulates insulin secretion and is seen as a potential therapeutic target in type 2 diabetes. The long-chain unsaturated fatty acid derivative oleoylethanolamide (OEA) is an endogenous agonist of GPR119 and, under certain conditions, some long-chain unsaturated fatty acids can promote β-cell cytoprotection. It is not known, however, if OEA is cytoprotective in β-cells. The present study has examined this and determined whether GPR119 is involved.
Clonal rat insulin-secreting cell lines, BRIN-BD11 or INS-1E, were exposed to fatty acids complexed with BSA. cAMP levels, insulin release and cell viability were measured. Protein expression was studied by Western blotting and receptor expression by RT-PCR.
GPR119 was expressed in both BRIN-BD11 and INS-1E cells and OEA was cytoprotective in these cells. However, cytoprotection was not reproduced by any of a range of selective, synthetic ligands of GPR119. The cytoprotective response to OEA was lost during exposure to inhibitors of fatty acid amide hydrolase (FAAH) suggesting that OEA per se is not the cytoprotective species but that release of free oleate is required. Similar data were obtained with anandamide, which was cytoprotective only under conditions favouring release of free arachidonate.
Activation of GPR119 is not required to mediate the cytoprotective actions of OEA in BRIN-BD11 or INS-1E cells. Rather, OEA is internalised and subjected to hydrolysis by FAAH to release free oleate, which then mediates the cytoprotection.
PMCID: PMC3423238  PMID: 22029844
lipotoxicity; palmitate; oleate; arachidonate; fatty acid amide hydrolase; anadamide
25.  Anticoagulant Use, the Prevalence of Bridging, and Relation to Length of Stay among Hospitalized Patients with Non-Valvular Atrial Fibrillation 
Objective: The objectives of this study were to describe inpatient anticoagulation and bridging in patients with non-valvular atrial fibrillation (NVAF) and to identify whether differences exist in length of stay (LOS) among bridged versus non-bridged NVAF patients.
Design: Administrative claims data were used to select patients ≥18 years with a primary or secondary discharge diagnosis of NVAF and inpatient warfarin use from 1 July 2004 to 30 September 2009. Patients with valvular or transient causes of NVAF or pregnancy were excluded. Inpatient bridging was defined as receipt of an anticoagulant in addition to warfarin during the hospitalization. LOS was reported for non-bridged patients (warfarin only) and compared with three bridging regimens: low molecular weight heparin/pentasaccharide (LMWH/PS); unfractionated heparin (UFH); and two-agent bridging (LMWH/PS and UFH). Multivariate analyses were performed to evaluate the association between bridging and LOS, adjusting for demographic and clinical variables.
Results: Of 6340 NVAF patients, 48% received inpatient warfarin (mean LOS 5.5 days); among them, 64% received bridging therapy (mean LOS 6.3 days) [LMWH/PS 45% (mean LOS 5.6 days), UFH 36% (mean LOS 6.0 days), two-agent bridging 18% (mean LOS 8.4 days)]. Following multivariate analysis, relative to patients who received inpatient warfarin only, LOS was significantly higher for patients with UFH (19.3%) and patients with two-agent bridging (45.1%). Patients with pre-period warfarin, cancer, or diabetes mellitus who received bridging agents had significantly longer LOS than patients with those conditions who were not bridged.
Conclusion: LOS was longer for bridged than non-bridged patients. Further studies are needed to identify predictors of bridging and to explain why bridged NVAF patients had longer LOS.
PMCID: PMC3713944  PMID: 23006024

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