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Uplifting fractured granitic rocks occur in substantial areas of countries such as Japan. Some of these areas might be considered when siting a deep geological repository for radioactive wastes. A repository site would be selected in such an area only if it is possible to make a safety case, accounting for the changing conditions during uplift. The safety case must include robust arguments that chemical processes in the rocks around the repository will contribute sufficiently to minimise radiological doses to biosphere receptors. Numerical modelling is an important aspect of making these arguments. To provide confidence in the safety arguments, numerical models need to be sufficiently realistic, but also parameterised conservatively (pessimistically). However, model development is challenging because uplift involves many complex couplings between groundwater flow, chemical reactions between water and rock, and changing rock properties. The couplings would affect radionuclide mobilisation and retardation, by influencing diffusive radionuclide fluxes between groundwater flowing in fractures and effectively immobile porewater in the rock matrix (rock matrix diffusion, RMD) and radionuclide partitioning between water and solid phases, via: (i) mineral precipitation/dissolution; (ii) mineral alteration; and (iii) sorption/desorption. It is difficult to represent all this complexity in numerical models while showing that they are parameterised conservatively. Here we present a modelling approach, illustrated by simulation cases for some exemplar radioelements, to identify realistically conservative process conceptualisations and model parameterisations., (Copyright © 2024. Published by Elsevier B.V.)

Alzheimer's disease and related disorders feature neurofibrillary tangles and other neuropathological lesions composed of detergent-insoluble tau protein. In recent structural biology studies of tau proteinopathy, aggregated tau forms a distinct set of conformational variants specific to the different types of tauopathy disorders. However, the constituents driving the formation of distinct pathological tau conformations on pathway to tau-mediated neurodegeneration remain unknown. Previous work demonstrated RNA can serve as a driver of tau aggregation, and RNA associates with tau containing lesions, but tools for evaluating tau/RNA interactions remain limited. Here, we employed molecular interaction studies to measure the impact of tau/RNA binding on tau microtubule binding and aggregation. To investigate the importance of tau/RNA complexes (TRCs) in neurodegenerative disease, we raised a monoclonal antibody (TRC35) against aggregated tau/RNA complexes. We showed that native tau binds RNA with high affinity but low specificity, and tau binding to RNA competes with tau-mediated microtubule assembly functions. Tau/RNA interaction in vitro promotes the formation of higher molecular weight tau/RNA complexes, which represent an oligomeric tau species. Coexpression of tau and poly(A)45 RNA transgenes in Caenorhabditis elegans exacerbates tau-related phenotypes including neuronal dysfunction and pathological tau accumulation. TRC35 exhibits specificity for Alzheimer's disease-derived detergent-insoluble tau relative to soluble recombinant tau. Immunostaining with TRC35 labels a wide variety of pathological tau lesions in animal models of tauopathy, which are reduced in mice lacking the RNA binding protein MSUT2. TRC-positive lesions are evident in many human tauopathies including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease. We also identified ocular pharyngeal muscular dystrophy as a novel tauopathy disorder, where loss of function in the poly(A) RNA binding protein (PABPN1) causes accumulation of pathological tau in tissue from post-mortem human brain. Tau/RNA binding drives tau conformational change and aggregation inhibiting tau-mediated microtubule assembly. Our findings implicate cellular tau/RNA interactions as modulators of both normal tau function and pathological tau toxicity in tauopathy disorders and suggest feasibility for novel therapeutic approaches targeting TRCs., (Published by Oxford University Press on behalf of the Guarantors of Brain 2023.)

Aggregates of Aβ peptide and the microtubule-associated protein tau are key molecular hallmarks of Alzheimer's disease (AD). However, the interaction between these two pathologies and the mechanisms underlying disease progression have remained unclear. Numerous failed clinical trials suggest the necessity for greater mechanistic understanding in order to refine strategies for therapeutic discovery and development. To this end, we have generated a transgenic Caenorhabditis elegans model expressing both human Aβ1-42 peptide and human tau protein pan-neuronally. We observed exacerbated behavioral dysfunction and age-dependent neurodegenerative changes in the Aβ;tau transgenic animals. Further, these changes occurred in the Aβ;tau transgenic animals at greater levels than worms harboring either the Aβ1-42 or tau transgene alone and interestingly without changes to the levels of tau expression, phosphorylation or aggregation. Functional changes were partially rescued with the introduction of a genetic suppressor of tau pathology. Taken together, the data herein support a synergistic role for both Aβ and tau in driving neuronal dysfunction seen in AD. Additionally, we believe that the utilization of the genetically tractable C. elegans model will provide a key resource for dissecting mechanisms driving AD molecular pathology., (Published by Oxford University Press 2020.)

