Microstructural imaging of the human brain with a 'super-scanner': 10 key advantages of ultra-strong gradients for diffusion MRI.

The key component of a microstructural diffusion MRI 'super-scanner' is a dedicated high-strength gradient system that enables stronger diffusion weightings per unit time compared to conventional gradient designs. This can, in turn, drastically shorten the time needed for diffusion encoding, increase the signal-to-noise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure, an initiative to establish a shared 300 mT/m-gradient facility amongst the microstructural imaging community, describes ten advantages of ultra-strong gradients for microstructural imaging. Specifically, we will discuss how the increase of the accessible measurement space compared to a lower-gradient systems (in terms of Δ, b-value, and TE) can accelerate developments in the areas of 1) axon diameter distribution mapping; 2) microstructural parameter estimation; 3) mapping micro-vs macroscopic anisotropy features with gradient waveforms beyond a single pair of pulsed-gradients; 4) multi-contrast experiments, e.g. diffusion-relaxometry; 5) tractography and high-resolution imaging in vivo and 6) post mortem; 7) diffusion-weighted spectroscopy of metabolites other than water; 8) tumour characterisation; 9) functional diffusion MRI; and 10) quality enhancement of images acquired on lower-gradient systems. We finally discuss practical barriers in the use of ultra-strong gradients, and provide an outlook on the next generation of 'super-scanners'.

Vitrectomy with fibrovascular membrane delamination for proliferative diabetic retinopathy with or without preoperative Avastin.

OBJECTIVE: To describe and compare 1. The changes in intraretinal microstructure using serial spectral domain optical coherence tomography (SD-OCT) preceding and following pars plana vitrectomy and delamination of fibrovascular membranes and 2. Intraoperative and postoperative complications in patients with proliferative diabetic retinopathy (PDR) who had preoperative Avastin (group A) or not (group B). SUBJECTS AND METHOD: This retrospective, interventional case series includes 113 eyes. Outcome measures included LogMAR distance best-corrected visual acuity (BCVA), SD-OCT integrity of photoreceptor inner and outer segments junction (IS/OS), and integrity of external limiting membrane (ELM), intraoperative and postoperative complications. RESULTS: Pre-operative central macular thickness (CMT) was significantly correlated with the final post-operative LogMAR BCVA in group A. Both groups were also categorised into three sub-groups based on post-operative IS/OS integrity (group 0: IS/OS intact; group 1: IS/OS irregular but not completely disrupted; group 2: IS/OS completely disrupted). Mean BCVA improved significantly and IS/OS integrity and ELM integrity postoperatively, were significantly and positively correlated with final BCVA in group A. Intraoperative complications such as iatrogenic tears and haemorrhage and postoperative such as vitreous haemorrhage and neovascular glaucoma were significantly less in group A compared to group B. CONCLUSION: Pre-operative Avastin reduces the risk of intraoperative and postoperative complications and results in better postoperative anatomic and functional outcomes in fibrovascular delamination surgery for patients with PDR.

GPR18 in microglia: implications for the CNS and endocannabinoid system signalling.

A review of what is presently known about the G protein coupled receptor GPR18 in terms of its expression and distribution, pharmacology and potential implications for central nervous system and endocannabinoid system signalling. LINKED ARTICLES This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8.

Visual and anatomical outcomes following vitrectomy for complications of diabetic retinopathy: the DRIVE UK study.

