Radiation damage by extensive local water ionization from two-step electron-transfer-mediated decay of solvated ions.

Biomolecular radiation damage is largely mediated by radicals and low-energy electrons formed by water ionization rather than by direct ionization of biomolecules. It was speculated that such an extensive, localized water ionization can be caused by ultrafast processes following excitation by core-level ionization of hydrated metal ions. In this model, ions relax via a cascade of local Auger-Meitner and, importantly, non-local charge- and energy-transfer processes involving the water environment. Here, we experimentally and theoretically show that, for solvated paradigmatic intermediate-mass Al3+ ions, electronic relaxation involves two sequential solute-solvent electron transfer-mediated decay processes. The electron transfer-mediated decay steps correspond to sequential relaxation from Al5+ to Al3+ accompanied by formation of four ionized water molecules and two low-energy electrons. Such charge multiplication and the generated highly reactive species are expected to initiate cascades of radical reactions.

High water vs. ad libitum water intake for autosomal dominant polycystic kidney disease: a randomized controlled feasibility trial.

BACKGROUND: Vasopressin stimulates cyst growth in autosomal dominant polycystic kidney disease (ADPKD) and is a key therapeutic target. Evaluation of high water intake as an alternative to pharmacological vasopressin blockade is supported by patients. However feasibility, safety and adherence-promoting strategies required to deliver this remain unknown. AIMS: Assess the feasibility of a definitive randomized high water intake trial in ADPKD. METHODS: In this prospective open-label randomized trial, adult ADPKD patients with eGFR ≥ 20 ml/min/1.73 m2 were randomized to prescribed high water (HW) intake targeting urine osmolality (UOsm) ≤270 mOsm/kg, or ad libitum (AW) intake (UOsm >300 mOsm/kg). Self-management strategies including home-monitoring of urine-specific gravity (USG) were employed to promote adherence. RESULTS: We enrolled 42 participants, baseline median eGFR (HW 68.4 [interquartile range (IQR) 35.9-107.2] vs. AW 75.8 [IQR 59.0-111.0 ml/min/1.73 m2, P = 0.22) and UOsm (HW 353 [IQR 190-438] vs. AW 350 [IQR 240-452] mOsm/kg, P = 0.71) were similar between groups. After 8 weeks, 67% in the HW vs. 24% in AW group achieved UOsm ≤270 mOsm/kg, P = 0.001. HW group achieved lower UOsm (194 [IQR 190-438] vs. 379 [IQR 235-503] mOsm/kg, P = 0.01) and higher urine volumes (3155 [IQR 2270-4295] vs. 1920 [IQR 1670-2960] ml/day, P = 0.02). Two cases of hyponatraemia occurred in HW group. No acute GFR effects were detected. In total 79% (519/672) of USG were submitted and 90% (468/519) were within target. Overall, 17% withdrew during the study. CONCLUSION: DRINK demonstrated successful recruitment and adherence leading to separation between treatment arms in primary outcomes. These findings suggest a definitive trial assessing the impact of high water on kidney disease progression in ADPKD is feasible.

Reduced vitamin D levels in painful diabetic peripheral neuropathy.