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of anticancer treatment with microtubule-targeted agents (MTAs). The frequency of severe CIPN, which can be dose limiting and even life threatening, varies widely among different MTAs. For example, paclitaxel induces a higher frequency of severe CIPN than does eribulin. Different MTAs also possess distinct mechanisms of microtubule-targeted action. Recently, we demonstrated that paclitaxel and eribulin differentially affect sciatic nerve axons, with paclitaxel inducing more pronounced neurodegenerative effects and eribulin inducing greater microtubule stabilizing biochemical effects. Here, we complement and extend these axonal studies by assessing the effects of paclitaxel and eribulin in the cell bodies of sciatic nerve axons, housed in the dorsal root ganglia (DRG). Importantly, the microtubule network in cell bodies is known to be significantly more dynamic than in axons. Paclitaxel induced activating transcription factor 3 expression, a marker of neuronal stress/injury. Paclitaxel also increased expression levels of acetylated tubulin and end binding protein 1, markers of microtubule stability and growth, respectively. These effects are hypothesized to be detrimental to the dynamic microtubule network within the cell bodies. In contrast, eribulin had no significant effect on any of these parameters in the cell bodies. Taken together, DRG cell bodies and their axons, two distinct neuronal cell compartments, contain functionally distinct microtubule networks that exhibit unique biochemical responses to different MTA treatments. We hypothesize that these distinct mechanistic actions may underlie the variability seen in the initiation, progression, persistence, and recovery from CIPN.

In this chapter, we describe methods for the purification of both untagged and polyhistidine-tagged tau protein. These protocols utilize a bacterial expression system to produce the tau isoform of interest, followed by heat treatment and column chromatography to separate tau from impurities. These techniques yield a biochemically pure protein with which to pursue any number of questions regarding the mechanisms of tau action., (© 2017 Elsevier Inc. All rights reserved.)

Despite extensive structure-function analyses, the molecular mechanisms of normal and pathological tau action remain poorly understood. How does the C-terminal microtubule-binding region regulate microtubule dynamics and bundling? In what biophysical form does tau transfer trans-synaptically from one neuron to another, promoting neurodegeneration and dementia? Previous biochemical/biophysical work led to the hypothesis that tau can dimerize via electrostatic interactions between two N-terminal 'projection domains' aligned in an anti-parallel fashion, generating a multivalent complex capable of interacting with multiple tubulin subunits. We sought to test this dimerization model directly. Native gel analyses of full-length tau and deletion constructs demonstrate that the N-terminal region leads to multiple bands, consistent with oligomerization. Ferguson analyses of native gels indicate that an N-terminal fragment (tau(45-230) ) assembles into heptamers/octamers. Ferguson analyses of denaturing gels demonstrates that tau(45-230) can dimerize even in sodium dodecyl sulfate. Atomic force microscopy reveals multiple levels of oligomerization by both full-length tau and tau(45-230) . Finally, ion mobility-mass spectrometric analyses of tau(106-144) , a small peptide containing the core of the hypothesized dimerization region, also demonstrate oligomerization. Thus, multiple independent strategies demonstrate that the N-terminal region of tau can mediate higher order oligomerization, which may have important implications for both normal and pathological tau action. The microtubule-associated protein tau is essential for neuronal development and maintenance, but is also central to Alzheimer's and related dementias. Unfortunately, the molecular mechanisms underlying normal and pathological tau action remain poorly understood. Here, we demonstrate that tau can homo-oligomerize, providing novel mechanistic models for normal tau action (promoting microtubule growth and bundling, suppressing microtubule shortening) and pathological tau action (poisoning of oligomeric complexes)., (© 2016 International Society for Neurochemistry.)

