TM technology being one of the most recent. Plant material, plasmids, viral particles, bacteria and animal blood have been stored and transported successfully using this technology, however the method of porcine DNA extraction from FTA Whatman™TM cards is a relatively new approach, allowing nucleic acids to be ready for downstream applications such as PCR, whole genome amplification, sequencing and subsequent application to single nucleotide polymorphism microarrays has hitherto been under-explored.The ability to transport and store DNA at room temperature in low volumes has the advantage of optimising cost, time and storage space. Blood spots on adapted filter papers are popular for this, with FTA (Flinders Technology Associates) Whatman™TM cards (following adaptations of the manufacturer’s instructions), whole genome amplified and subsequently analysed to validate the integrity of the DNA for downstream SNP analysis. DNA was successfully extracted from 288/288 samples and amplified by WGA. Allele dropout post WGA, was observed in less than 2% of samples and there was no clear evidence of amplification bias nor contamination. Acceptable call rates on porcine SNP chips were also achieved using DNA extracted and amplified in this way.DNA was extracted from FTA Whatman™DNA extracted from FTA Whatman cards is of a high enough quality and quantity following whole genomic amplification to perform meaningful SNP chip studies. Extraction of DNA from white blood cells, although a routine procedure, can be time consuming and costly when large numbers of samples are to be isolated and stored. Indeed, full extraction and −20°C storage is sometimes unnecessary due to the fact that for many (e.g. PCR based) applications, only very small amounts are needed. For this reason, in recent years, many institutes and commercial organisations have taken to storing human or other animal DNA by means of dried blood spots on adapted filter paper. In this way, only a drop of blood is required and subsequent PCR based tests can be performed on the small amount of DNA isolated. Storage of DNA in this way is far more space and energy efficient .A number of different approaches have been used to extract DNA from dried blood spots. DNA extracted using the proteinase K method has been used for the detection of perinatal HIV , the CheTM cards are a patented technology that can also be used to store DNA by means of dried blood spots. The cards are impregnated with a mixture of chemicals including free radical traps and strong protein denaturing buffers that hold the DNA on the card, stabilising and protecting it from damaging factors such as UV, oxidation and microbial degradation [TM cards [FTA (Flinders Technology Associates) Whatman™radation . Many diradation . RajendrTM cards .TM cards is a relatively novel approach that allows nucleic acids to be ready for downstream applications such as PCR and sequencing. One drawback of storage and analysis by this approach however is the small quantity of DNA that is extracted.The manufacturers claim that DNA on the cards remains stable at room temperature for over 17 years, permitting compact storage and eliminating the need for freezing. They also claim that the separation of blood products that normally inhibit downstream applications such as PCR is not necessary. Indeed, the method of extraction from FTA Whatman™TM card and thus, if such archived material is to be used for SNP chip interrogation, a robust means of whole genome amplification (WGA) is necessary. In recent years it has been demonstrated the use of WGA on single or small numbers of cells and their application for array comparative genomic hybridisation (aCGH) and SNP chip analysis [TM cards. In so doing, a novel approach through which meaningful whole genomic information can be derived from archived blood spots has been generated.The interrogation and analysis of both flat bed microarrays and single-nucleotide polymorphism (SNP) chips have a range of applications in scientific enquiry including clinical diagnostic studies , genome analysis -12. HereTM ‘FTA classic’ card was the chosen platform for this study. This card has four sample areas for up to 500 μl of whole blood (one card per sample). A total of 288 porcine blood spots stored on these cards were sourced from JSR Genetics Ltd  from three breeds, Sire Line Large White (SLLW), Duroc and a synthetic Pietrain line (96 from each breed). The blood samples used in this study were originally taken as part of routine testing at JSR Genetics in order to determine the halothane status of the animals. FTA Whatman™TM cards were spotted with blood at time of original testing.The Whatman™TM cards is outlined below. Before this protocol was adopted as the optimum, the length of time at which the punches were heated to was tested  as well as the length of time that the punches were washed . Using a 3 mm Harris Micro Punch and Harris cutting mat , two punches were removed from one 11 mm single sample circle. These punches were then dispensed into 0.2 ml micro-centrifuge tubes and placed on a thermocycler (Eppendorf Mastercycler EP Gradient S) for 15 minutes at 80°C with no lid heating. The punches were then moved to 1.5 ml micro-centrifuge tubes using sterile forceps and the lids were left open and allowed to cool for 10 minutes. 