AIM: Recent studies have reported an association between low vitamin D levels and diabetic peripheral neuropathy. However, many of these did not differentiate between people with painful diabetic peripheral neuropathy and those with painless diabetic peripheral neuropathy, or assess major confounding factors including sunlight exposure and daily activity. Our study addressed these limitations and evaluated vitamin D levels in people with carefully phenotyped diabetic peripheral neuropathy and controls. METHODS: Forty-five white Europeans with Type 2 diabetes and 14 healthy volunteers underwent clinical and neurophysiological assessments. People with Type 2 diabetes were then divided into three groups (17 with painful diabetic peripheral neuropathy, 14 with painless diabetic peripheral neuropathy and 14 with no diabetic peripheral neuropathy). All had seasonal sunlight exposure and daily activity measured, underwent a lower limb skin biopsy and had 25-hydroxyvitamin D measured during the summer months, July to September. RESULTS: After adjusting for age, BMI, activity score and sunlight exposure, 25-hydroxyvitamin D levels (nmol/l) (se) were significantly lower in people with painful diabetic peripheral neuropathy [painful diabetic peripheral neuropathy 34.9 (5.8), healthy volunteers 62.05 (6.7), no diabetic peripheral neuropathy 49.6 (6.1), painless diabetic peripheral neuropathy 53.1 (6.2); ANCOVAP = 0.03]. Direct logistic regression was used to assess the impact of seven independent variables on painful diabetic peripheral neuropathy. Vitamin D was the only independent variable to make a statistically significant contribution to the model with an inverted odds ratio of 1.11. Lower 25-hydroxyvitamin D levels also correlated with lower cold detection thresholds (r = 0.39, P = 0.02) and subepidermal nerve fibre densities (r = 0.42, P = 0.01). CONCLUSIONS: We have demonstrated a significant difference in 25-hydroxyvitamin D levels in well-characterized people with painful diabetic peripheral neuropathy, while accounting for the main confounding factors. This suggests a possible role for vitamin D in the pathogenesis of painful diabetic peripheral neuropathy. Further prospective and intervention trials are required to prove causality between low vitamin D levels and painful diabetic peripheral neuropathy.

Magnetic resonance for assessment of axillary lymph node status in early breast cancer: a systematic review and meta-analysis.

INTRODUCTION: Current methods of identifying axillary node metastases in breast cancer patients are highly accurate, but are associated with several adverse events. This review evaluates the diagnostic accuracy of magnetic resonance imaging (MRI) techniques for identification of axillary metastases in early stage newly diagnosed breast cancer patients. METHODS: Comprehensive searches were conducted in April 2009. Study quality was assessed. Sensitivity and specificity were meta-analysed using a bivariate random effects approach, utilising pathological diagnosis via node biopsy as the comparative gold standard. RESULTS: Based on the highest sensitivity and specificity reported in each of the nine studies evaluating MRI (n = 307 patients), mean sensitivity was 90% (95% CI: 78-96%; range 65-100%) and mean specificity 90% (95% CI: 75-96%; range 54-100%). Across five studies evaluating ultrasmall super-paramagnetic iron oxide (USPIO)-enhanced MRI (n = 93), mean sensitivity was 98% (95% CI: 61-100%) and mean specificity 96% (95% CI: 72-100%). Across three studies of gadolinium-enhanced MRI (n = 187), mean sensitivity was 88% (95% CI: 78-94%) and mean specificity 73% (95% CI: 63-81%). In the single study of in-vivo proton MR spectroscopy (n = 27), sensitivity was 65% (95% CI: 38-86%) and specificity 100% (95% CI: 69-100%). CONCLUSIONS: USPIO-enhanced MRI showed a trend towards higher sensitivity and specificity and may make a useful addition to the current diagnostic pathway. Additional larger studies with standardised methods and standardised criteria for classifying a node as positive are needed. Current estimates of sensitivity and specificity do not support replacement of SLNB with any current MRI technology in this patient group.

Cytological recognition of herpes simplex virus infection in bronchoscopic samples from the respiratory tract.

Cytological features suggesting herpes simplex virus (HSV) infection in samples obtained at bronchoscopy have been described only very rarely in routinely processed samples. We report four cases where evidence of HSV infection was identified morphologically in samples processed using thin-layer techniques, with polymerase chain reaction confirmation of the presence of virus in three cases. We suggest that the increased morphological clarity provided by this technique for processing these cytology samples may result in the morphological features of viral infection being seen more frequently. Pathologists reporting such samples need to be aware of this possibility in order to avoid potential misinterpretations. In addition, however, respiratory and intensive care physicians unused to receiving cytology reports indicating 'HSV infection' need to be aware that the significance is uncertain and in most cases it is likely to indicate the reactivation of a latent infection.

Positron emission tomography (PET) and magnetic resonance imaging (MRI) for the assessment of axillary lymph node metastases in early breast cancer: systematic review and economic evaluation.