Microtubule targeting agents (MTAs) often lead to treatment limiting and life threatening side effects, including chemotherapy-induced peripheral neuropathy (CIPN). The frequency of severe CIPN varies among different MTAs. Since the microtubule binding interactions and mechanisms of action also vary among MTAs, we hypothesized that these distinct mechanisms may underlie the variability in frequency of severe CIPN. Using a two-week, maximum tolerated dose model, we morphologically and biochemically analyzed sciatic nerves from mice treated with either paclitaxel or eribulin. These drugs differ in their manner of microtubule binding and mechanisms of action and reports indicate paclitaxel also induces a higher frequency of severe CIPN than does eribulin. Morphologically, paclitaxel increased the frequency of observed signs of axon degeneration more significantly than did eribulin. Alternatively, eribulin but not paclitaxel induced occasional myelin "halo" structures. Biochemically, paclitaxel, and eribulin both induced α-tubulin expression (~1.9- and ~2.5-fold, respectively) and tubulin acetylation, a marker for microtubule stability, (~5- and ~11.7-fold, respectively). Eribulin but not paclitaxel-induced EB1 expression ~2.2-fold while paclitaxel but not eribulin mildly suppressed EB3 expression. Both EB proteins are associated with microtubule growth. Eribulin's combination of relatively mild deleterious morphological effects coupled with more potent biochemical changes promoting microtubule stability and growth in mice correlate with lower frequencies of severe CIPN in humans. We suggest that these eribulin-induced effects create a relatively stable microtubule network that compensates, in part, for the toxic anti-cancer effects of the drug, leading to fewer reported incidences of CIPN than for paclitaxel.

Chemotherapy-induced peripheral neuropathy is a common, dose-limiting side effect of cancer treatment. This conference was the first of its kind to bring together a wide range of clinicians, researchers, and industry professionals to address the potential causes, preventions, and treatments for this drug toxicity. Intraepidermal nerve fiber loss, axonal degeneration, immune cell infiltration, alterations in tubulin protein expression and microtubule stability, axonal transport, and mitochondrial dysfunction were addressed as possible mechanisms. Problems with animal models of the disease were discussed, as well as the potential of patient-derived induced sensory neurons to serve as a novel in vitro model., (Copyright © 2015, American Association for Cancer Research)

A safety case for the disposal of Intermediate Level (radioactive) Waste (ILW) in a deep geological disposal facility (GDF) requires consideration of the potential for waste-derived light non-aqueous phase liquid (LNAPL) to migrate under positive buoyancy from disposed waste packages. Were entrainment of waste-derived radionuclides in LNAPL to occur, such migration could result in a shorter overall travel time to environmental or human receptors than radionuclide migration solely associated with the movement of groundwater. This paper provides a contribution to the assessment of this issue through multiphase-flow numerical modelling underpinned by a review of the UK's ILW inventory and literature to define the nature of the associated ILW LNAPL source term. Examination has been at the waste package-local GDF environment scale to determine whether proposed disposal of ILW would lead to significant likelihood of LNAPL migration, both from waste packages and from a GDF vault into the local host rock. Our review and numerical modelling support the proposition that the release of a discrete free phase LNAPL from ILW would not present a significant challenge to the safety case even with conservative approximations. 'As-disposed' LNAPL emplaced with the waste is not expected to pose a significant issue. 'Secondary LNAPL' generated in situ within the disposed ILW, arising from the decomposition of plastics, in particular PVC (polyvinyl chloride), could form the predominant LNAPL source term. Released high molecular weight phthalate plasticizers are judged to be the primary LNAPL potentially generated. These are expected to have low buoyancy-based mobility due to their very low density contrast with water and high viscosity. Due to the inherent uncertainties, significant conservatisms were adopted within the numerical modelling approach, including: the simulation of a deliberately high organic material--PVC content wastestream (2D03) within an annular grouted waste package vulnerable to LNAPL release; upper bound inventory estimates of LNAPLs; incorporating the lack of any hydraulic resistance of the package vent; the lack of any degradation of dissolved LNAPL; and, significantly, the small threshold displacement pressure assumed at which LNAPL is able to enter initially water-saturated pores. Initial scoping calculations on the latter suggested that the rate at which LNAPL is able to migrate from a waste package is likely to be very small and insignificant for likely representative displacement pressure data: this represents a key result. Adopting a conservative displacement pressure, however, allowed the effect of other features and processes in the system to be assessed. High LNAPL viscosity together with low density contrast with water reduces LNAPL migration potential. Migration to the host rock is less likely if waste package vent fluxes are small, solubility limits are high and path lengths through the backfill are short. The capacity of the system to dissolve all of the free LNAPL will, however, depend on groundwater availability. Even with the conservatisms invoked, the overall conclusion of model simulations of intact and compromised (cracked or corroded) waste packages, for a range of realistic ILW LNAPL scenarios, is that it is unlikely that significant LNAPL would be able to migrate from the waste packages and even more unlikely it would be sufficiently persistent to reach the host rock immediately beyond the GDF., (Copyright © 2014. Published by Elsevier B.V.)

