Golgi cell mediated inhibition in the cerebellar granule cell layer

The cerebellar cortex integrates multimodal information from mossy fibre (MF) and climbing fibre inputs to perform a variety of computations relating to movement, motor learning and balance. Before MF information can be combined with climbing fibre input in Purkinje cells (PCs) it must pass through the granule cell (GrC) layer wherein it is transformed by the anatomical connectivity and local inhibitory circuit. GrCs receive both tonic and phasic inhibition, the latter arising from the release of gamma aminobutyric acid (GABA) from Golgi cell (GoC) axons. However, the properties of GoC mediated inhibition and its computational significance are not well understood. I have characterised the GoC–GrC synaptic connection using paired whole-cell patch-clamp recordings. My results show that unitary GoC inputs are smaller than previously realised and are frequently mediated purely by spillover from synapses onto adjacent GrCs. I have used the dynamic clamp method to investigate how changes in the frequency and synchrony of spiking in the GoC network can affect GrC computation. I found that changes in GoC firing rate strongly modulate the gain of the GrC input–output (I–O) function, while GoC synchrony can create permissive and non-permissive windows resulting in a patternation of GrC firing that may convey a temporal signal to downstream PCs. GoCs are subject to regulation through the activation of metabotropic glutamate receptors (mGluRs) and nicotinic acetylcholine receptors (nAChRs). I have investigated how these modulatory inputs to GoCs might affect their inhibitory output and show that mGluR activation dramatically reduces GABA release while nAChR activation dramatically increases GABA release from GoCs. My results show that GoCs can exert potent inhibitory control over GrCs that could be relevant to the processing of both temporally coded and rate coded information

Preliminary results on electrophoretic and immunoelectrophoretic fractionation of bovine muscle extract

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Vascular risk factors and diabetic neuropathy

Background: Other than glycemic control, there are no treatments for diabetic neuropathy. Thus, identifying potentially modifiable risk factors for neuropathy is crucial. We studied risk factors for the development of distal symmetric neuropathy in 1172 patients with type 1 diabetes mellitus from 31 centers participating in the European Diabetes (EURODIAB) Prospective Complications Study. Methods: Neuropathy was assessed at baseline (1989 to 1991) and at follow-up (1997 to 1999), with a mean (±SD) follow-up of 7.3±0.6 years. A standardized protocol included clinical evaluation, quantitative sensory testing, and autonomic-function tests. Serum lipids and lipoproteins, glycosylated hemoglobin, and the urinary albumin excretion rate were measured in a central laboratory. Results: At follow-up, neuropathy had developed in 276 of 1172 patients without neuropathy at baseline (23.5 percent). The cumulative incidence of neuropathy was related to the glycosylated hemoglobin value and the duration of diabetes. After adjustment for these factors, we found that higher levels of total and low-density lipoprotein cholesterol and triglycerides, a higher body-mass index, higher von Willebrand factor levels and urinary albumin excretion rate, hypertension, and smoking were all significantly associated with the cumulative incidence of neuropathy. After adjustment for other risk factors and diabetic complications, we found that duration of diabetes, current glycosylated hemoglobin value, change in glycosylated hemoglobin value during the follow-up period, body-mass index, and smoking remained independently associated with the incidence of neuropathy. Cardiovascular disease at baseline was associated with double the risk of neuropathy, independent of cardiovascular risk factors. Conclusions: This prospective study indicates that, apart from glycemic control, the incidence of neuropathy is associated with potentially modifiable cardiovascular risk factors, including a raised triglyceride level, body-mass index, smoking, and hypertension

Aspirin Resistance in Cardiovascular Disease: A Review

AbstractBackground. Aspirin is effective at reducing the cardiovascular event rate in defined patient groups. The introduction of antiplatelet therapies other than aspirin and the concept of aspirin resistance have led to critical reappraisal of current treatment. This review aims to clarify the evidence for aspirin resistance in patients with atherosclerosis.Methods. Medline search was performed to identify publications concerned with antiplatelet effects of aspirin and failure of aspirin therapy. Manual cross referencing was also performed.Results and conclusion. Wide variations in the rate of aspirin resistance (5.5–75%) have been reported. The lack of consensus on an appropriate definition and the number of different tests used to investigate aspirin resistance needs to be addressed. There are few studies where the primary aim was to document aspirin resistance or aspirin non-response. Further work should aim to investigate if aspirin resistance is clinically important and, if it is, what treatments may be beneficial to the at risk patient