BACKGROUND: Breast cancer is the most common type of cancer in women. Evaluation of axillary lymph node metastases is important for breast cancer staging and treatment planning. OBJECTIVES: To evaluate the diagnostic accuracy, cost-effectiveness and effect on patient outcomes of positron emission tomography (PET), with or without computed tomography (CT), and magnetic resonance imaging (MRI) in the evaluation of axillary lymph node metastases in patients with newly diagnosed early-stage breast cancer. DATA SOURCES: A systematic review of literature and an economic evaluation were carried out. Key databases (including MEDLINE, EMBASE and nine others) plus research registers and conference proceedings were searched for relevant studies up to April 2009. A decision-analytical model was developed to determine cost-effectiveness in the UK. REVIEW METHODS: One reviewer assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. Data from included studies were extracted by one reviewer using a standardised data extraction form and checked by a second reviewer. Discrepancies were resolved by discussion. Quality of included studies was assessed using the quality assessment of diagnostic accuracy studies (QUADAS) checklist, applied by one reviewer and checked by a second. RESULTS: Forty-five citations relating to 35 studies were included in the clinical effectiveness review: 26 studies of PET and nine studies of MRI. Two studies were included in the cost-effectiveness review: one of PET and one of MRI. Of the seven studies evaluating PET/CT (n = 862), the mean sensitivity was 56% [95% confidence interval (CI) 44% to 67%] and mean specificity 96% (95% CI 90% to 99%). Of the 19 studies evaluating PET only (n = 1729), the mean sensitivity was 66% (95% CI 50% to 79%) and mean specificity 93% (95% CI 89% to 96%). PET performed less well for small metastases; the mean sensitivity was 11% (95% CI 5% to 22%) for micrometastases (≤ 2 mm; five studies; n = 63), and 57% (95% CI 47% to 66%) for macrometastases (> 2 mm; four studies; n = 111). The smallest metastatic nodes detected by PET measured 3 mm, while PET failed to detect some nodes measuring > 15 mm. Studies in which all patients were clinically node negative showed a trend towards lower sensitivity of PET compared with studies with a mixed population. Across five studies evaluating ultrasmall super-paramagnetic iron oxide (USPIO)-enhanced MRI (n = 93), the mean sensitivity was 98% (95% CI 61% to 100%) and mean specificity 96% (95% CI 72% to 100%). Across three studies of gadolinium-enhanced MRI (n = 187), the mean sensitivity was 88% (95% CI 78% to 94%) and mean specificity 73% (95% CI 63% to 81%). In the single study of in vivo proton magnetic resonance spectroscopy (n = 27), the sensitivity was 65% (95% CI 38% to 86%) and specificity 100% (95% CI 69% to 100%). USPIO-enhanced MRI showed a trend towards higher sensitivity and specificity than gadolinium-enhanced MRI. Results of the decision modelling suggest that the MRI replacement strategy is the most cost-effective strategy and dominates the baseline 4-node sampling (4-NS) and sentinel lymph node biopsy (SLNB) strategies in most sensitivity analyses undertaken. The PET replacement strategy is not as robust as the MRI replacement strategy, as its cost-effectiveness is significantly affected by the utility decrement for lymphoedema and the probability of relapse for false-negative (FN) patients. LIMITATIONS: No included studies directly compared PET and MRI. CONCLUSIONS: Studies demonstrated that PET and MRI have lower sensitivity and specificity than SLNB and 4-NS but are associated with fewer adverse events. Included studies indicated a significantly higher mean sensitivity for MRI than for PET, with USPIO-enhanced MRI providing the highest sensitivity. However, sensitivity and specificity of PET and MRI varied widely between studies, and MRI studies were relatively small and varied in their methods; therefore, results should be interpreted with caution. Decision modelling based on these results suggests that the most cost-effective strategy may be MRI rather than SLNB or 4-NS. This strategy reduces costs and increases quality-adjusted life-years (QALYs) because there are fewer adverse events for the majority of patients. However, this strategy leads to more FN cases at higher risk of cancer recurrence and more false- positive (FP) cases who would undergo unnecessary axillary lymph node dissection. Adding MRI prior to SLNB or 4-NS has little effect on QALYs, though this analysis is limited by lack of available data. Future research should include large, well-conducted studies of MRI, particularly using USPIO; data on the long-term impacts of lymphoedema on cost and patient utility; studies of the comparative effectiveness and cost-effectiveness of SLNB and 4-NS; and more robust UK cost data for 4-NS and SLNB as well as the cost of MRI and PET techniques. FUNDING: This study was funded by the Health Technology Assessment programme of the National Institute of Health Research.