Aims: To examine the natural history of chronic painful diabetic neuropathy (CPDN)., Methods: A cross-sectional study of 350 people with diabetes was performed during 1998-1999 to assess the prevalence of CPDN in the community. Fifty-six patients with CPDN were identified and were followed up an average of 5 years later., Results: From the original cohort, 12 patients had died and 14 had moved away or were unable to participate in the follow-up study. Thus 30 patients with CPDN [21 male, mean (SD) age 68.6 years (9.4), mean (SD) duration of diabetes 15.4 years (8.7)] were re-assessed. Seven (23%) had been pain free for at least 12 months and 23 continued to report neuropathic pain of similar quality and severity [total McGill Pain Questionnaire Score median (interquartile range) at follow-up 22 (16-39) vs. 20 (16-33) at baseline, P = 0.3; mean (SD) visual analogue scale (VAS) score for pain over the preceding 24 h 5.3 cm (2.9) vs. 4.6 cm (2.5) at baseline, P = 0.1]. Only 65% had ever received treatment for CPDN despite 96% (22/23) reporting pain to their physician; 43.5% had received antidepressants, 17.4% anticonvulsants, 39% opiates and 30% had tried complementary therapies., Conclusions: The neuropathic pain of CPDN can resolve completely over time in a minority (23%). In those in whom painful neuropathic symptoms had persisted over 5 years, no significant improvement in pain intensity was observed. Despite the improvement in treatment modalities for chronic pain in recent years, patients with CPDN continue to be inadequately treated.

Aims: Electrical spinal cord stimulation (ESCS) is a technique for the management of chronic painful diabetic neuropathy (CPDN) affecting the lower limbs. We assessed the efficacy and complication rate of ESCS implanted at least 7 years previously in eight patients., Methods: After a trial period of percutaneous stimulation, eight male patients had been implanted with a permanent system. Mean age at implantation was 53.5 years and all patients were insulin treated with stage 3 severe disabling CPDN of at least 1 year's duration. The ESCS was removed from one patient at 4 months because of system failure and one patient died 2 months after implantation from a myocardial infarction., Results: Six patients were reviewed a mean of 3.3 years post-implantation. With the stimulator off, McGill pain questionnaire (MPQ) scores (a measure of the quality and severity of pain) were similar to MPQ scores prior to ESCS insertion. Pain scores (visual analogue scale) were measured with the stimulator off and on, respectively: background pain [74.5 (63-79) mm vs. 25 (17-33) mm, median (interquartile range), P = 0.03), peak pain (85 (80-92) mm vs. 19 (11-47) mm, P = 0.03]. There were two further cardiovascular deaths (these patients had continued pain relief) and the four surviving patients were reassessed at 7.5 (range 7-8.5) years: background pain [73 (65-77) mm vs. 33 (28-36) mm, median (interquartile range)], peak pain [86 (81-94) mm vs. 42 (31-53) mm]. Late complications (> 6 months post-insertion) occurred in two patients; electrode damage secondary to trauma requiring replacement (n = 1), and skin peeling under the transmitter site (n = 1). One patient had a second electrode implanted in the cervical region which relieved typical neuropathic hand pains., Conclusions: ESCS can continue to provide significant pain relief over a prolonged period of time with little associated morbidity.

