Distributional coding of associative learning in discrete populations of midbrain dopamine neurons.

Midbrain dopamine neurons are thought to play key roles in learning by conveying the difference between expected and actual outcomes. Recent evidence suggests diversity in dopamine signaling, yet it remains poorly understood how heterogeneous signals might be organized to facilitate the role of downstream circuits mediating distinct aspects of behavior. Here, we investigated the organizational logic of dopaminergic signaling by recording and labeling individual midbrain dopamine neurons during associative behavior. Our findings show that reward information and behavioral parameters are not only heterogeneously encoded but also differentially distributed across populations of dopamine neurons. Retrograde tracing and fiber photometry suggest that populations of dopamine neurons projecting to different striatal regions convey distinct signals. These data, supported by computational modeling, indicate that such distributional coding can maximize dynamic range and tailor dopamine signals to facilitate specialized roles of different striatal regions.

Coincidence of cholinergic pauses, dopaminergic activation and depolarisation of spiny projection neurons drives synaptic plasticity in the striatum.

Dopamine-dependent long-term plasticity is believed to be a cellular mechanism underlying reinforcement learning. In response to reward and reward-predicting cues, phasic dopamine activity potentiates the efficacy of corticostriatal synapses on spiny projection neurons (SPNs). Since phasic dopamine activity also encodes other behavioural variables, it is unclear how postsynaptic neurons identify which dopamine event is to induce long-term plasticity. Additionally, it is unknown how phasic dopamine released from arborised axons can potentiate targeted striatal synapses through volume transmission. To examine these questions we manipulated striatal cholinergic interneurons (ChIs) and dopamine neurons independently in two distinct in vivo paradigms. We report that long-term potentiation (LTP) at corticostriatal synapses with SPNs is dependent on the coincidence of pauses in ChIs and phasic dopamine activation, critically accompanied by SPN depolarisation. Thus, the ChI pause defines the time window for phasic dopamine to induce plasticity, while depolarisation of SPNs constrains the synapses eligible for plasticity.

A computational framework for complex disease stratification from multiple large-scale datasets.

BACKGROUND: Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states. METHODS: The framework is divided into four major steps: dataset subsetting, feature filtering, 'omics-based clustering and biomarker identification. RESULTS: We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-'omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. CONCLUSIONS: This framework will help health researchers plan and perform multi-'omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine.

Obstructive Sleep Apnea and Retinopathy in Patients with Type 2 Diabetes. A Longitudinal Study.

RATIONALE: Obstructive sleep apnea (OSA) is associated with several pathophysiological deficits found in diabetic retinopathy (DR). Hence, it's plausible that OSA could play a role in the pathogenesis of sight-threatening DR (STDR). OBJECTIVES: To assess the relationship between OSA and DR in patients with type 2 diabetes and to assess whether OSA is associated with its progression. METHODS: A longitudinal study was conducted in diabetes clinics within two U.K. hospitals. Patients known to have any respiratory disorder (including OSA) were excluded. DR was assessed using two-field 45-degree retinal images for each eye. OSA was assessed using a home-based multichannel cardiorespiratory device. MEASUREMENTS AND MAIN RESULTS: A total of 230 patients were included. STDR and OSA prevalence rates were 36.1% and 63.9%, respectively. STDR prevalence was higher in patients with OSA than in those without OSA (42.9% vs. 24.1%; P = 0.004). After adjustment for confounders, OSA remained independently associated with STDR (odds ratio, 2.3; 95% confidence interval, 1.1-4.9; P = 0.04). After a median (interquartile range) follow-up of 43.0 (37.0-51.0) months, patients with OSA were more likely than patients without OSA to develop preproliferative/proliferative DR (18.4% vs. 6.1%; P = 0.02). After adjustment for confounders, OSA remained an independent predictor of progression to preproliferative/proliferative DR (odds ratio, 5.2; 95% CI confidence interval, 1.2-23.0; P = 0.03). Patients who received continuous positive airway pressure treatment were significantly less likely to develop preproliferative/proliferative DR. CONCLUSIONS: OSA is associated with STDR in patients with type 2 diabetes. OSA is an independent predictor for the progression to preproliferative/proliferative DR. Continuous positive airway pressure treatment was associated with reduction in preproliferative/proliferative DR. Interventional studies are needed to assess the impact of OSA treatment on STDR.

Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism.

Midbrain dopaminergic neurons are essential for appropriate voluntary movement, as epitomized by the cardinal motor impairments arising in Parkinson's disease. Understanding the basis of such motor control requires understanding how the firing of different types of dopaminergic neuron relates to movement and how this activity is deciphered in target structures such as the striatum. By recording and labeling individual neurons in behaving mice, we show that the representation of brief spontaneous movements in the firing of identified midbrain dopaminergic neurons is cell-type selective. Most dopaminergic neurons in the substantia nigra pars compacta (SNc), but not in ventral tegmental area or substantia nigra pars lateralis, consistently represented the onset of spontaneous movements with a pause in their firing. Computational modeling revealed that the movement-related firing of these dopaminergic neurons can manifest as rapid and robust fluctuations in striatal dopamine concentration and receptor activity. The exact nature of the movement-related signaling in the striatum depended on the type of dopaminergic neuron providing inputs, the striatal region innervated, and the type of dopamine receptor expressed by striatal neurons. Importantly, in aged mice harboring a genetic burden relevant for human Parkinson's disease, the precise movement-related firing of SNc dopaminergic neurons and the resultant striatal dopamine signaling were lost. These data show that distinct dopaminergic cell types differentially encode spontaneous movement and elucidate how dysregulation of their firing in early Parkinsonism can impair their effector circuits.

LRRK2 BAC transgenic rats develop progressive, L-DOPA-responsive motor impairment, and deficits in dopamine circuit function.

Mutations in leucine-rich repeat kinase 2 (LRRK2) lead to late-onset, autosomal dominant Parkinson's disease, characterized by the degeneration of dopamine neurons of the substantia nigra pars compacta, a deficit in dopamine neurotransmission and the development of motor and non-motor symptoms. The most prevalent Parkinson's disease LRRK2 mutations are located in the kinase (G2019S) and GTPase (R1441C) encoding domains of LRRK2. To better understand the sequence of events that lead to progressive neurophysiological deficits in vulnerable neurons and circuits in Parkinson's disease, we have generated LRRK2 bacterial artificial chromosome transgenic rats expressing either G2019S or R1441C mutant, or wild-type LRRK2, from the complete human LRRK2 genomic locus, including endogenous promoter and regulatory regions. Aged (18-21 months) G2019S and R1441C mutant transgenic rats exhibit L-DOPA-responsive motor dysfunction, impaired striatal dopamine release as determined by fast-scan cyclic voltammetry, and cognitive deficits. In addition, in vivo recordings of identified substantia nigra pars compacta dopamine neurons in R1441C LRRK2 transgenic rats reveal an age-dependent reduction in burst firing, which likely results in further reductions to striatal dopamine release. These alterations to dopamine circuit function occur in the absence of neurodegeneration or abnormal protein accumulation within the substantia nigra pars compacta, suggesting that nigrostriatal dopamine dysfunction precedes detectable protein aggregation and cell death in the development of Parkinson's disease. In conclusion, our longitudinal deep-phenotyping provides novel insights into how the genetic burden arising from human mutant LRRK2 manifests as early pathophysiological changes to dopamine circuit function and highlights a potential model for testing Parkinson's therapeutics.

The impact of bariatric surgery on retinopathy in patients with type 2 diabetes: a retrospective cohort study.

