Pontospinal noradrenergic neurons form a component of an endogenous analgesic system and represent a potential therapeutic target. We tested the principle that genetic manipulation of their excitability can alter nociception using an adenoviral vector (AVV-PRS-hKir 2.1 ) containing a catecholaminergic-selective promoter (PRS) to retrogradely transduce and inhibit the noradrenergic neurons projecting to the lumbar dorsal horn through the expression of a potassium channel (hKir 2.1 ). Expression of hKir 2.1 in catecholaminergic PC12 cells hyperpolarized the membrane potential and produced a barium-sensitive inward rectification. LC neurons transduced by AVV-PRShKir 2.1 in slice cultures also showed barium-sensitive inward rectification and reduced spontaneous firing rate (median 0.2 Hz; n ϭ 19 vs control 1.0 Hz; n ϭ 18, p Ͻ 0.05). Pontospinal noradrenergic neurons were retrogradely transduced in vivo by injection of AVV into the lumbar dorsal horn (L4 -5). Rats transduced with AVV-PRS-hKir 2.1 showed thermal but not mechanical hyperalgesia. Similar selective augmentation of thermal hyperalgesia was seen in the CFA-inflammatory pain model after AVV-PRS-hKir 2.1 . In the formalin test, rats transduced with hKir 2.1 showed enhanced nocifensive behaviors (both Phase I and II, p Ͻ 0.05, n ϭ 11/group) and increased c-Fos-positive cells in the lumbar dorsal horn. Transduction with AVV-PRS-hKir 2.1 before spared nerve injury produced no change in tactile or cold allodynia. Thus, the selective genetic inhibition of ϳ150 pontospinal noradrenergic neurons produces a modality-specific thermal hyperalgesia, increased nocifensive behaviors, and spinal c-Fos expression in the formalin test, but not in the spared nerve injury model of neuropathic pain, indicating that these neurons exert a selective tonic restraining influence on in vivo nociception.
The aetiology of central post-stroke pain (CPSP) is poorly understood and such pains are often refractory to treatment. We report the case of a 56-year-old man, who, following a temporo-parietal infarct, suffered from debilitating and refractory hemi-body cold dysaesthesia and severe tactile allodynia. This was associated with thermal and tactile hypoaesthesia and hypoalgesia on his affected side. Implantation of a deep brain stimulating electrode in his periventricular gray (PVG) region produced an improvement in his pain that was associated with a striking normalisation of his deficits in somatosensory perception. This improvement in pain and thermal sensibility was reversed as stimulation became less effective, because of increased electrode impedance. Therefore, we postulate that the analgesic benefit may have occurred as a consequence of the normalisation of somatosensory function and we discuss these findings in relation to the theories of central pain generation and the potential to engage useful plasticity in central circuits.
The lack of primary care representation on the Medical Schools Council and medical school websites is interesting. 1 However, this is just one aspect of a complex problem and does not explain, for example, the variation between medical schools in the proportion of graduates entering primary care.The GP Task Force Report and research papers have called for studies on why this difference exists. 2 3 What role does selection to schools play (nature) and what role do the schools themselves play (nurture)? Do we take truly undifferentiated "stem doctors," as they have been described, and mould them during their time at medical school, or do these students already have strong preconceived ideas? Many studies have looked at factors that influence choice of specialty. 4 We know the recruitment figures. What we don't know is why 11.2% of Cambridge graduates were appointed to GP training in 2012 compared with 38.5% from Keele. 5 Investigation into the differences between the "worst" and "best" performers in terms of producing future GPs will probably shed light on how we can improve recruitment, and seems less radical than firing the Medical Schools Council.
Payment by results was initially introduced into the NHS in 2004 in foundation hospitals. It was then introduced in the rest of the NHS for elective work in April 2005 and for non-elective work in April 2006. Departments are now expected to cost their trauma workload and justify expenditure. Payment by results should mean that a department gets financial credit via payments to the trust for the work it actually does on a patient-by-patient basis. However, a department will only get full credit for the work it does if all patient interactions are recorded accurately.
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