Aims: A cross-sectional study has been performed in order to estimate the prevalence, severity, and current treatment of chronic painful peripheral neuropathy (CPPN) in people with diabetes in the community., Methods: Using a structured questionnaire and examination we have assessed these factors in a community sample of people with diabetes (n=350) and compared them with 344 age- and sex-matched people without diabetes from the same locality., Results: The prevalence of CPPN was estimated to be 16.2%[95% confidence interval (CI): 6.8-16%] in people with diabetes compared with 4.9% (95% CI: 2.6-7.2%) in the control sample (P < 0.0001). Diabetic subjects with and without CPPN did not differ in age, sex, type and duration of diabetes, body mass index, smoking status and glycaemic control. However, CPPN diabetic subjects had significantly higher Visual Analogue Scale (VAS) scores for pain over the preceding 24 h [median (interquartile range) 3.5 (1.5-6.7) cm vs. 0.7 (0-3.9) cm, P < 0.0001]. Also, the total McGill Pain Questionnaire Score (a measure of pain quality and severity) was 18 (13-31.5) vs. 10 (4-16) (P < 0.0001). Of patients with diabetes and CPPN, 12.5% (7/56) had never reported their symptoms to their treating physician and 39.3% (22/56) had never received any treatment for their painful symptoms., Conclusions: CPPN is common, often severe but frequently unreported and inadequately treated.

Severely unstable, or brittle, diabetes can be disruptive to patients, carers and diabetes care teams. The peak age-group for brittle diabetes is 15-30, but there are reports of its occurrence in much older patients. To explore the characteristics and cause of brittle instability perceived by diabetologists in elderly patients we circulated a questionnaire to all UK hospital diabetic clinics for adults. 130 (56%) of 231 replied. Reports were obtained on 55 patients fulfilling our criteria for 'elderly brittle diabetes'--namely, age > or =60 years, on insulin treatment, and experiencing life-disrupting glycaemic instability of any kind associated with frequent or long admissions to hospital. Further information was obtained by a research nurse who visited the relevant clinics. The mean age of patients was 74 years (range 60-89) and 71% were female. The brittleness was classed as mixed glycaemic instability in 22 (44%), recurrent ketoacidosis in 16 (29%) and recurrent hypoglycaemia in 15 (27%). In 2 cases there was insufficient information for classification. The diabetes care team judged the brittleness to have multiple origins in two-thirds of the cases: problems with memory or behaviour were rare, and in only 4 cases was deliberate manipulation of therapy considered a possibility. 84% of the patients were living independently. In younger patients the principal manifestation of brittle diabetes is recurrent ketoacidosis. The present survey, though possibly subject to ascertainment bias, indicates that the patterns of instability and their causation may be different in elderly patients. With the growing use of insulin in the elderly, brittle diabetes is likely to be encountered increasingly often in this age-group.

We compared the diet of residents with diabetes with current British Diabetic Association (BDA) recommendations, and the nutritional adequacy and content of the diet using 3-day food diaries. We studied 52 residents with diabetes and 48 age- and sex-matched controls from 37 nursing, residential and elderly mentally infirm homes in one city. The daily intake of fat, protein, carbohydrate and fibre of the group with diabetes did not comply with current BDA guidelines, and 52% of diabetic residents and 46% of controls had a lower daily energy intake than currently recommended. The diet of diabetic residents did not comply with current recommendations. Undernutrition is common in both groups.

Chronic painful diabetic neuropathy causes symptoms that can last for many years and severely impair the quality of life of affected patients. This review describes the epidemiology, pathophysiology and treatment of chronic neuropathic pain. Particular emphasis is placed on a comprehensive review of the management of painful symptoms through a detailed review of the published literature using a variety of databases particularly Medline and EMBASE.

The quality of life (QOL) of 79 people with type 1 and type 2 diabetes and 37 non-diabetic controls was assessed using the Nottingham Health Profile (NHP). The NHP consists of six domains assessing energy, sleep, pain, physical mobility, emotional reactions and social isolation. Symptomatic diabetic neuropathy was present in 41 of the patients. The neuropathy patients had significantly higher scores (impaired QOL) in 5/6 NHP domains than either the other diabetic patients (p < 0.01) or the non-diabetic (p < 0.001) controls. These were: emotional reaction, energy, pain, physical mobility and sleep. The diabetic patients without neuropathy also had significantly impaired QOL for 4/6 NHP domains compared with the non-diabetic control group (p < 0.05) (energy, pain, physical mobility and sleep). This quantification of the detrimental effect on QOL of diabetes, and in particular of chronic symptomatic peripheral diabetic neuropathy, emphasizes the need for further research into effective management of these patients.