INTRODUCTION: End-stage diabetic eye disease is an important cause of severe visual impairment in the working-age group. With the increasing availability of refined surgical techniques as well as the early diagnosis of disease because of screening, one would predict that the prevalence of this condition is decreasing and the visual outcome is improving. AIM: To study the prevalence and visual outcome following vitrectomy for complications of diabetic retinopathy. MATERIALS AND METHODS: This study identified the patients who underwent vitrectomy from January 2007 to December 2009 because of diabetes-related complications in South East London. Data collected included baseline demographics, best-corrected visual acuity, indication for the vitrectomy, complication, outcome, and duration of follow-up. RESULTS: The prevalence of people requiring vitrectomy who are registered in the diabetes register of this region was 2 per 1000 people with diabetes. Vitrectomy was required in 185 eyes of 158 patients during this period. These included 83 Caucasians, 51 Afro-Caribbeans, 17 South Asians, and 7 from other ethnic groups. There were 58 patients with type I diabetes and 100 with type II, with a mean duration of diabetes of 23 and 16.5 years, respectively. The reason for vitrectomy included tractional retinal detachment (TRD) in 109 eyes, non-clearing vitreous haemorrhage (NCVH) in 68 eyes, and other causes in 8 eyes. In all, 50% of the eyes with TRD and NCVH, and 87% of the eyes with NCVH improved by at least three ETDRS lines at 12 months. Poor predictors of visual success included longer duration of diabetes (OR: 0.69), use of insulin (OR: 0.04), presence of ischaemic heart disease (OR: 0.04), delay in surgery (OR: 0.59), and the failure to attend clinic appointments (OR: 0.58). Preoperative use of intravitreal bevacizumab in eyes with TRD undergoing vitrectomy showed a marginal beneficial effect on co-existent maculopathy (P=0.08) and required less laser intervention post procedure, but did not affect the number of episodes of late-onset vitreous haemorrhage post vitrectomy (P=0.81). CONCLUSION: Visual outcome has improved significantly in eyes with complications due to diabetic retinopathy compared with the previously reported Diabetic Vitrectomy Study.

Ultrasound imaging to assess inter- and intra-fraction motion during bladder radiotherapy and its potential as a verification tool.

AIMS: Organ motion is the principle source of error in bladder cancer radiotherapy. The aim of this study was to evaluate ultrasound bladder volume measurement as a surrogate measure of organ motion during radiotherapy: (1) to assess inter- and intra-fraction bladder variation and (2) as a potential treatment verification tool. MATERIALS AND METHODS: Twenty patients receiving radical radiotherapy for bladder cancer underwent post-void ultrasound bladder volume measurement at the time of radiotherapy treatment planning (RTP), and immediately before (post-void) and after receiving daily fractions. RESULTS: Ultrasound bladder volume measurement was found to be a simple and acceptable method to estimate relative bladder volume changes. Six patients showed significant changes to post-void bladder volume over the treatment course (P<0.05). The mean inter-fraction post-void bladder volume of five patients exceeded their RTP ultrasound bladder volume by more than 50%. Intra-fraction bladder volume increased on 275/308 (89%) assessed fractions, with the mean intra-fraction volume increases of seven patients exceeding their RTP ultrasound bladder volume by more than 50%. CONCLUSIONS: Both day-to-day bladder volume variation and bladder filling during treatment should be considered in RTP and delivery. Ultrasound may provide a practical daily verification tool by: supporting volume limitation as a method of treatment margin reduction; allowing detection of patients who may require interventions to promote bladder reproducibility; and identifying patients with prominent volume changes for the selective application of more advanced adaptive/image-guided radiotherapy techniques.

Evidence that TASK1 channels contribute to the background current in AH/type II neurons of the guinea-pig intestine.