1 ml of molecular grade water was then added to the sample and vortexed for 5 seconds before all the liquid was removed. This step was then repeated and 100 μl of sterile water was then added to each of the samples, which were placed in a thermocycler for 20 minutes at 96°C. After 20 minutes the tubes were flicked 4–5 times to resuspend the DNA; the punches were then removed from the solution after having squeezed out any excess water by gripping with forceps. The DNA was then suspended in the solution and was stored at −20°C until further use.The final method of DNA extraction from FTA Whatman™Extracted samples were amplified via Whole Genome Amplification (WGA) using the Sigma-Aldrich WGA2 kit  are a type of molecular marker, which can be di-nucleotide (two bases repeating), tri-nucleotide (three bases repeating) or longer . These sFluorescent capillary electrophoresis is a method that separates ionic species by their size to charge ratio with fluorescent tags being used as the method for detection. 2 μl of Cy3 ladder was added to an aliquot of formamide (320 μl). Using a non-filter tip, 40 μl of this was pipetted into a 96-well opaque plate and 10-15 ng/μl of sample was added. One drop of mineral oil was added to the top of each of the wells. Buffer was added to a separate clear plate in the same locations as the samples in the opaque plate. Plates were subsequently loaded into a Beckman Coulter Genetic Analyser CEQ8000. One of four default separation methods, namely Frag-4 was implemented with an aim to employ the 600 set of standards (60 to 640 nucleotides). Frag-4 uses a higher separation temperature and a lower separation voltage, allowing for the allele patterns to be interpreted easily. Results were analysed by examination of the peaks produced and comparing results after PCR alone and also after WGA followed by PCR in order to ensure allele drop-out/amplification bias had not occurred.Following the manufacturer’s instructions the Sigma GenElute PCR Clean-Up Kit was used to clean up whole genome amplified DNA. A GenElute Miniprep binding column was inserted into a 2 ml collection tube. 0.5 ml of column preparation solution was added to each column and centrifuged at 12000 g for 30 seconds and the eluate was subsequently discarded. 5 volumes of binding solution was added to 1 volume of amplified DNA and was added to the column. This was centrifuged at 16000 g for 1 minute and the eluate was once again discarded. 0.5 ml of wash solution was then added to the column and spun at 16000 g for 1 minute, discarding the eluate afterwards. Without any additional wash solution the column was spun for a further 2 minutes to remove excess ethanol. Any residual eluate and the collection tube were discarded and the column was transferred to a clean 2 ml collection tube. 50 μl of elution solution was applied directly to the centre of each column, incubated at room temperature for 1 minute and centrifuged at 16000 g for 1 minute. Products were stored at −20°C until needed. DNA quantification was performed as per section.et al. 2010 [et al. 2011 [Tecan manifold equilibrated at 44°C, all SNP chips underwent enzymatic single-base extension reaction, followed by two-colour immunofluorescence signal development, coated with a polymer resin and dried under vacuum for 1 hour to preserve signal fluorescence during scanning. The SNP chips were then scanned in the Illumina BeadStation 500 dual-laser, <1-micron resolution scanner, with laser excitations at 532 nm and 635 nm, emitting a spectra of 550–600 nm and 650–700 to score fluorescence values. Raw fluorescence data were captured and normalized, using internal and external controls, and stored as image files. Following scanning, image data were transferred to the GenomeStudio Software framework V2010.1 and converted from fluorescence data to genotypic data based on the manufacturer’s design algorithms. The ‘call rates’ produced by the Illumina software were determined. These call rates give an indication of the sample quality. A ‘call’ is defined as a genotype assignment while the call rate is the number of called SNPs  divided by the total number of SNPs on the chip. A ‘No Call’ value occurs when a SNP’s probe intensity does not pass the detection filter score (DS) or the risk allele scores (RAS) fall outside of the statistical model boundaries [The Illumina Bead chip system (Illumina Porcine SNP60 Genotyping BeadChip) microarrays were interrogated with WGA amplified DNA from each porcine sample in an approach similar to that described by Handyside al. 2010  and Gabrundaries .A variation of the manufacturer’s recommendations was successfully developed to extract the DNA from FTA Whatman™ cards in order to give the optimum yield. Trial and error experimentation led to variations in the length of time that the punches from the card were heated to and the length of time that the punches were washed in molecular grade water. The optimum for which the punches were heated to was deemed to be 15 seconds (less or more than this led to less DNA being extracted) and the optimum length of time that the punches were washed for was deemed to be 5 seconds (more time had no impact on results).Both the final protocol and the modifications are outlined above in the materials and methods. DNA was successfully extracted from 288/288 samples and amplified by WGA. The quantity and purity of DNA amplified was measured using a nanodrop spectrophotometer and using gel electrophoresis.Short Tandem Repeat Polymerase Chain Reaction (STR-PCR) established in all cases (apart from two), that WGA DNA was of the same origin as the directly extracted DNA (i.e. the WGA did not introduce any contamination). An example of the results from capillary electrophoresis is shown in Figure According to the manufacturer’s claims, the DNA on the cards remains stable for up to 17 years . AlthougThe call rates (percentage success rate of experiment) obtained when genomic DNA was used on the porcine Illumina SNP chip were typically between 0.80 and 0.96, with an average of 0.91 and a standard deviation of 0.046. Table TM cards as a means of porcine genomic DNA storage for subsequent SNP chip analysis.The results therefore demonstrate the effectiveness of FTA