Positron emission tomography (PET) for assessment of axillary lymph node status in early breast cancer: A systematic review and meta-analysis.

PURPOSE: Sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) are used to assess axillary nodal status in breast cancer, but are invasive procedures associated with morbidity, including lymphoedema. This systematic review evaluates the diagnostic accuracy of positron emission tomography (PET), with or without computed tomography (CT), for assessment of axillary nodes in early breast cancer. METHODS: Eleven databases including MEDLINE, EMBASE and the Cochrane Library, plus research registers and conference proceedings, were searched in April 2009. Study quality was assessed using the QUality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist. Sensitivity and specificity were meta-analysed using a bivariate random effects approach. RESULTS: Across 26 studies evaluating PET or PET/CT (n = 2591 patients), mean sensitivity was 63% (95% CI: 52-74%; range 20-100%) and mean specificity 94% (95% CI: 91-96%; range 75-100%). Across 7 studies of PET/CT (n = 862), mean sensitivity was 56% (95% CI: 44-67%) and mean specificity 96% (90-99%). Across 19 studies of PET-only (n = 1729), mean sensitivity was 66% (50-79%) and mean specificity 93% (89-96%). Mean sensitivity was 11% (5-22%) for micrometastases (≤2 mm; five studies; n = 63), and 57% (47-66%) for macrometastases (>2 mm; four studies; n = 111). CONCLUSIONS: PET had lower sensitivity and specificity than SLNB. Therefore, replacing SLNB with PET would avoid the adverse effects of SLNB, but lead to more false negative patients at risk of recurrence and more false positive patients undergoing unnecessary ALND. The present evidence does not support the routine use of PET or PET-CT for the assessment of the clinically negative axilla.

Corpus callosum morphology and microstructure assessed using structural MR imaging and diffusion tensor imaging: initial findings in adults with neurofibromatosis type 1.

BACKGROUND AND PURPOSE: Imaging studies have shown that children with NF-1 have increased brain volumes compared with age-matched controls and the CCs are disproportionately large. The purpose of this study was to determine if the CC in adults with NF-1 differed from that in matched controls by using DTI and volumetric imaging. MATERIALS AND METHODS: MR imaging with DTI was performed in 10 adults with NF-1 and in 10 age-, sex-, and handedness-matched controls by using a 3T system. Total brain volumes and the areas and central lengths of the CC were calculated, along with the radial width of callosal subdivisions, in the 2 groups. RESULTS: Our results showed that the total brain volume was not significantly different between adults with NF-1 and matched controls. The length and total cross-sectional area of the CC were statistically larger in adults with NF-1 compared with controls (approximately 10% longer and 20% greater area). On DTI we found a preservation of the primary eigenvalue with increases in the minor eigenvalues at the genu. CONCLUSIONS: We have shown that the increased size of the CC found in children with NF-1 is also present in adults with the syndrome, whereas no difference in total brain volume was found.

Sympathetic nerve damage as a potential cause of lymphoedema after axillary dissection for breast cancer.

BACKGROUND: The physiological disturbances leading to lymphoedema after breast cancer surgery are poorly understood. Damage to sympathetic nerves during axillary lymph node dissection (ALND), leading to increased capillary fluid filtration, was investigated as a possible contributory factor. METHODS: The integrity of the upper limb sympathetic nervous system was tested in 36 patients before, and 3 and 12 months after ALND. Forearm vascular resistance (FVR), calculated from forearm blood flow and mean systemic arterial pressure, was measured before and after exposure to lower-body negative pressure. Forearm venous compliance was measured using (99m)Tc-labelled autologous erythrocytes and radionuclide plethysmography before and after cold water immersion of the feet. RESULTS: There were clear changes in FVR and venous compliance in response to sympathetic stimulation but no differences attributable to surgery or between the nine patients who developed lymphoedema and the 27 who did not; nor were there differences between the two arms. There was a trend towards lower preoperative FVR in patients who developed lymphoedema. CONCLUSION: Lymphoedema is not the result of sympathetic nerve damage sustained during ALND. Preoperative FVR may help predict who will get lymphoedema following this surgery.