Neurons that have AH (designation of neurons with a prominent and prolonged after hyperpolarizing potential that follows the action potential) electrophysiological characteristics and type II morphology (AH/type II neurons) are the first neurons in reflex circuits in the small intestine. Thus, the state of excitation of these neurons strongly influences the properties of enteric reflexes. The resting outward current in the type II neurons is reduced, causing depolarization and increased excitability, when protein kinase C (PKC) or synaptic inputs are activated, suggesting that regulation of background channels is an important determinant of the state of excitability of these neurons. However, the channels that carry the background current are not yet identified. We used intracellular microelectrodes to record from myenteric AH/type II neurons of the guinea-pig ileum, immunohistochemistry to localize channels and reverse transcriptase-polymerase chain reaction (RT-PCR) to characterize channel transcripts. The blockers of TASK1 channels, bupivacaine (1 mM) and methanandamide (10 muM), depolarized AH/type II neurons by 11.6 mV and 7.9 mV, respectively, and increased resting input resistance by about 30%. The reversal potential determined for the effect of bupivacaine was -92 mV, indicating that bupivacaine acts at K(+) channels, without significant action on other channel types that are open at rest. The membrane potential of type II neurons was depolarized by acidification to pH 6.4, but this depolarization was associated with decreased input resistance and was not reduced by bupivacaine. Thus an unidentified current that is activated by reduced pH masks effects on TASK channels. Slow excitatory post-synaptic potentials in the neurons were reduced in amplitude by methanandamide, suggesting that they are generated in part by closure of TASK1 channels. TASK1 immunoreactivity occurred in all type II neurons (determined by double labeling for IB4 and NeuN), but no type II neurons were immunoreactive for TASK2 or TASK3. These latter channels were localized to non-type II neurons. Transcripts for TASK1, TASK2, TASK3 and other two-pore-domain potassium channels were found in ganglion extracts. It is concluded that TASK1 channels contribute to the resting outward current in AH/type II neurons, and that neurotransmitters that evoke slow depolarizations in these neurons do so through the closure of resting K(+) channels that include TASK1 channels.

Upregulated TRPC1 channel in vascular injury in vivo and its role in human neointimal hyperplasia.

Occlusive vascular disease is a widespread abnormality leading to lethal or debilitating outcomes such as myocardial infarction and stroke. It is part of atherosclerosis and is evoked by clinical procedures including angioplasty and grafting of saphenous vein in bypass surgery. A causative factor is the switch in smooth muscle cells to an invasive and proliferative mode, leading to neointimal hyperplasia. Here we reveal the importance to this process of TRPC1, a homolog of Drosophila transient receptor potential. Using 2 different in vivo models of vascular injury in rodents we show hyperplasic smooth muscle cells have upregulated TRPC1 associated with enhanced calcium entry and cell cycle activity. Neointimal smooth muscle cells after balloon angioplasty of pig coronary artery also express TRPC1. Furthermore, human vein samples obtained during coronary artery bypass graft surgery commonly exhibit an intimal structure containing smooth muscle cells that expressed more TRPC1 than the medial layer cells. Veins were organ cultured to allow growth of neointimal smooth muscle cells over a 2-week period. To explore the functional relevance of TRPC1, we used a specific E3-targeted antibody to TRPC1 and chemical blocker 2-aminoethoxydiphenyl borate. Both agents significantly reduced neointimal growth in human vein, as well as calcium entry and proliferation of smooth muscle cells in culture. The data suggest upregulated TRPC1 is a general feature of smooth muscle cells in occlusive vascular disease and that TRPC1 inhibitors have potential as protective agents against human vascular failure.

Is the coactivation of biceps femoris during isometric knee extension affected by adiposity in healthy young humans?

This study aimed to verify if the level of biceps femoris antagonist activity measured during isometric knee extension was affected by the individual degree of adiposity in 14 young healthy subjects of both genders aged between 18 and 24. Surface EMG signals were recorded from the biceps femoris muscle of the dominant leg during isometric knee extension at three levels of voluntary contraction: maximum (MVC), 80% MVC and 200 N, respectively. In addition, whole-body percentage of fat, volume of the thigh and skinfold thickness below the electrodes were achieved. Biceps femoris coactivation values were: 28.5 +/- 17.9%, 30.9 +/- 17.7% and 25.3 +/- 17.5% for MVC, 80% MVC and 200 N trials, respectively (NS). Neither the whole-body percentage of fat nor the skinfold thickness influenced percentage coactivation, irrespective of the intensity of contraction. However, an increase in the whole-body percentage of fat showed a tendency to augment the biceps femoris coactivation (P(I)=0.079; P(II)=0.575). No differences in coactivation were observed between genders. In addition, the duration of contraction did not affect the level of coactivation.