Vascular risk factors and diabetic neuropathy

Background: Other than glycemic control, there are no treatments for diabetic neuropathy. Thus, identifying potentially modifiable risk factors for neuropathy is crucial. We studied risk factors for the development of distal symmetric neuropathy in 1172 patients with type 1 diabetes mellitus from 31 centers participating in the European Diabetes (EURODIAB) Prospective Complications Study. Methods: Neuropathy was assessed at baseline (1989 to 1991) and at follow-up (1997 to 1999), with a mean (±SD) follow-up of 7.3±0.6 years. A standardized protocol included clinical evaluation, quantitative sensory testing, and autonomic-function tests. Serum lipids and lipoproteins, glycosylated hemoglobin, and the urinary albumin excretion rate were measured in a central laboratory. Results: At follow-up, neuropathy had developed in 276 of 1172 patients without neuropathy at baseline (23.5 percent). The cumulative incidence of neuropathy was related to the glycosylated hemoglobin value and the duration of diabetes. After adjustment for these factors, we found that higher levels of total and low-density lipoprotein cholesterol and triglycerides, a higher body-mass index, higher von Willebrand factor levels and urinary albumin excretion rate, hypertension, and smoking were all significantly associated with the cumulative incidence of neuropathy. After adjustment for other risk factors and diabetic complications, we found that duration of diabetes, current glycosylated hemoglobin value, change in glycosylated hemoglobin value during the follow-up period, body-mass index, and smoking remained independently associated with the incidence of neuropathy. Cardiovascular disease at baseline was associated with double the risk of neuropathy, independent of cardiovascular risk factors. Conclusions: This prospective study indicates that, apart from glycemic control, the incidence of neuropathy is associated with potentially modifiable cardiovascular risk factors, including a raised triglyceride level, body-mass index, smoking, and hypertension

Coastal inundation and damage exposure estimation: a case study for Jakarta

Coastal flooding poses serious threats to coastal areas, and the vulnerability of coastal communities and economic sectors to flooding will increase in the coming decades due to environmental and socioeconomic changes. It is increasingly recognised that estimates of the vulnerability of cities are essential for planning adaptation measures. Jakarta is a case in point, since parts of the city are subjected to regular flooding on a near-monthly basis. In order to assess the current and future coastal flood hazard, we set up a GIS-based flood model of northern Jakarta to simulate inundated area and value of exposed assets. Under current conditions, estimated damage exposure to extreme coastal flood events with return periods of 100 and 1,000 years is high (€4.0 and €5.2 billion, respectively). Under the scenario for 2100, damage exposure associated with these events increases by a factor 4-5, with little difference between low/high sea-level rise scenarios. This increase is mainly due to rapid land subsidence and excludes socioeconomic developments. We also develop a detemporalised inundation scenario for assessing impacts associated with any coastal flood scenario. This allows for the identification of critical points above which large increases in damage exposure can be expected and also for the assessment of adaptation options against hypothetical user-defined levels of change, rather than being bound to a discrete set of a priori scenarios. The study highlights the need for urgent attention to the land subsidence problem; a continuation of the current rate would result in catastrophic increases in damage exposure. © 2010 The Author(s)

Out-of-equilibrium singlet-triplet Kondo effect in a single C_60 quantum dot

We have used an electromigration technique to fabricate a $\rm{C_{{60}}}$ single-molecule transistor (SMT). Besides describing our electromigration procedure, we focus and present an experimental study of a single molecule quantum dot containing an even number of electrons, revealing, for two different samples, a clear out-of-equilibrium Kondo effect. Low temperature magneto-transport studies are provided, which demonstrates a Zeeman splitting of the finite bias anomaly.Comment: 6 pages, 4 figure

A computationally and cognitively plausible model of supervised and unsupervised learning

Author version made available in accordance with the publisher's policy. "The final publication is available at link.springer.com”The issue of chance correction has been discussed for many decades in the context of statistics, psychology and machine learning, with multiple measures being shown to have desirable properties, including various definitions of Kappa or Correlation, and the psychologically validated ΔP measures. In this paper, we discuss the relationships between these measures, showing that they form part of a single family of measures, and that using an appropriate measure can positively impact learning

Measurements of Scintillation Efficiency and Pulse-Shape for Low Energy Recoils in Liquid Xenon

Results of observations of low energy nuclear and electron recoil events in liquid xenon scintillator detectors are given. The relative scintillation efficiency for nuclear recoils is 0.22 +/- 0.01 in the recoil energy range 40 keV - 70 keV. Under the assumption of a single dominant decay component to the scintillation pulse-shape the log-normal mean parameter T0 of the maximum likelihood estimator of the decay time constant for 6 keV < Eee < 30 keV nuclear recoil events is equal to 21.0 ns +/- 0.5 ns. It is observed that for electron recoils T0 rises slowly with energy, having a value ~ 30 ns at Eee ~ 15 keV. Electron and nuclear recoil pulse-shapes are found to be well fitted by single exponential functions although some evidence is found for a double exponential form for the nuclear recoil pulse-shape.Comment: 11 pages, including 5 encapsulated postscript figure

Herd-level risk factors of bovine tuberculosis in England and Wales after the 2001 foot-and-mouth disease epidemic

We present the results of a 2005 case–control study of bovine tuberculosis (bTB) breakdowns in English and Welsh herds. The herd management, farming practices, and environmental factors of 401matched pairs of case and control herds were investigated to provide a picture of herd-level risk factors in areas of varying bTB incidence. A global conditional logistic regression model, with region-specific variants, was used to compare case herds that had experienced a confirmed bTB breakdown to contemporaneous control herds matched on region, herd type, herd size, and parish testing interval. Contacts with cattle from contiguous herds and sourcing cattle from herds with a recent history of bTB were associated with an increased risk in both the global and regional analyses. Operating a farm over several premises, providing cattle feed inside the housing, and the presence of badgers were also identified as significantly associated with an increased bTB risk. Steps taken to minimize cattle contacts with neighboring herds and altering trading practices could have the potential to reduce the size of the bTB epidemic. In principle, limiting the interactions between cattle and wildlife may also be useful; however this study did not highlight any specific measures to implement