Interobserver variability in the measurement of abdominal aortic calcification using unenhanced CT.

Arterial calcification is well recognized as being associated with an increased risk of adverse cardiovascular events. Numerous methods for its quantification have been published, with no consensus on the technique used. In order to assess the reproducibility of a novel technique for quantifying aortic calcification, we measured the interobserver variability between two observers analysing the abdominal aortas of 34 volunteer patients. Using non-contrast abdominal CT images together with commercial imaging software, the quantity of calcium in a pre-determined section of aorta was calculated for each patient, and the difference in values obtained between the two observers compared using a Bland-Altman plot. Minimal interobserver variability was observed, with a significant difference in results occurring for only two patients. This protocol therefore represents a reliable technique that may be applied as a future standard in order to facilitate comparison between studies.

Increased arterial stiffness in patients with chronic obstructive pulmonary disease: a mechanism for increased cardiovascular risk.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with a 2-3-fold increase in the risk of ischaemic heart disease, stroke and sudden death. The mechanisms responsible for this association are not clear and appear to be independent of smoking history. OBJECTIVE: We test the hypothesis that patients with COPD have increased arterial stiffness and blood pressure in comparison with age and smoking matched controls. METHODS: In a prospective case control study, we recruited 102 patients with COPD and 103 healthy controls matched for age and smoking status. Patients were assessed by clinical history and spirometry, with arterial stiffness and blood pressure determined using radial artery applanation tonometry and sphygmomanometry. RESULTS: Patients with COPD had increased arterial stiffness compared with matched controls, with elevated augmentation pressure (17 (1) vs 14 (1) mm Hg; p = 0.005) and a reduced time to wave reflection (131 (1) vs 137 (2) ms; p = 0.004). These differences were associated with increases in both diastolic (82 (1) vs 78 (1) mm Hg; p = 0.005) and systolic blood pressure (147 (2) vs 132 (2) mm Hg; p<0.001). Serum C reactive protein concentrations were threefold higher in patients (6.1 (0.9) vs 2.3 (0.4) mg/l; p = 0.001). Data are presented as mean (SEM). CONCLUSIONS: Patients with COPD have increased arterial stiffness and blood pressure in comparison with controls matched for age and smoking status. We speculate that increased systemic inflammation and vascular dysfunction could potentially explain the excess cardiovascular morbidity and mortality associated with COPD.

Magnetic resonance perfusion imaging in malformations of cortical development.

BACKGROUND: Malformations of cortical development vary in neuronal maturity and level of functioning. PURPOSE: To characterize regional relative cerebral blood volume (rCBV) and difference in first moment transit time (TTfm) in polymicrogyria and cortical tubers using magnetic resonance (MR) perfusion imaging. MATERIAL AND METHODS: MR imaging and dynamic T2*-weighted MR perfusion imaging were performed in 13 patients with tuberous sclerosis complex, 10 with polymicrogyria, and 18 controls with developmental delay but no macroscopic brain abnormality. Regions of interest were placed in cortical tubers or polymicrogyric cortex and in the contralateral normal-appearing side in patients with malformations. In "control" subjects, regions of interest were placed in the frontal and parietal lobes in both hemispheres. The rCBV and TTfm of the tuber/contralateral side (rCBV(R)TSC and DeltaTT(FM)TSC) as well as those of the polymicrogyria/contralateral side (rCBV(R)PMG and DeltaTT(FM)PMG) were assessed. The right-to-left asymmetry of rCBV and TTfm in the control group was also assessed (rCBV(R)Controls and DeltaTT(FM)Controls). RESULTS: There was no significant asymmetry between right and left rCBV or TTfm (P>0.05) in controls. There was significant reduction in rCBV(R)TSC compared to rCBV(R)Controls (P<0.05), but no significant difference in DeltaTT(FM)TSC compared to DeltaTT(FM)Controls (P>0.05). There were no significant differences between rCBV(R)PMG and rCBV(R)Controls (P>0.05) or DeltaTT(FM)PMG and DeltaTT(FM)Controls (P>0.05). CONCLUSION: Our findings imply that cerebral blood volume of polymicrogyria is similar to normal cortex, but there is reduced cerebral blood volume in cortical tubers. The lower rCBV ratio of cortical tubers may be related to known differences in pathogenetic timing of the underlying abnormalities during brain development or the presence of gliosis.