TRPC1 store-operated cationic channel subunit.

TRPC1 is a membrane protein that is highly conserved in mammals, amphibians and birds. It is widely expressed in cells throughout the body including in the heart and nervous system. Amino acid sequence analysis and over-expression studies indicate it is an ion channel that allows the transmembrane flux of small cations including sodium and calcium. In some cell types it is apparent that at least a fraction of TRPC1 exists in the plasma membrane. Inhibition of TRPC1 expression or block by TRPC1-specific antibody leads to attenuation of the plasma membrane calcium influx that occurs in response to depletion of calcium levels in sarcoplasmic or endoplasmic reticulum. TRPC1 would, therefore, seem to be a key subunit of store-operated channels (SOCs). TRPC1 is, nevertheless, unlikely to act alone. There is good evidence that it can heteromultimerise with the related proteins TRPC4, TRPC5 and polycystin-2; a tetrameric arrangement is envisaged, but not demonstrated. Like its relative in Drosophila, TRPC1 looks likely to function in a signalplex, a protein complex including inositol 1,4,5-triphosphate (IP(3)) receptor, plasma membrane calcium-ATPase, caveolin-1 and calmodulin. Its localisation in membranes is punctate and associated with functionally discrete calcium signals. TRPC1's function may not only be linked to SOCs but also to other cellular events including the nuclear translocation of the NFAT transcription factor. There is still much to be learned about this fundamental protein.

Acceleration of diabetic retinopathy in pregnancy: a case report.

AIMS: Diabetic retinopathy can deteriorate during pregnancy. This usually manifests itself as an increase in the number of background retinopathy lesions, notably the appearance of new cotton wool spots, predominantly during the first trimester. The changes are usually attributed to the rapid attainment of tight glycaemic control during pregnancy. We present a case report of catastrophic deterioration in retinopathy during a period of stable glycaemic control. RESULTS: J.P. had normal fundoscopic appearance at booking and during the early part of pregnancy. She experienced rapid deterioration in visual acuity secondary to cystoid macular oedema and vitreous haemorrhage during the third trimester of pregnancy. Her glycaemic control was stable at that stage and had not changed when compared with earlier stages of pregnancy. She required three sessions of intrapartum laser therapy and postpartum vitrectomy. CONCLUSIONS: The case highlights the importance of regular retinal surveillance in a diabetic pregnancy, even in the absence of sudden improvements in glycaemic control.

Frequency-doubled Nd:YAG laser for the treatment of exudative diabetic maculopathy.

PURPOSE: To determine the clinical efficacy of frequency-doubled Nd:YAG (FD YAG) laser for the treatment of diabetic clinically significant macular oedema (CSMO). METHODS: A prospective pilot study was carried out on 55 eyes with CSMO. FD YAG laser exposures were applied in a focal or grid pattern. The results were evaluated by Snellen visual acuity, slit-lamp biomicroscopy, colour photography and fundus fluorescein angiography. RESULTS: At mean review of 5.3 months, macular oedema had resolved either completely or partly in 44 (80%) eyes, was unchanged in 10 (18%) eyes and progressed in 1 (2%) eye. Visual acuity improved in 11 (20%), stabilised in 40 (73%) and deteriorated in 4 (7%) eyes. CONCLUSION: FD YAG laser therapy is effective in the treatment of CSMO. It combines the ergonomic advantages of a solid-state laser with the benefits of its wavelength. A comparison between the clinical results of FD YAG and other lasers used in the treatment of CSMO is, however, required.

Inhibition of cardiac L-type calcium channels by protein kinase C phosphorylation of two sites in the N-terminal domain.