BACKGROUND: The impact of bariatric surgery on diabetic retinopathy (DR) is unclear. DR might improve after surgery because of improvement in DR risk factors, but the rapid improvement in hyperglycemia after surgery could worsen DR. OBJECTIVES: To assess the impact of bariatric surgery on the progression to sight-threatening DR (STDR) in patients with type 2 diabetes mellitus (T2DM) and compare STDR progression in patients with T2DM who underwent bariatric surgery with a group of matched patients receiving routine care between January 2005 and December 2012 at a single center. SETTING: Single-center university hospital. METHODS: DR was assessed using 2×45-degree retinal images obtained from the English National Diabetic Eye Screening Programme. Only patients who had retinal images within 1 year before surgery and at least 1 image after surgery were included in the analysis. STDR was defined as the presence of preproliferative/proliferative DR, maculopathy, or laser treatment. The comparator group comprised patients with T2DM who attended the same center for diabetes care and who had not undergone bariatric surgery. RESULTS: This analysis comprised 152 patients (mean age, 50.7±8.2 yr; baseline body mass index, 49.0±7.3 kg/m(2)) who were followed-up for 3.0±1.9 years. Of the 141 patients without STDR at baseline, 8 (5.7%) developed STDR by the end of the study. Of 106 patients with no DR at baseline, 2 (1.9%) developed preproliferative DR. Of 41 patients with background DR at baseline, 5 (12.2%) developed preproliferative DR. Of the 143 patients with no maculopathy at baseline, 8 (5.6%) developed maculopathy. Compared with a matched group for age, glycated hemoglobin, and follow-up duration, the progression to STDR and maculopathy was less in patients who underwent surgery versus those who received routine care (STDR: 5.7% [8/141] versus 12.1% [12/99], P = .075; maculopathy: 5.6% [8/143] versus 15.4% [16/104], P = .01, respectively). CONCLUSIONS: After bariatric surgery, patients with T2DM remain at risk for developing STDR, even those who did not have evidence of DR before surgery. However, surgery was associated with a lower progression to STDR or maculopathy compared with routine care. Randomized clinical trials are needed to ascertain the impact of bariatric surgery on DR.

Hippocampal Theta Input to the Amygdala Shapes Feedforward Inhibition to Gate Heterosynaptic Plasticity.

The dynamic interactions between hippocampus and amygdala are critical for emotional memory. Theta synchrony between these structures occurs during fear memory retrieval and may facilitate synaptic plasticity, but the cellular mechanisms are unknown. We report that interneurons of the mouse basal amygdala are activated during theta network activity or optogenetic stimulation of ventral CA1 pyramidal cell axons, whereas principal neurons are inhibited. Interneurons provide feedforward inhibition that transiently hyperpolarizes principal neurons. However, synaptic inhibition attenuates during theta frequency stimulation of ventral CA1 fibers, and this broadens excitatory postsynaptic potentials. These effects are mediated by GABAB receptors and change in the Cl(-) driving force. Pairing theta frequency stimulation of ventral CA1 fibers with coincident stimuli of the lateral amygdala induces long-term potentiation of lateral-basal amygdala excitatory synapses. Hence, feedforward inhibition, known to enforce temporal fidelity of excitatory inputs, dominates hippocampus-amygdala interactions to gate heterosynaptic plasticity. VIDEO ABSTRACT.

Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice.

Midbrain dopaminergic (mDA) neurons are implicated in cognitive functions, neuropsychiatric disorders, and pathological conditions; hence understanding genes regulating their homeostasis has medical relevance. Transcription factors FOXA1 and FOXA2 (FOXA1/2) are key determinants of mDA neuronal identity during development, but their roles in adult mDA neurons are unknown. We used a conditional knockout strategy to specifically ablate FOXA1/2 in mDA neurons of adult mice. We show that deletion of Foxa1/2 results in down-regulation of tyrosine hydroxylase, the rate-limiting enzyme of dopamine (DA) biosynthesis, specifically in dopaminergic neurons of the substantia nigra pars compacta (SNc). In addition, DA synthesis and striatal DA transmission were reduced after Foxa1/2 deletion. Furthermore, the burst-firing activity characteristic of SNc mDA neurons was drastically reduced in the absence of FOXA1/2. These molecular and functional alterations lead to a severe feeding deficit in adult Foxa1/2 mutant mice, independently of motor control, which could be rescued by L-DOPA treatment. FOXA1/2 therefore control the maintenance of molecular and physiological properties of SNc mDA neurons and impact on feeding behavior in adult mice.