Proton spectroscopy and imaging at 3T in ataxia-telangiectasia.

BACKGROUND AND PURPOSE: Ataxia-telangiectasia (A-T) is an autosomal recessive disorder with characteristic neurodegeneration of the cerebellum. We used MR spectroscopy to test the hypothesis that cerebellar metabolism in A-T patients would be abnormal relative to healthy controls. METHODS: Twelve adults with A-T and 12 healthy control subjects underwent MR imaging and long-echo time (1)H-MR spectroscopy at 3T. Voxels were acquired in the region of the dentate nucleus of the cerebellum and in parietooccipital white matter, and ratios for N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) were calculated. RESULTS: All of the A-T patients showed marked cerebellar atrophy of the vermis and hemispheres. Two patients showed multiple small foci of hypointensity on T2*-weighted images throughout their brain suggestive of capillary telangiectasia. A further 2 patients had single low-signal-intensity foci. One patient had a tumor, thought to be meningioma radiologically, that was not suspected clinically. No group differences were found in the cerebral spectra, but analysis of the cerebellum revealed significantly lower NAA/Cho and higher Cho/Cr ratios in the A-T patients compared with the controls. There was no difference between groups for the NAA/Cr ratio. CONCLUSION: The findings suggest increased Cho signal intensity in the cerebellum of adult A-T patients. If this finding is shown through the course of the disease, it may assist in the differentiation of early A-T from other forms of ataxia and provide a marker for monitoring treatment efficacy.

Membrane reinsertion of a myristoyl-peptidyl anchored extracellular domain growth hormone receptor.

The actions of GH are mediated through a cell surface cytokine receptor. We previously demonstrated that naturally occurring truncated membrane bound GH receptors (GHRs) can block GH receptor signaling. We have now investigated whether recombinant extracellular GHR can be conjugated to a myristoylated-peptide (mp) tail and inserted into cell membranes to modulate GHR signaling. Recombinant human extracellular domain (1-241) GHR was expressed in Escherichia coli, purified, and refolded from cell lysate. The free C-terminal cysteine was then reduced and conjugated to an activated preformed mp tail. The properties of the purified tailed GHR (GHR-mp) were then compared with those of the untailed purified GHR 1-241. Fluorescence-activated cell sorter analysis and cell surface binding assays demonstrated that GHR-mp inserted into the cell surface membranes of CHO cells, whereas untailed GHR 1-241 showed no insertion. In a cell-based bioassay GHR-mp partially inhibited wild-type GHR signaling, whereas GHR 1-241 had no effect. Truncated extracellular domain GHR can, when specifically modified with a membrane-localizing mp unit, insert into cell surface membranes and modulate GHR signaling.

Stereotactic radiosurgery for brain arteriovenous malformations: quantitative MR assessment of nidal response at 1 year and angiographic factors predicting early obliteration.