We have investigated the mechanism underlying the modulation of the cardiac L-type Ca(2+) current by protein kinase C (PKC). Using the patch-clamp technique, we found that PKC activation by 4-alpha-phorbol 12-myristate 13-acetate (PMA) or rac-1-oleyl-2-acetylglycerol (OAG) caused a substantial reduction in Ba(2+) current through Ca(v)1.2 channels composed of alpha(1)1.2, beta(1b), and alpha(2)delta(1) subunits expressed in tsA-201 cells. In contrast, Ba(2+) current through a cloned brain isoform of the Ca(v)1.2 channel (rbC-II) was unaffected by PKC activation. Two potential sites of PKC phosphorylation are present at positions 27 and 31 in the cardiac form of Ca(v)1.2, but not in the brain form. Deletion of N-terminal residues 2-46 prevented PKC inhibition. Conversion of the threonines at positions 27 and 31 to alanine also abolished the PKC sensitivity of Ca(v)1.2. Mutant Ca(v)1.2 channels in which the threonines were converted singly to alanines were also insensitive to PKC modulation, suggesting that phosphorylation of both residues is required for PKC-dependent modulation. Consistent with this, mutating each of the threonines individually to aspartate in separate mutants restored the PKC sensitivity of Ca(v)1.2, indicating that a change in net charge by phosphorylation of both sites is responsible for inhibition. Our results define the molecular basis for inhibition of cardiac Ca(v)1.2 channels by the PKC pathway.

Myzostomida: a link between trochozoans and flatworms?

Myzostomids are obligate symbiotic invertebrates associated with echinoderms with a fossil record that extends to the Ordovician period. Due to their long history as host-specific symbionts, myzostomids have acquired a unique anatomy that obscures their phylogenetic affinities to other metazoans: they are incompletely segmented, parenchymous, acoelomate organisms with chaetae and a trochophore larva. Today, they are most often classified within annelids either as an aberrant family of polychaetes or as a separate class. We inferred the phylogenetic position of the Myzostomida by analysing the DNA sequences of two slowly evolving nuclear genes: the small subunit ribosomal RNA and elongation factor-1alpha. All our analyses congruently indicated that myzostomids are not annelids but suggested instead that they are more closely related to flatworms than to any trochozoan taxon. These results, together with recent analyses of the myzostomidan ultrastructure, have significant implications for understanding the evolution of metazoan body plans, as major characters (segmentation, coeloms, chaetae and trochophore larvae) might have been independently lost or gained in different animal phyla.

Transpupillary thermotherapy for retinal capillary hemangioma in von Hippel-Lindau disease.

Retinal capillary hemangiomas are a common manifestation of von Hippel-Lindau disease. We report the treatment of a peripapillary retinal capillary hemangioma in the left eye of a 30-year-old woman with this condition, using infrared diode laser transpupillary thermotherapy (TTT). The hemangioma was evaluated before and after treatment by ophthalmoscopy, fundus fluorescein angiography, and Doppler ultrasonography. Infrared diode laser TTT was delivered over 3 sessions during a period of 22 weeks, resulting in an improvement in visual acuity from counting fingers to 6/24 and a marked decrease in exudates surrounding the hemangioma. Doppler ultrasonography demonstrated a decrease in intralesional blood flow from 7 cm per second to less than 3 cm per second, together with a decrease in the size of the lesion. Infrared diode laser TTT provides a useful modality in the treatment of retinal capillary hemangiomas, and may be particularly favorable for peripapillary lesions because of its relatively nondestructive characteristics.

Development of proliferative retinopathy in patients with long-standing insulin-dependent diabetes mellitus.

PURPOSE AND METHOD: Some patients with long-standing insulin-dependent diabetes mellitus (IDDM) develop little or no retinopathy. Using a clinic-based questionnaire and examination, we investigated a group of patients with over 40 years or more of IDDM who had been followed up at the King's Diabetes Centre for an average of 40 years. We compared those who had developed proliferative diabetic retinopathy during their disease with those with minimal or no retinopathy. RESULTS: The study did not find any statistically significant differences between the two groups to suggest why some long-term insulin-dependent diabetics develop little retinopathy. Those who developed sight-threatening retinal complications did so at an average of 35 years after diagnosis and it resulted in little visual disablement. Very few patients in either group had developed other significant complications. CONCLUSIONS: This study details an interesting group of patients with long-term IDDM mellitus with a mean follow-up period of 40 years. Some patients with long-standing IDDM develop little or no retinopathy. With the advent of community ophthalmic screening, these patients are now rarely seen in the eye clinic. Those who did develop retinal complications and required treatment have remarkably little visual disablement. However, these complications developed late in the history of their disease, emphasising the need for continued screening.

