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1.  Thalamic Dysfunction in Schizophrenia Suggested by Whole-Night Deficits in Slow and Fast Spindles 
The American journal of psychiatry  2010;167(11):1339-1348.
Slow waves and sleep spindles are the two main oscillations occurring during NREM sleep. While slow oscillations are primarily generated and modulated by the cortex, sleep spindles are initiated by the thalamic reticular nucleus (TRN), and regulated by thalamo-reticular and thalamo-cortical circuits. In a recent high-density electroencephalographic (hd-EEG) study we found that 18 medicated schizophrenics had reduced sleep spindles compared to healthy and depressed subjects during the first NREM episode. Here we investigated whether spindle deficits were: a) present in a larger sample of schizophrenic patients; b) consistent across the night; c) related to antipsychotic medications; d) suggestive of impairments in specific neuronal circuits. Whole night hd-EEG recordings were performed in 49 schizophrenics, 20 non-schizophrenic patients on antipsychotics and 44 healthy subjects. In addition to sleep spindles, several parameters of slow waves were assessed. Schizophrenics had whole-night deficits in spindle power (12–16 Hz) and in slow (12–14 Hz) and fast (14–16 Hz) spindle amplitude, duration, number and integrated spindle activity (ISA) in prefrontal, centroparietal and temporal regions. ISA and spindle number had the largest effect sizes (ES≥2.21). By contrast, no slow wave deficits were found in schizophrenics. These results indicate that spindle deficits i) can be reliably established in schizophrenics, ii) are stable across the night, iii) are unlikely to be due to antipsychotic medications, and iv) point to deficits in TRN and thalamo-reticular circuits.
doi:10.1176/appi.ajp.2010.09121731
PMCID: PMC2970761  PMID: 20843876
2.  Obesity-Induced Insulin Resistance in Human Skeletal Muscle Is Characterised by Defective Activation of p42/p44 MAP Kinase 
PLoS ONE  2013;8(2):e56928.
Insulin resistance (IR), an impaired cellular, tissue and whole body response to insulin, is a major pathophysiological defect of type 2 diabetes mellitus. Although IR is closely associated with obesity, the identity of the molecular defect(s) underlying obesity-induced IR in skeletal muscle remains controversial; reduced post-receptor signalling of the insulin receptor substrate 1 (IRS1) adaptor protein and downstream effectors such as protein kinase B (PKB) have previously been implicated. We examined expression and/or activation of a number of components of the insulin-signalling cascade in skeletal muscle of 22 healthy young men (with body mass index (BMI) range, 20–37 kg/m2). Whole body insulin sensitivity (M value) and body composition was determined by the hyperinsulinaemic (40 mU. min−1.m−2.), euglycaemic clamp and by dual energy X-ray absorptiometry (DEXA) respectively. Skeletal muscle (vastus lateralis) biopsies were taken before and after one hour of hyperinsulinaemia and the muscle insulin signalling proteins examined by western blot and immunoprecipitation assay. There was a strong inverse relationship between M-value and BMI. The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity. However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions. In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident. These findings implicate defective p42/44 MAP kinase signalling as a potential contributor to obesity-related IR in a non-diabetic population, although clearly multiple signalling defects underlie obesity associated IR.
doi:10.1371/journal.pone.0056928
PMCID: PMC3585240  PMID: 23468892
3.  Impact of student choice on academic performance: cross-sectional and longitudinal observations of a student cohort 
BMC Medical Education  2013;13:26.
Background
Student choice plays a prominent role in the undergraduate curriculum in many contemporary medical schools. A key unanswered question relates to its impact on academic performance.
Methods
We studied 301 students who were in years 2 and 3 of their medical studies in 2005/06. We investigated the relationship between SSC grade and allocated preference. Separately, we examined the impact of ‘self-proposing’ (students designing and completing their own SSC) on academic performance in other, standard-set, summative assessments throughout the curriculum. The chi-squared test was used to compare academic performance in SSC according to allocated preference. Generalised estimating equations were used to investigate the effect of self-proposing on performance in standard-set examinations.
