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1.  Unbalanced Peptidergic Inhibition in Superficial Neocortex Underlies Spike and Wave Seizure Activity 
The Journal of Neuroscience  2015;35(25):9302-9314.
Slow spike and wave discharges (0.5–4 Hz) are a feature of many epilepsies. They are linked to pathology of the thalamocortical axis and a thalamic mechanism has been elegantly described. Here we present evidence for a separate generator in local circuits of associational areas of neocortex manifest from a background, sleep-associated delta rhythm in rat. Loss of tonic neuromodulatory excitation, mediated by nicotinic acetylcholine or serotonin (5HT3A) receptors, of 5HT3-immunopositive interneurons caused an increase in amplitude and slowing of the delta rhythm until each period became the “wave” component of the spike and wave discharge. As with the normal delta rhythm, the wave of a spike and wave discharge originated in cortical layer 5. In contrast, the “spike” component of the spike and wave discharge originated from a relative failure of fast inhibition in layers 2/3—switching pyramidal cell action potential outputs from single, sparse spiking during delta rhythms to brief, intense burst spiking, phase-locked to the field spike. The mechanisms underlying this loss of superficial layer fast inhibition, and a concomitant increase in slow inhibition, appeared to be precipitated by a loss of neuropeptide Y (NPY)-mediated local circuit inhibition and a subsequent increase in vasoactive intestinal peptide (VIP)-mediated disinhibition. Blockade of NPY Y1 receptors was sufficient to generate spike and wave discharges, whereas blockade of VIP receptors almost completely abolished this form of epileptiform activity. These data suggest that aberrant, activity-dependent neuropeptide corelease can have catastrophic effects on neocortical dynamics.
PMCID: PMC4478250  PMID: 26109655
epilepsy; inhibition; neuropeptides; sleep; spike and wave discharges
2.  Generalised sensory system abnormalities in amyotrophic lateral sclerosis: a European multicentre study 
Amyotrophic lateral sclerosis (ALS) is defined as a disease of the motor neurones, although several studies indicate involvement of the sensory nervous system.
To evaluate the sensory nerve conduction studies (NCS) in 88 patients with ALS as part of a European multicentre study.
Seven European clinical neurophysiologists examined consecutive series of ALS patients. The examinations were peer reviewed, and the diagnosis of ALS was confirmed clinically.
20 (22.7%) patients with ALS had sensory NCS abnormalities in at least one nerve. Of those, 11 (12.5% of all patients) obtained an additional peer review diagnosis of electrophysiological polyneuropathy. There was no difference between the subgroups of patients with normal versus abnormal sensory NCS findings with respect to age, duration and region of onset.
The findings support previous reports of sensory involvement in ALS, and raise the question of whether patients with ALS with sensory nerve abnormalities represent a variant of ALS. ALS associated with generalised sensory system abnormalities may be consistent with degeneration of motor neurones and dorsal root ganglion cells.
PMCID: PMC2117695  PMID: 17575020
3.  Multivariate prediction of major adverse cardiac events after 9914 percutaneous coronary interventions in the north west of England 
Heart  2005;92(5):658-663.
To develop a multivariate prediction model for major adverse cardiac events (MACE) after percutaneous coronary interventions (PCIs) by using the North West Quality Improvement Programme in Cardiac Interventions (NWQIP) PCI Registry.
All NHS centres undertaking adult PCIs in north west England.
Retrospective analysis of prospectively collected data on 9914 consecutive patients undergoing adult PCI between 1 August 2001 and 31 December 2003. A multivariate logistic regression analysis was undertaken, with the forward stepwise technique, to identify independent risk factors for MACE. The area under the receiver operating characteristic (ROC) curve and the Hosmer‐Lemeshow goodness of fit statistic were calculated to assess the performance and calibration of the model, respectively. The statistical model was internally validated by using the technique of bootstrap resampling.
Main outcome measures
MACE, which were in‐hospital mortality, Q wave myocardial infarction, emergency coronary artery bypass graft surgery, and cerebrovascular accidents.
Independent variables identified with an increased risk of developing MACE were advanced age, female sex, cerebrovascular disease, cardiogenic shock, priority, and treatment of the left main stem or graft lesions during PCI. The ROC curve for the predicted probability of MACE was 0.76, indicating a good discrimination power. The prediction equation was well calibrated, predicting well at all levels of risk. Bootstrapping showed that estimates were stable.
A contemporaneous multivariate prediction model for MACE after PCI was developed. The NWQIP tool allows calculation of the risk of MACE permitting meaningful risk adjusted comparisons of performance between hospitals and operators.
PMCID: PMC1860907  PMID: 16159983
major adverse cardiac events; percutaneous coronary interventions; risk prediction
4.  An open-label phase II study of low-dose thalidomide in androgen-independent prostate cancer 
British Journal of Cancer  2003;88(6):822-827.
PMCID: PMC2377091  PMID: 12644816
prostate cancer; androgen-independent; thalidomide
7.  An analysis of CPR decision-making by elderly patients. 
Journal of Medical Ethics  1997;23(4):207-212.
Traditionally clinicians have determined their patients' resuscitation status without consultation. This has been condemned as morally indefensible in cases where not for resuscitation (NFR) orders are based on quality of life considerations and when the patient's true wishes are not known. Such instances would encompass most resuscitation decisions in elderly patients. Having previously involved patients in CPR decision-making, we chose formally to explore the reasons behind the choices made. Although the patients were not upset, and readily decided at the time of initial consultation, on later analysing the decision-making we found poor understanding of the procedure, poor recall of information given and in some cases evidence of harm. This may be attributed to impaired decision-making capacity of elderly hospitalised patients as previously shown, or to the discomfort precipitated by having to contemplate the apparent immediacy of cardiac arrest by these patients. We propose that subscribing to autonomy as a general principle needs to be balanced against particular cases where distress may be caused by, or result in, diminished competence and limited autonomy.
PMCID: PMC1377268  PMID: 9279741
9.  Multiple intracranial enterogenous cysts. 
The case of a 40-year-old woman with increasing ataxia is described. Although the clinical presentation and evoked response studies raised the possibility of multiple sclerosis, further investigation revealed multiple cystic intracranial lesions. Surgical excision of one of the lesions relieved the patient's symptoms. Histological examination revealed that this was an enterogenous cyst. Although single cysts of this type have rarely been reported occurring in the posterior cranial fossa, the occurrence of multiple lesions, some in the supratentorial compartment, appears to be unique.
PMCID: PMC1028773  PMID: 3701354
10.  Visual, cortical somatosensory and brainstem auditory evoked potentials following incidental irradiation of the rhombencephalon. 
Visual, cortical somatosensory and brainstem auditory evoked potentials were recorded before incidental irradiation of the rhombencephalon and at 11 weeks and eight months after completion of treatment. No patient experienced neurological symptoms during this period. No consistent changes in evoked potentials were found. The failure to demonstrate subclinical radiation-induced demyelination suggests either that the syndrome of early-delayed radiation rhombencephalopathy occurs in an idiosyncratic manner, or that any subclinical lesions are not detectable by serial evoked potential recordings.
PMCID: PMC1027650  PMID: 6693921

Results 1-10 (10)