Prototypic and arkypallidal neurons in the dopamine-intact external globus pallidus.

Studies in dopamine-depleted rats indicate that the external globus pallidus (GPe) contains two main types of GABAergic projection cell; so-called "prototypic" and "arkypallidal" neurons. Here, we used correlative anatomical and electrophysiological approaches in rats to determine whether and how this dichotomous organization applies to the dopamine-intact GPe. Prototypic neurons coexpressed the transcription factors Nkx2-1 and Lhx6, comprised approximately two-thirds of all GPe neurons, and were the major GPe cell type innervating the subthalamic nucleus (STN). In contrast, arkypallidal neurons expressed the transcription factor FoxP2, constituted just over one-fourth of GPe neurons, and innervated the striatum but not STN. In anesthetized dopamine-intact rats, molecularly identified prototypic neurons fired at relatively high rates and with high regularity, regardless of brain state (slow-wave activity or spontaneous activation). On average, arkypallidal neurons fired at lower rates and regularities than prototypic neurons, and the two cell types could be further distinguished by the temporal coupling of their firing to ongoing cortical oscillations. Complementing the activity differences observed in vivo, the autonomous firing of identified arkypallidal neurons in vitro was slower and more variable than that of prototypic neurons, which tallied with arkypallidal neurons displaying lower amplitudes of a "persistent" sodium current important for such pacemaking. Arkypallidal neurons also exhibited weaker driven and rebound firing compared with prototypic neurons. In conclusion, our data support the concept that a dichotomous functional organization, as actioned by arkypallidal and prototypic neurons with specialized molecular, structural, and physiological properties, is fundamental to the operations of the dopamine-intact GPe.

Distinct developmental origins manifest in the specialized encoding of movement by adult neurons of the external globus pallidus.

Transcriptional codes initiated during brain development are ultimately realized in adulthood as distinct cell types performing specialized roles in behavior. Focusing on the mouse external globus pallidus (GPe), we demonstrate that the potential contributions of two GABAergic GPe cell types to voluntary action are fated from early life to be distinct. Prototypic GPe neurons derive from the medial ganglionic eminence of the embryonic subpallium and express the transcription factor Nkx2-1. These neurons fire at high rates during alert rest, and encode movements through heterogeneous firing rate changes, with many neurons decreasing their activity. In contrast, arkypallidal GPe neurons originate from lateral/caudal ganglionic eminences, express the transcription factor FoxP2, fire at low rates during rest, and encode movements with robust increases in firing. We conclude that developmental diversity positions prototypic and arkypallidal neurons to fulfil distinct roles in behavior via their disparate regulation of GABA release onto different basal ganglia targets.

Improving the cost-effectiveness of photographic screening for diabetic macular oedema: a prospective, multi-centre, UK study.

BACKGROUND/AIMS: Retinal screening programmes in England and Scotland have similar photographic grading schemes for background (non-proliferative) and proliferative diabetic retinopathy, but diverge over maculopathy. We looked for the most cost-effective method of identifying diabetic macular oedema from retinal photographs including the role of automated grading and optical coherence tomography, a technology that directly visualises oedema. METHODS: Patients from seven UK centres were recruited. The following features in at least one eye were required for enrolment: microaneurysms/dot haemorrhages or blot haemorrhages within one disc diameter, or exudates within one or two disc diameters of the centre of the macula. Subjects had optical coherence tomography and digital photography. Manual and automated grading schemes were evaluated. Costs and QALYs were modelled using microsimulation techniques. RESULTS: 3540 patients were recruited, 3170 were analysed. For diabetic macular oedema, England's scheme had a sensitivity of 72.6% and specificity of 66.8%; Scotland's had a sensitivity of 59.5% and specificity of 79.0%. When applying a ceiling ratio of £30,000 per quality adjusted life years (QALY) gained, Scotland's scheme was preferred. Assuming automated grading could be implemented without increasing grading costs, automation produced a greater number of QALYS for a lower cost than England's scheme, but was not cost effective, at the study's operating point, compared with Scotland's. The addition of optical coherence tomography, to each scheme, resulted in cost savings without reducing health benefits. CONCLUSIONS: Retinal screening programmes in the UK should reconsider the screening pathway to make best use of existing and new technologies.

Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model.

The pathological end-state of Parkinson disease is well described from postmortem tissue, but there remains a pressing need to define early functional changes to susceptible neurons and circuits. In particular, mechanisms underlying the vulnerability of the dopamine neurons of the substantia nigra pars compacta (SNc) and the importance of protein aggregation in driving the disease process remain to be determined. To better understand the sequence of events occurring in familial and sporadic Parkinson disease, we generated bacterial artificial chromosome transgenic mice (SNCA-OVX) that express wild-type α-synuclein from the complete human SNCA locus at disease-relevant levels and display a transgene expression profile that recapitulates that of endogenous α-synuclein. SNCA-OVX mice display age-dependent loss of nigrostriatal dopamine neurons and motor impairments characteristic of Parkinson disease. This phenotype is preceded by early deficits in dopamine release from terminals in the dorsal, but not ventral, striatum. Such neurotransmission deficits are not seen at either noradrenergic or serotoninergic terminals. Dopamine release deficits are associated with an altered distribution of vesicles in dopaminergic axons in the dorsal striatum. Aged SNCA-OVX mice exhibit reduced firing of SNc dopamine neurons in vivo measured by juxtacellular recording of neurochemically identified neurons. These progressive changes in vulnerable SNc neurons were observed independently of overt protein aggregation, suggesting neurophysiological changes precede, and are not driven by, aggregate formation. This longitudinal phenotyping strategy in SNCA-OVX mice thus provides insights into the region-specific neuronal disturbances preceding and accompanying Parkinson disease.

Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers.

RATIONALE: Exacerbations of chronic obstructive pulmonary disease (COPD) are heterogeneous with respect to inflammation and etiology. OBJECTIVES: Investigate biomarker expression in COPD exacerbations to identify biologic clusters and determine biomarkers that recognize clinical COPD exacerbation phenotypes, namely those associated with bacteria, viruses, or eosinophilic airway inflammation. METHODS: Patients with COPD were observed for 1 year at stable and exacerbation visits. Biomarkers were measured in sputum and serum. Viruses and selected bacteria were assessed in sputum by polymerase chain reaction and routine diagnostic bacterial culture. Biologic phenotypes were explored using unbiased cluster analysis and biomarkers that differentiated clinical exacerbation phenotypes were investigated. MEASUREMENTS AND MAIN RESULTS: A total of 145 patients (101 men and 44 women) entered the study. A total of 182 exacerbations were captured from 86 patients. Four distinct biologic exacerbation clusters were identified. These were bacterial-, viral-, or eosinophilic-predominant, and a fourth associated with limited changes in the inflammatory profile termed "pauciinflammatory." Of all exacerbations, 55%, 29%, and 28% were associated with bacteria, virus, or a sputum eosinophilia. The biomarkers that best identified these clinical phenotypes were sputum IL-1ß, 0.89 (area under receiver operating characteristic curve) (95% confidence interval [CI], 0.83­0.95); serum CXCL10, 0.83 (95% CI, 0.70­0.96); and percentage peripheral eosinophils, 0.85 (95% CI, 0.78­0.93), respectively. CONCLUSIONS: The heterogeneity of the biologic response of COPD exacerbations can be defined. Sputum IL-1ß, serum CXCL10, and peripheral eosinophils are biomarkers of bacteria-, virus-, or eosinophil-associated exacerbations of COPD. Whether phenotype-specific biomarkers can be applied to direct therapy warrants further investigation.