Results
(1) Performance in staff-designed SSC was not related to allocated preference. (2) Performance in year 1 main examination was one of the key predictors of performance in written and OSCE examinations in years 2, 3 and 4 (p<0.001). (3) The higher the score in the year 1 examination, the more likely a student was to self-propose in subsequent years (OR [CI] 1.07 [1.03-1.11], p<0.001). (4) Academic performance of students who self-proposed at least once in years 2 and/or 3 varied according to gender and year of course.
Conclusion
In this study, no association was observed between allocated preference and SSC grade. The effect of self-proposing on academic performance in standard-set examinations was small. Our findings suggest instead that academically brighter students are more likely to design their own modules. Although student choice may have educational benefits, this report does not provide convincing evidence that it improves academic performance.
doi:10.1186/1472-6920-13-26
PMCID: PMC3599899  PMID: 23421549
4.  The comparative effectiveness of statin therapy in selected chronic diseases compared with the remaining population 
BMC Public Health  2012;12:712.
Background
Total cholesterol (TC) concentration is the most commonly used measure of statin efficacy in the UK. This study aimed to evaluate the effectiveness of statins in lowering TC, cardiovascular events (CV) and mortality five common chronic diseases (chronic obstructive pulmonary disease (COPD), osteoarthritis (OA), rheumatoid arthritis (RA), chronic kidney disease (CKD), and diabetes mellitus (DM)) and to compare effectiveness with the rest of the population not recorded as having these diseases.
Methods
A population-based cohort study was conducted in Tayside population who had at least two TC measurements between 1993 and 2007. There were 12,140 patients with chronic diseases and 9,481 patients in the rest of the population not recorded as having these chronic diseases. The main outcomes were TC change from baseline, CV events and all-cause mortality.
Results
Statin-associated TC reductions varied from 15% to 28% with baseline value of between 5.1 and 5.9 mmol/L in the primary prevention (PP) and from 7% to 23% with baseline value of 4.5 to 5.2 mmol/L in the secondary prevention (SP) among chronic diseases patients. In the rest of the population, TC reductions with statins were 31% in PP and 28% in SP with baselines of 6.3 mmol/L and 5.3 mmol/L, respectively (test of heterogeneity with chronic disease groups: p < 0.001). A notional reduction of 0.5 mmol/L in TC predicted variable reductions in incident CV events of 30% in RA, 19% in CKD, and 20% in DM, and recurrent CV events by 62% in COPD, 16% in CKD, and 19% in DM. The corresponding figures for the rest of population were 12% for incident CV events and 17% for the recurrent CV events, respectively. Risk reductions for all-cause mortality varied from 20% to 36% in PP and from 18% to 40% in SP, except in OA or RA patients in the chronic diseases and 11% in PP and 16% in the rest of population (test of heterogeneity: p > 0.05).
Conclusions
The effectiveness of statins in common chronic diseases varied. With the exception of diabetes, statins tends to be less effective in patients with the chronic diseases compared with the rest of the study population. Changes in TC with statins appear not to correlate well with the changes in cardiovascular events and all-cause mortality.
doi:10.1186/1471-2458-12-712
PMCID: PMC3490740  PMID: 22935195
Statins; Total cholesterol; Cardiovascular; Mortality; Chronic diseases
5.  ‘Real-life’ reduction in cholesterol with statins, 1993 to 2002 
AIMS
To evaluate the impact of lipid-lowering treatment on cholesterol concentrations in the setting of normal care.
METHODS
This was a retrospective review of all cholesterol measurements made in Tayside, Scotland, between 1993 and 2002, linked to dispensed prescribing data for lipid-lowering drugs. It was conducted in the setting of normal care and included all patients who underwent cholesterol measurement. The main outcome measure was cholesterol concentration.
RESULTS
A total of 401 489 cholesterol measurements were made on 128 240 patients over the study period. Measurements were categorized as treated and untreated according to whether patients were exposed to lipid-lowering treatment at the time the total cholesterol concentration was measured. Those categorized as untreated fell by 0.86 mmol l−1 (13.9%) and those categorized as treated by 1.45 mmol l−1 (23.5%). The difference between baseline and follow-up cholesterol concentrations in intention-to-treat patients was 1.53 mmol l−1 (24%) in 2002. In the same year, mean cholesterol concentration was 4.71 mmol l−1 (a fall of 1.65 mmol l−1 or 25.9%) in patients judged to be taking their lipid-lowering medication, compared with 5.20 mmol l−1 (a fall of 1.16 mmol l−1 or 18.2%) in those judged not to be taking treatment. Cholesterol fell by 0.38 mmol l−1 (6.3%) in a cohort of never treated patients (n = 33 679) between 1993 and 2002.