In order to assess the relationship between chronic painful diabetic neuropathy and current--or lifetime--smoking habits, the smoking history of 49 diabetic patients was investigated and compared with that of 23 diabetic patients without chronic pain (age 51.0 +/- 1.9 years, mean +/- SEM). Current level of nicotine intake was measured using urinary cotinine (a nicotine metabolite), and expressed as cotinine/creatinine ratio (COT/Cr), and lifetime smoking load by pack years (20 cigarettes per day for 1 year equals 1 pack year). Current pain intensity was evaluated using a visual analogue scale (VAS). The presence of chronic painful diabetic neuropathy was based on clinical history and examination. Of those patients with painful neuropathy, 26% were current smokers (age 54.2 +/- 3.2 years, mean +/- SEM), 31% ex-smokers (age 57.0 +/- 2.9 years), and 43% lifelong nonsmokers (age 58.0 +/- 2.9 years). Pain duration and intensity were similar in all three groups. COT/Cr levels were similar in current diabetic smokers with pain [5.0 (0.2-10.6) micrograms/mg] and the diabetic control group of smokers without pain [6.8 (1.8-13.3) micrograms/mg, NS]. There was no relationship between VAS and either COT/Cr levels or pack years in current smokers, or between duration of pain and pack years in diabetic current or ex-smokers. In conclusion, we found no relationship between current or previous levels of smoking and severity or duration of chronic painful diabetic neuropathy.

Objective: In elderly patients there are few data on the efficacy and safety of pituitary surgery and radiotherapy (DXT). The aim of the present study was to assess the mode of presentation, treatment and outcome of patients > 64 years with a pituitary tumour presenting to a regional neuroendocrine service., Design: A retrospective case note review of all patients with a pituitary tumour, from 1986 to 1993, was performed with DXT information from computerized records., Patients: Forty-four patients were identified: median age 70 (65-83) years; 25 males; followed for a mean of 34 (range 0-84) months., Results: The commonest presenting symptom was with visual disturbance (24 patients) with a further 9 with asymptomatic visual field defects. Five patients had acromegaly and two prolactinoma. Thirty-two patients underwent transsphenoidal surgery (TSS) (with post-operative DXT in 14 cases) and 6 craniotomy. Two patients had DXT as the primary procedure and four were observed. Visual fields improved in 21 of 29 patients. Perioperative complications occurred significantly more often after craniotomy (5/6) than after TSS (6/32) (P < 0.01). Eight patients died during the follow-up period (three deaths tumour related; one death followed DXT)., Conclusions: Pituitary adenoma is a remediable cause of visual disturbance in the elderly. Most tumours were non-functioning. Age alone is not a contraindication to active treatment particularly with transsphenoidal surgery and radiotherapy.