Dorsal-ventral organization of theta-like activity intrinsic to entorhinal stellate neurons is mediated by differences in stochastic current fluctuations.

The membrane potential dynamics of stellate neurons in layer II of the medial entorhinal cortex are important for neural encoding of location. Previous studies suggest that these neurons generate intrinsic theta-frequency membrane potential oscillations, with a period that depends on neuronal location on the dorsal­ventral axis of themedial entorhinal cortex, and which in behaving animals could support generation of grid-like spatial firing fields. To address the nature and organization of this theta-like activity, we adopt the Lombmethod of least-squares spectral analysis. We demonstrate that peaks in frequency spectra that differ significantly from Gaussian noise do not necessarily imply the existence of a periodic oscillator, but can instead arise from filtered stochastic noise or a stochastic random walk. We show that theta-like membrane potential activity recorded fromstellate neurons in mature brain slices is consistentwith stochastic mechanisms, but not with generation by a periodic oscillator. The dorsal­ventral organization of intrinsic theta-likemembrane potential activity, and themodification of this activity during block of HCN channels, both reflect altered frequency distributions of stochastic spectral peaks, rather than tuning of a periodic oscillator. Our results demonstrate the importance of distinguishing periodic oscillations from stochastic processes.We suggest that dorsal­ventral tuning of theta-like membrane potential activity is due to differences in stochastic current fluctuations resulting from organization of ion channels that also control synaptic integration.

Residual microvascular risk in diabetes: unmet needs and future directions.

The burden of microvascular disease in patients with type 2 diabetes mellitus continues to escalate worldwide. Current standards of care reduce but do not eliminate the risk of diabetic retinopathy, nephropathy or neuropathy in these patients. Correction of atherogenic dyslipidemia, which is characterized by elevated triglyceride levels and low levels of HDL cholesterol, might provide additional benefit. Whereas promising data have been published with respect to fibrate therapy for maculopathy, fenofibrate for diabetic retinopathy, and statin or fibrate therapy for diabetic nephropathy, further studies are warranted to define optimal management strategies for reducing the residual microvascular risk. Such strategies are especially relevant in cases of diabetic peripheral neuropathy, where even optimal care fails to affect disease progression. Identification of those factors that are most relevant to residual diabetes-related microvascular risk is a priority of an ongoing multinational epidemiological study. In this Review, we highlight an urgent need to address the issue of microvascular residual risk in patients with or at risk of type 2 diabetes mellitus.

Exubera inhaled insulin in patients with type 1 and type 2 diabetes: the first 12 months.

BACKGROUND: Following National Institute for Clinical Excellence approval of inhaled insulin Exubera (Pfizer, New York, NY) in 2006, we established a dedicated clinic in January 2007 to monitor the efficacy and safety of Exubera. Between January and October 2007, eight patients started Exubera: six because of needle phobia (DSM-IV criteria) and two with injection site problems. METHODS: Data were collected at the clinic over a 12-month period from February 2007 at 3-, 6-, 9-, and 12-month intervals. The clinic is jointly led by a consultant diabetologist and a diabetes specialist nurse within the secondary care setting. RESULTS: Inhaled insulin was well tolerated in all eight patients who had previously experienced significant problems with initiation or intensification of subcutaneous insulin injections. Mean hemoglobin A1c was 10.7% (range, 8.1-14.2%) at initiation, 8.3% (7.2-9.4%) at 3 months, 7.7% (6.9-9.0%) at 6 months, 7.4% (6.7-8.4%) at 9 months, and 7.5% (6.5-8.7%) at 12 months. At 6 months, six patients had a reduction in forced expiratory volume in the first second (FEV1) by 4-12%, whereas five patients had a reduction of 2-12% at 12 months. One developed dyspnea, with a 29% fall in FEV1, which was transient and secondary to an upper respiratory tract infection. Two patients with the highest starting and most improved hemoglobin A1c developed significant retinopathy. CONCLUSIONS: Our 12-month audit data demonstrate that the initiation of inhaled insulin in this difficult-to-treat group of patients resulted in a significant improvement in glycemic control. The subsequent withdrawal of an alternative and acceptable form of insulin treatment now presents a renewed challenge for our patients and healthcare professionals.