CONCLUSIONS
The impact of lipid-lowering drugs on population cholesterol concentrations in the setting of normal care was significant and comparable with the cholesterol reductions seen in the setting of major statin trials, despite a significant proportion of the population receiving low dose treatment. In those subjects judged to be taking their medication, the benefits achieved were substantial. The impact of nondrug factors is indicated by the fall in population cholesterol seen in the absence of lipid-lowering treatment.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Statins reduce cholesterol concentrations and cardiovascular events in randomized clinical trials.Much less is known about their impact in the setting of normal care.
WHAT THIS STUDY ADDS This is the first study to assess the effectiveness of lipid-lowering treatment in the general population.We have also estimated the resultant impact on major vascular events.We have examined the actual and potential impact of lipid-lowering treatment.
doi:10.1111/j.1365-2125.2007.03066.x
PMCID: PMC2291374  PMID: 18241286
coronary heart disease; effectiveness; lipid-lowering treatment; population cholesterol; statin prescribing
6.  ‘Real-life’ reduction in cholesterol with statins, 1993 to 2002 
AIMS
To evaluate the impact of lipid-lowering treatment on cholesterol concentrations in the setting of normal care.
METHODS
This was a retrospective review of all cholesterol measurements made in Tayside, Scotland, between 1993 and 2002, linked to dispensed prescribing data for lipid-lowering drugs. It was conducted in the setting of normal care and included all patients who underwent cholesterol measurement. The main outcome measure was cholesterol concentration.
RESULTS
A total of 401 489 cholesterol measurements were made on 128 240 patients over the study period. Measurements were categorized as treated and untreated according to whether patients were exposed to lipid-lowering treatment at the time the total cholesterol concentration was measured. Those categorized as untreated fell by 0.86 mmol l−1 (13.9%) and those categorized as treated by 1.45 mmol l−1 (23.5%). The difference between baseline and follow-up cholesterol concentrations in intention-to-treat patients was 1.53 mmol l−1 (24%) in 2002. In the same year, mean cholesterol concentration was 4.71 mmol l−1 (a fall of 1.65 mmol l−1 or 25.9%) in patients judged to be taking their lipid-lowering medication, compared with 5.20 mmol l−1 (a fall of 1.16 mmol l−1 or 18.2%) in those judged not to be taking treatment. Cholesterol fell by 0.38 mmol l−1 (6.3%) in a cohort of never treated patients (n = 33 679) between 1993 and 2002.
CONCLUSIONS
The impact of lipid-lowering drugs on population cholesterol concentrations in the setting of normal care was significant and comparable with the cholesterol reductions seen in the setting of major statin trials, despite a significant proportion of the population receiving low dose treatment. In those subjects judged to be taking their medication, the benefits achieved were substantial. The impact of nondrug factors is indicated by the fall in population cholesterol seen in the absence of lipid-lowering treatment.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Statins reduce cholesterol concentrations and cardiovascular events in randomized clinical trials.Much less is known about their impact in the setting of normal care.
WHAT THIS STUDY ADDS This is the first study to assess the effectiveness of lipid-lowering treatment in the general population.We have also estimated the resultant impact on major vascular events.We have examined the actual and potential impact of lipid-lowering treatment.
doi:10.1111/j.1365-2125.2007.03066.x
PMCID: PMC2291374  PMID: 18241286
coronary heart disease; effectiveness; lipid-lowering treatment; population cholesterol; statin prescribing
7.  Temporal dynamics of cortical sources underlying spontaneous and peripherally evoked slow waves 
Progress in brain research  2011;193:201-218.