Background: Conventional treatment for painful peripheral diabetic neuropathy is largely symptomatic and often ineffective, with unacceptable side-effects. We tested electrical spinal-cord stimulation for the management of chronic neuropathic pain., Methods: Ten diabetic patients who did not respond to conventional treatment (mean age 51 [SD 9.3] years, six with type II diabetes, mean duration of diabetes 12 [6.3] years, mean duration of neuropathy 5 [2.1] years) were studied. The electrode was implanted in the thoracic/lumbar epidural space. Immediate neuropathic pain relief was assessed by visual analogue scale (VAS) after connecting the electrode, in a random order, to a percutaneous electrical stimulator or to a placebo stimulator. Exercise tolerance was assessed on a treadmill., Findings: Eight subjects had statistically significant pain relief with the electrical stimulator (p < 0.02) and were therefore converted to a permanent system. Statistically significant relief of both background and peak neuropathic pain was achieved at 3 months (n = 7, p = 0.016), at 6 months (n = 7, p = 0.03), and at the end of the study (14 months, n = 7, background pain p = 0.06, peak pain p = 0.03). One patient died 2 months after the start of the study of unrelated cause while continuing to benefit from treatment and another patient ceased to benefit at 4 months. McGill pain questionnaire scores with the stimulator turned off did not change significantly from baseline scores, indicating that the severity of the underlying pain was unaltered. However, with the stimulator turned on, there was a statistically significant (p < 0.05) improvement in all four components of the score, by the end of the study. At the end of the study, six patients continued to gain significant pain relief and used the stimulator as the sole treatment for their neuropathic pain. For example, median background and peak pain scores at the end of study, were, respectively, 77 and 81 with the stimulator off and 23 and 20 with the stimulator on. Exercise tolerance significantly improved at 3 months (n = 7, median % increase 85 [IQR, 62-360], p = 0.015) and at 6 months (n = 6, 163 [61-425], p = 0.0007). Electrophysiological tests, vibration perception-threshold, and glycaemic control were unchanged., Interpretation: Electrical spinal-cord stimulation offers a new and effective way of relieving chronic diabetic neuropathic pain and improves exercise tolerance. The technique should be considered in patients with neuropathic pain who do not respond to conventional treatment.

1. Flow motion is the cyclical variation in blood flow owing to the rhythmical opening and closing of arterioles. Previous studies have suggested that cutaneous flow motion may be altered in diabetic neuropathy but have not been consistent in their findings. 2. In order to assess the effect of diabetic peripheral neuropathy on flow motion, we have examined the frequency and amplitude of flow motion in 12 patients with diabetic peripheral neuropathy, 10 age-matched diabetic patients without peripheral neuropathy and 10 age-matched non-diabetic controls. 3. Peripheral neuropathy was diagnosed by a history of foot ulceration or chronic painful neuropathy, clinical examination and abnormal peroneal nerve conduction velocities. Blood flow, using laser Doppler flowmetry, was measured at four sites on the dorsum of both hands and feet. Flow motion was analysed using fast Fourier transform analysis, between 0.05 and 0.2 Hz, and displayed on a power spectral density graph. Predominant frequency and relative amplitude of flow motion were calculated. 4. Relative amplitude and frequency of flow motion were similar in the hands of all three groups, as was the frequency in the feet of the three groups. Relative amplitude was significantly smaller in the feet of diabetic patients with neuropathy (median 7.2%, 95% confidence interval 4.9-9.4%) than in diabetic patients without neuropathy (median 13.5%, 95% confidence interval 6.3-21.5%, P < 0.02) or in non-diabetic control subjects (median 10.3%, 95% confidence interval 6.9-27.4%, P < 0.02). 5. Flow motion amplitude is reduced in diabetic peripheral neuropathy. The control of flow motion amplitude appears to be at least partly under neurological control.

Objective: To assess whether the development of plantar foot ulceration could be predicted from the mean plantar foot temperature (MFT), as assessed by liquid-crystal contact thermography (LCT), in patients with peripheral neuropathy., Research Design and Methods: Fifty patients with painful diabetic sensorimotor neuropathy were studied prospectively. Initially, 30 patients had no significant peripheral vascular disease (PVD) (ankle:brachial systolic blood pressure ratio > 1.0). LCT was used to assess the MFT from eight standard plantar sites., Results: Initial MFT was higher in the patients without PVD (28.2 +/- 2.9 degrees C, mean +/- SD) than in patients with PVD (25.6 +/- 1.9 degrees C, P < 0.001) and in nondiabetic control subjects (25.7 +/- 2.1 degrees C, P < 0.001). At review, on average 3.6 (range 3.0-4.1) years later, 11 patients had died (6 of whom had PVD), and one was lost to follow-up. Six patients (seven feet) from the group without PVD had developed neuropathic plantar foot ulcers. The initial MFT was significantly higher in these seven feet (30.5 +/- 2.6 degrees C) than in the 38 feet of the 19 survivors in this group (27.8 +/- 2.3 degrees C, P < 0.01). Only one patient with PVD developed a plantar ulcer, although four required foot surgery for ischemic feet., Conclusions: LCT is a simple, inexpensive, and noninvasive method of identifying the neuropathic foot at increased risk of ulceration. Patients with high plantar foot temperatures are at increased risk of neuropathic foot ulceration. A normal or low MFT in the neuropathic foot is a marker of PVD, which confers an increased risk of ischemic foot disease.