INTRODUCTION: We investigated the role of magnetic resonance angiography (MRA) in the early follow-up of patients after stereotactic radiosurgery (STRS) for cerebral arteriovenous malformations (AVMs) and determined the influence of individual morphological factors of AVMs in early response to treatment. METHODS: A group of 40 patients (41 AVMs) consented to a dedicated 1.5-T MR protocol 12 months after receiving STRS for a brain AVM. In addition to standard spin echo sequences, 3-D contrast-enhanced sliding interleaved Ky MRA (CE-SLINKY) and dynamic time-resolved subtraction angiography (MR-DSA) were performed. Nidal volumes were calculated using CE-SLINKY data in patients with a persisting arteriovenous shunt. Planning angiographic data was investigated in all 40 patients. The following AVM factors were used in the statistical analysis to determine their role in nidus obliteration: (1) maximum linear dimension, (2) nidal volume, (3) AVM location (4) nidal morphology, (5) venous drainage, (6) "high-flow angiographic change", (7) prior embolization, and (8) dose reduction. RESULTS: Complete nidal obliteration was found in 9 patients, 26 showed greater than 50% nidal reduction and 6 had less than 50%. Two AVM factors, venous drainage and AVM location, were found to significantly correlate with rate of obliteration. CONCLUSION: We successfully demonstrated the use of MRA to quantitatively assess the response of AVMs to STRS. Two AVM factors, venous drainage and AVM location were found to correlate with rate of obliteration prior to the application of the Bonferroni correction, but if this more rigorous statistical test was applied then none of the factors was found to be significant.

MR imaging of patients with localisation-related seizures: initial experience at 3.0T and relevance to the NICE guidelines.

The purpose of this study is to describe our initial experience of imaging adults with localisation-related epilepsy using MR imaging at 3.0T. We discuss the findings in the context of the recently released NICE guidelines that provide detailed advice on imaging people with epilepsy in the UK. 120 consecutive people over the age of 16 years with localisation-related epilepsy were referred for clinical MR examinations from a regional neuroscience centre in England. None of the people had had MR examinations prior to the present study. High resolution MR imaging was performed taking advantage of the high field strength and high performance gradients of the system. Two experienced neuroradiologists reported on the examinations independently and the presence and type of pathology was recorded. There was complete agreement between the two reporters in all 120 cases. The overall frequency of abnormalities shown by MR was 31/120 (26%) and the commonest abnormality shown was mesial temporal sclerosis found in 10/120 (8%). Tumours were shown in 4/120, all of which appeared low grade as judged by imaging criteria. Epilepsy is the commonest neurological condition and demands a significant resource in order to provide good care for sufferers. Recent guidelines published in the UK have suggested that the majority of people with epilepsy should receive brain MR as part of their routine assessment. Our work shows that using the most sophisticated MR imaging in a highly selected population there is a modest pick-up rate of brain abnormalities. If a widespread epilepsy-imaging programme is started the detection rate is likely to be much lower. Although MR is acknowledged to be a reliable way of detecting pathology in people with epilepsy there is a dearth of information studying the health economics of imaging epilepsy in relation to patient management and outcomes.

The nonspecific nature of proton spectroscopy in brain masses in children: a series of demyelinating lesions.

MRI imaging has significantly improved the detection of brain lesions over the past few decades. It has high sensitivity to intracranial pathology but confident preoperative tissue diagnosis is relatively unusual. MR spectroscopy provides in-vivo biochemical information and has been used to improve the low specificity of tumour diagnosis. During the last decade there have been a number of reports making the case that proton spectroscopy can distinguish different grades of glial tumours and in some situations provide information on histological type. We report four children who presented with neurological symptoms and focal masses on MRI. MRS in each of them gave results consistent with textbook descriptions of malignancy, but in all four cases the abnormalities were subsequently shown to be due to demyelination. We reiterate that spectroscopic appearances are nonspecific and spectroscopic data should be evaluated in the light of concurrent imaging features and the clinical presentation.

MR imaging and spectroscopy in Lhermitte-Duclos disease.

Lhermitte-Duclos disease is a rare abnormality occurring in the cerebellum with only 130 cases reported in the literature. There is debate as to whether this abnormality is a hamartoma, a malformation or a tumour. In this case report we discuss the spectroscopy findings from two patients presenting with this disease. The patients, one 40-year-old Caucasian woman with a 6-year history of headaches, unsteady gait and falls, deterioration in vision and another 28-year-old Caucasian man with a 1-year history of headaches and a previous history of a transient stroke, were found to have this lesion in the cerebellum. Proton spectroscopic data were obtained using a single-voxel PRESS technique (TE=135 ms, TR=1600 ms), from the region of the abnormality. The results were expressed as ratios under the three prominent resonances representing choline (Cho), creatine (Cr), and N-acetyl (NA) moieties. The metabolite ratios were compared to normative data. The two cases demonstrated reduced ratios in NA/Cho and NA/Cr in relation to the controls. The ratios of Cho/Cr appeared closer to the normal mean ratio. There were peaks attributable to lactate in both cases. The low NA/Cr and NA/Cho ratios could be due to the apparent lack of neuronal architecture and the presence of embryonic neural tissue, which does not express NA, indicating more favourably towards a 'benign' hamartoma rather than a tumour.