Amylase and lipase in the emergency department evaluation of acute pancreatitis.

Serum amylase and lipase levels are commonly obtained in the emergency department for the diagnosis of acute pancreatitis. The role of these enzymes has frequently been the subject of confusion and controversy. This article comprehensively reviews the history, biochemistry, clinical, and laboratory literature on both enzymes as used in the evaluation of pancreatitis. Specific guidelines are presented to assist the Emergency Physician in the appropriate use and interpretation of these clinical laboratory tests.

Block of human aorta Kir6.1 by the vascular KATP channel inhibitor U37883A.

1. A human aorta cDNA library was screened at low stringency with a rat pancreatic Kir6.1 cDNA probe and a homologue of Kir6.1 (hKir6.1) was isolated and sequenced. 2. Metabolic poisoning of Xenopus laevis oocytes with sodium azide and application of the K+ channel opener drug diazoxide induced K+ channel currents in oocytes co-injected with cRNA for hKir6.1 and hamster sulphonylurea receptor (SUR1), but not in oocytes injected with water or cRNA for hKir6.1 or SUR1 alone. 3. K+ channel currents due to hKir6.1+SUR1 or mouse Kir6.2+SUR1 were strongly inhibited by 1 microM glibenclamide. K+-current carried by hKir6.1+SUR1 was inhibited by the putative vascular-selective KATP channel inhibitor U37883A (IC50 32 microM) whereas current carried by Kir6.2+SUR1 or Shaker K+ channels was unaffected. 4. The data support the hypothesis that hKir6.1 is a component of the vascular KATP channel, although the lower sensitivity of hKir6.1+SUR1 to U37883A compared with native vascular tissues suggests the need for another factor or subunit. Furthermore, the data suggest that pharmacology of KATP channels can be determined by the pore-forming subunit as well as the sulphonylurea receptor and point to a molecular basis for the pharmacological distinction between vascular and pancreatic/cardiac KATP channels.

Accident and emergency medicine in the United Kingdom.

This article describes the history and current status of the practice of hospital-based accident and emergency (A&E) medicine in the United Kingdom of Great Britain and Northern Ireland. Included are comments on training and certification, the operations of the typical A&E department, and developments in research and academics. Also included are the authors' thoughts on issues of future importance to A&E medicine. As transatlantic links at all levels become increasingly common in this dynamic specialty, we clarify unfamiliar terminology and practices for international readers.

Analgesia in the accident and emergency department: do SHOs have the knowledge to provide optimal analgesia?

OBJECTIVE: To assess senior house officers' knowledge in prescribing emergency analgesia for acute presentations in the accident and emergency (A&E) department. DESIGN: Prospective telephone survey of a defined population of SHOs, using a standardised structured questionnaire, in the months of October and November, 1995; 231 SHOs from 215 A&E departments were interviewed. The questionnaire required responses to hypothetical scenarios. A six member expert panel from the local region was consulted for suggestions for appropriate responses. MAIN OUTCOME MEASURES: Comparisons between SHO responses and those of an expert panel. RESULTS: For choice of analgesic agent, 83% of SHO responses were appropriate, for route of administration 57%, and for the dose of drug 34%. The scenario with the best overall response was a sprained ankle. The paediatric case with partial burns faired worse. Responses to a myocardial infarction scenario were the most consistent. CONCLUSIONS: A&E SHOs lack knowledge and confidence when asked to prescribe emergency analgesia for acute conditions. Responses to certain scenarios were extremely varied, indicating a need for national analgesia guidelines and protocols. Recognised training in pain management should be more readily available.