The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia.

Despite achieving targets for low-density lipoprotein (LDL) cholesterol, blood pressure, and glycemia in accordance with current standards of care, patients with dyslipidemia remain at high residual risk of vascular events. Atherogenic dyslipidemia, characterized by elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, often with elevated apolipoprotein B and non-HDL cholesterol, is common in patients with established cardiovascular disease (CVD), type 2 diabetes mellitus, or metabolic syndrome and contributes to both macrovascular and microvascular residual risk. However, atherogenic dyslipidemia is largely underdiagnosed and undertreated in clinical practice. The Residual Risk Reduction Initiative (R3i) was established to address this highly relevant clinical issue. The aims of this position paper are (1) to highlight evidence that atherogenic dyslipidemia is associated with residual macrovascular and microvascular risk in patients at high risk for CVD, despite current standards of care for dyslipidemia and diabetes; and (2) to recommend therapeutic intervention for reducing this residual vascular risk supported by evidence and expert consensus. Lifestyle modification with nutrition and exercise is an important, effective, and underutilized first step in reducing residual vascular risk. Therapeutic intervention aimed at achievement of all lipid targets is also often required. Combination lipid-modifying therapy, with the addition of niacin, a fibrate, or omega-3 fatty acids to statin therapy, increases the probability of achieving all lipid goals. Outcomes studies are in progress to evaluate whether these combination treatment strategies translate to a clinical benefit greater than that achieved with statins alone. The R3i highlights the need to address with lifestyle and/or pharmacotherapy the high level of residual risk of CVD events and microvascular complications among patients with dyslipidemia receiving therapy for high levels of LDL cholesterol and for diabetes in accordance with current standards of care.

Tuning of synaptic integration in the medial entorhinal cortex to the organization of grid cell firing fields.

Neurons important for cognitive function are often classified by their morphology and integrative properties. However, it is unclear if within a single class of neuron these properties tune synaptic responses to the salient features of the information that each neuron represents. We demonstrate that for stellate neurons in layer II of the medial entorhinal cortex, the waveform of postsynaptic potentials, the time window for detection of coincident inputs, and responsiveness to gamma frequency inputs follow a dorsal-ventral gradient similar to the topographical organization of grid-like spatial firing fields of neurons in this area. We provide evidence that these differences are due to a membrane conductance gradient mediated by HCN and leak potassium channels. These findings suggest key roles for synaptic integration in computations carried out within the medial entorhinal cortex and imply that tuning of neural information processing by membrane ion channels is important for normal cognitive function.

The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient.

Despite current standards of care aimed at achieving targets for low-density lipoprotein (LDL) cholesterol, blood pressure and glycaemia, dyslipidaemic patients remain at high residual risk of vascular events. Atherogenic dyslipidaemia, specifically elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, often with elevated apolipoprotein B and non-HDL cholesterol, is common in patients with established cardiovascular disease, type 2 diabetes, obesity or metabolic syndrome and is associated with macrovascular and microvascular residual risk. The Residual Risk Reduction Initiative (R3I) was established to address this important issue. This position paper aims to highlight evidence that atherogenic dyslipidaemia contributes to residual macrovascular risk and microvascular complications despite current standards of care for dyslipidaemia and diabetes, and to recommend therapeutic intervention for reducing this, supported by evidence and expert consensus. Lifestyle modification is an important first step. Additionally, pharmacotherapy is often required. Adding niacin, a fibrate or omega-3 fatty acids to statin therapy improves achievement of all lipid risk factors. Outcomes studies are evaluating whether these strategies translate to greater clinical benefit than statin therapy alone. In conclusion, the R3I highlights the need to address with lifestyle and/or pharmacotherapy the high level of residual vascular risk among dyslipidaemic patients who are treated in accordance with current standards of care.