Slow waves are the most prominent electroencephalographic (EEG) feature of non-rapid eye movement (NREM) sleep. During NREM sleep, cortical neurons oscillate approximately once every second between a depolarized upstate, when cortical neurons are actively firing, and a hyperpolarized downstate, when cortical neurons are virtually silent (Steriade et al., 1993a; Destexhe et al., 1999; Steriade et al., 2001). Intracellular recordings indicate that the origins of the slow oscillation are cortical and that cortico-cortical connections are necessary for their synchronization (Steriade et al. 1993b; Amzica and Steriade, 1995; Timofeev and Steriade, 1996; Timofeev et al., 2000). The currents produced by the near-synchronous slow oscillation of large populations of neurons appear on the scalp as EEG slow waves (Amzica and Steriade, 1997).
Despite this cellular understanding, questions remain about the role of specific cortical structures in individual slow waves. Early EEG studies of slow waves in humans were limited by the small number of derivations employed and by the difficulty of relating scalp potentials to underlying brain activity (Brazier 1949; Roth et al 1956). Functional neuroimaging methods offer exceptional spatial resolution but lack the temporal resolution to track individual slow waves (Maquet, 2000; Dang-Vu et al., 2008). Intracranial recordings in patient populations are limited by the availability of medically necessary electrode placements and can be confounded by pathology and medications (Nir et al., 2010; Cash et al., 2009; Wenneberg 2010).
Source modeling of high-density EEG recordings offers a unique opportunity for neuroimaging sleep slow waves. So far, the results have challenged several of the influential topographic observations about slow waves that had persisted since the original EEG recordings of sleep. These recent analyses revealed that individual slow waves are idiosyncratic cortical events and that the negative peak of the EEG slow wave often involves cortical structures not necessarily apparent from the scalp, like the inferior frontal gyrus, anterior cingulate, posterior cingulate and precuneus (Murphy et al., 2009). In addition, not only do slow waves travel (Massimini et al., 2004), but they often do so preferentially through the areas comprising the major connectional backbone of the human cortex (Hagmann et al., 2008). In this chapter we will review the cellular, intracranial recording and neuroimaging results concerning EEG slow waves. We will also confront a long held belief about peripherally evoked slow waves, also known as K-complexes, namely that they are modality-independent and do not involve cortical sensory pathways. The analysis included here is the first to directly compare K-complexes evoked with three different stimulation modalities within the same subject on the same night using high-density EEG.
doi:10.1016/B978-0-444-53839-0.00013-2
PMCID: PMC3160723  PMID: 21854964
slow oscillation; source modeling; K-complex; neuroimaging; electroencephalography
9.  Estimated GFR reporting is associated with decreased nonsteroidal anti-inflammatory drug prescribing and increased renal function 
Kidney International  2013;84(1):174-178.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used; however, they are also nephrotoxic with both acute and chronic effects on kidney function. Here we determined NSAID prescribing before and after estimated GFR (eGFR) reporting and evaluate renal function in patients who used NSAIDs but stopped these after their first eGFR report. A population-based longitudinal analysis using a record-linkage database was conducted with the GFR estimated using the four-variable equation from the MDRD study and analyzed by trend test, paired t-test, and logistic regression modeling. Prescriptions for NSAIDs significantly decreased from 39,459 to 35,415 after implementation of eGFR reporting from the second quarter of 2005 compared with the first quarter of 2007. Reporting eGFR was associated with reduced NSAID prescriptions (adjusted odds ratio, 0.78). NSAID prescription rates in the 6 months before April 2006 were 18.8, 15.4, and 7.0% in patients with CKD stages 3, 4, and 5 and 15.5, 10.7, and 6.3%, respectively, after eGFR reporting commenced. In patients who stopped NSAID treatment, eGFR significantly increased from 45.9 to 46.9, 23.9 to 27.1, and 12.4 to 26.4 ml/min per 1.73 m2 in 1340 stage 3 patients, 162 stage 4 patients, and 9 stage 5 patients, respectively. Thus, NSAID prescribing decreased after the implementation of eGFR reporting, and there were significant improvements in estimated renal function in patients who stopped taking NSAIDs. Hence, eGFR reporting may result in safer prescribing.
doi:10.1038/ki.2013.76
PMCID: PMC3697045  PMID: 23486517
eGFR; NSAIDs; prescribing rate; renal function

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