Fifty diabetic patients with chronic painful sensorimotor neuropathy were studied prospectively to clarify the natural history of this condition and the roles of small-fibre damage and concomitant peripheral vascular disease (PVD). Initially, 30 patients had no significant PVD (ankle:brachial Doppler ratio > 1.0). Pain was assessed using a visual analogue scale (0-10 cm), and small-fibre function by thermal limen (TL), heat-pain threshold (HPT), and weighted pinprick threshold (PPT). At follow-up, on average 3.6 years later (range 3.0-4.1), 11 patients had died (6 with PVD) and contact had been lost with 6. Pain scores fell in subjects without PVD (n = 24; median (range), from 4.8 (0.5-10.0) to 2.0 (0.0-9.2) cm, p < 0.001) and also in those with PVD (n = 9; from 5.1 (2.0-8.2) to 2.1 (0.0-8.0) cm, p < 0.05). Seven patients (5 without PVD) became painfree; at presentation, these 7 patients had experienced pain for a shorter period of time. Despite this symptomatic improvement, small-fibre function generally deteriorated in both groups, with significant worsening (p < 0.05) of HPT and PPT in patients without PVD, and in HPT and TL in patients with PVD. Neuropathic pain therefore tends to improve with time and can resolve completely. By contrast, small-fibre function continues to deteriorate, indicating that these peripheral measures do not predict the evolution of painful symptoms. The presence or absence of PVD does not appear to affect the natural history of neuropathic pain or its symptomatology.

The attitudes of elderly patients towards clinical teaching of medical students was assessed by a structured interview carried out by a doctor unknown to the patient immediately prior to discharge. One hundred and thirty alert patients were approached on three acute geriatric medicine wards in the Royal Liverpool (Teaching) Hospital. A total of 106 (81.5%) patients were suitable for inclusion in the study (mean age, 80.2 years). Twenty-nine per cent did not know what a medical student was despite having been interviewed and examined by one. Fifty-nine per cent of patients had no prior knowledge that clinical teaching occurred. Fourteen patients (13 women, 1 man, P < 0.05) objected to being examined. Nineteen women patients were examined by a man student without a chaperone. Students usually (95%) asked permission to interview and examine the patients whereas doctors only asked patients in the context of bedside teaching (33%). Elderly patients were sympathetic towards ('They have to learn') and positive about ('It's good to have them') medical students. However, 29% of patients were not aware that a medical student was going to be a doctor despite being interviewed and examined. We suggest that the term should be used either with explanation or abandoned in favour of 'student doctor'. The level of awareness of clinical teaching was poor and examination of women patients without a chaperone caused distress and should be rectified.

We assessed doctors' knowledge on laws and recommendations regarding fitness to drive in certain medical conditions by a questionnaire survey. A total of 646 doctors consisting of 400 general practitioners and 246 hospital doctors of all grades were circulated with the questionnaire. The survey was anonymous so non-responders could not be re-circulated. The response rate was 26% general practitioners and 32% (hospital doctors). The results show the poor knowledge of doctors on several aspects of fitness to drive. It is necessary for all doctors to have a basic knowledge on the laws and recommendations on fitness to drive so that they can advise their patients correctly. Our survey clearly shows that doctors' knowledge is poor. Many drivers may therefore be placing themselves and others at risk. It is mandatory that this subject receives more attention in undergraduate and postgraduate education and that doctors should be regularly updated on new recommendations from the Driver and Vehicle Licensing Agency.

Doctors' knowledge of socio-legal aspects of patient care is poor. To quantify this a questionnaire on certain socio-legal topics was sent to 400 general practitioners and 250 hospital doctors. The responses were compared to a group of social workers. Both hospital doctors and general practitioners did badly on all topics considered. Social workers' knowledge was significantly better overall, (P < 0.01). Our results confirm the lack of knowledge amongst a broad spectrum of doctors. We suggest that this may be related to a lack of emphasis on these aspects in both undergraduate and postgraduate education.