Infliximab improves endothelial dysfunction in systemic vasculitis: a model of vascular inflammation.

BACKGROUND: Endothelial vasomotor dysfunction and markers of systemic inflammation are independent determinants of cardiovascular risk. However, the link between clinical inflammation and endothelial dysfunction is unclear. The aim of this study was to use anti-neutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) as a model of systemic inflammation in which to test the hypothesis that inflammation is associated with endothelial dysfunction and can be reversed with anti-tumor necrosis factor-alpha (TNF-alpha) therapy. METHODS AND RESULTS: Fourteen patients with active AASV and 21 age-matched control subjects were studied. Endothelial function was assessed through the use of forearm plethysmography and related to clinical disease activity: Birmingham Vasculitis Activity Score (BVAS) and serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), and TNF-alpha. The effects of anti-TNF-alpha therapy (infliximab), either alone (n=6) or in combination with standard treatment (n=4), on endothelial function were subsequently determined. Patients had a mean BVAS of 11+/-1, and CRP and IL-6 were higher in the AASV group than in control subjects (34.8+/-10.5 versus 1.6+/-0.2 pg/mL, P<0.001; 9.0+/-0.7 versus 6.7+/-0.6 pg/mL, P=0.02). Forearm blood flow response to acetylcholine (ACh) was reduced in the patients compared with control subjects (P=0.002), but sodium nitroprusside (SNP) responses were not (P=0.3). The response to ACh improved with infliximab treatment (P=0.004) in particular, with infliximab alone (P=0.03). CONCLUSIONS: AASV is associated with endothelial dysfunction. Anti-TNF-alpha therapy, alone or in combination with standard treatment, results in clinical remission, reduced inflammation, and improved endothelium-dependent vasomotor responses.

Inflammation and arterial stiffness in systemic vasculitis: a model of vascular inflammation.

OBJECTIVE: Arterial stiffness, an independent determinant of cardiovascular risk, is regulated by both structural and functional factors, including endothelium-derived nitric oxide. Endothelial dysfunction is associated with acute and chronic systemic inflammation. However, the role of systemic inflammation in arterial stiffening has not been determined. The aim of this study was to investigate the relationship between inflammation and arterial stiffness in patients with antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) as a model of systemic inflammation. METHODS: Thirty-one patients with AASV (15 with active disease) and 32 age-matched controls were studied. Pulse wave velocity (PWV) and the augmentation index (AIx) were assessed noninvasively and related to serum levels of C-reactive protein (CRP), interleukin-6, and tumor necrosis factor alpha. RESULTS: In subjects with active disease, the AIx, PWV, and level of CRP were elevated compared with that in controls (mean +/- SEM 31 +/- 3% versus 22 +/- 2% [P = 0.003], 9.2 +/- 0.7 versus 7.5 +/- 0.3 meters/second [P = 0.03], and 16.0 +/- 4.0 versus 1.1 +/- 0.1 mg/liter [P < 0.001], respectively). However, PWV and the AIx were not significantly different between patients with disease in remission and controls (8.0 +/- 0.5 versus 7.5 +/- 0.3 meters/second and 19 +/- 3% versus 22 +/- 2%, respectively). The CRP level was positively correlated with both PWV and the AIx. Multiple regression analysis indicated that age, mean arterial pressure (MAP), and CRP were independently related to PWV, and that age, MAP, CRP, sex, and heart rate were associated with the AIx. CONCLUSION: These data indicate that AASV is associated with increased arterial stiffness, and that stiffness correlates with the degree of active inflammation.