Whatman™TM cards as a tool for storing porcine genomic DNA at room temperature largely supporting the manufacturer’s claims. Moreover, it demonstrates the use of prior WGA and effective interrogation of the Illumina SNP60 Genotyping BeadChip. The reported call rates were comparable to those commonly seen in our own experience and very similar to published data when non-amplified porcine DNA was used [This study has successfully demonstrated the efficacy of FTA Whatman™was used -19.TM cards after three years post initial blood spotting. Due to the large sample number in this study, storage of whole blood is inconvenient at −20°C due to limited freezer space. When using FTA Whatman™TM cards however the samples were able to be collected at the same time and processed before each experiment.For the first time, it can clearly be seen that genomic DNA can be extracted from FTA Whatman™TM cards were also evaluated for their use of long-term blood storage as well as for sex-determination via PCR. A similar study was carried out in birds with respect to avian influenza. In this case, FTA Whatman™TM cards as a means of ensuring biosafety [TM cards). Another comparable study was carried out in pigs as a way of detecting porcine reproductive and respiratory syndrome [TM cards as a means of storage.A similar DNA extraction study was carried out in 2002 in birds which produced comparable results to those obtained in this study . In thissyndrome . Once agA study in 2011  comparedTM cards have been shown to be very useful for the storage of genomic porcine (and presumably other species’) DNA at room temperature and extraction of DNA from these cards has been shown to be stable for at least 3 years. The extracted DNA was shown to be of a high enough concentration and quality (after WGA) to perform meaningful SNP chip studies. This could, in turn, facilitate many other studies for which sample acquisition and storage is problematic and facilitate other studies with reference to both SNPs (e.g. genome wide association studies) and copy number variants (CNVs) amongst others.FTA Whatman™FTA: Flinders Technology Associates; DNA: Deoxyribonucleic acid; SNP: Single nucleotide polymorphism; WGA: Whole Genome Amplification; PCR: Polymerase chain reaction; aCGH: array Comparative Genomic Hybridisation; SLLW: Sire Line Large White; DS: Detection filter Score; RAS: Risk Allele Score; STR: Short tandem repeat.All authors declare that they have no conflict of interest.KF performed most of the experiments in the paper and co-wrote the manuscript, CR performed the microarray experiments and generated the call rate data, GW co-conceived the project and collected all the samples and DG co-conceived the project, supervised all aspects of it and co-wrote the manuscript. All authors read and approved the final manuscript.


Intravenous acetaminophen (IVA) has rapid and effective analgesic properties. Recent studies have shown several benefits of using IVA perioperatively. However, due to its relatively high cost and limited clinical data concerning its efficacy compared with other agents, physicians are hesitant to use IVA in the perioperative period. This brief review examines the utility of this medication in the perioperative period and highlights future areas of clinical and epidemiological research regarding its use. Intravenous acetaminophen (IVA), or paracetamol, was made available in Europe in 2002, but only approved for use in the United States in November of 2010. IVA has both rapid and effective analgesic properties and is considered to be safe and well tolerated  than when ingested orally, making IVA a safer alternative. Intravenous infusion produces a peak acetaminophen concentration in the liver estimated to be 50% less than the same oral dose  on postoperative day one after total hip replacement or total knee replacement and found an increased time to receive rescue morphine  compared with placebo (0.8 h) (p < 0.001)  . Additio h . Addip < 0.01). In addition, total opiate consumption was significantly reduced in the IVA group compared with referents. Other studies based in the ICU have focused on delirium in cardiac surgery patients. Reports have estimated that over 50% of patients undergoing major cardiac surgery experience delirium during admission and postoperative pain and excessive opioid consumption potentially lead to this complication (The use of IVA in the ICU setting also has been investigated. A study including patients admitted to the ICU after major abdominal or pelvic surgery examined the amount of opioids used, time to extubation, and opioid-related adverse effects in patients receiving 1 g of IVA every 6 h over 24 h (lication . AlthougThe use of IVA is approved by the Food and Drug Administration for the management of mild to moderate pain, the management of moderate to severe pain with opioid analgesic adjuncts, and fever reduction in adults and children over the age of two . Recent The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Dear Editor,We read with interest the article by Leonardi and La Rosa 2010) that deals with the hypothesis that nonintestinal inflammatory diseases, such as hepatitis B virus (HBV), may trigger immunologic gluten intolerance in susceptible people 0 that de. Despite


Rapid growth in global health activity among US medical specialty education programs has lead to heterogeneity in types of activities and global health training models. The breadth and scope of this activity is not well chronicled.Using a standardized search protocol, we examined the characteristics of US medical residency global health programs by number of programs, clinical specialty, nature of activity , and geographic location across seven different clinical medical residency education specialties. We tabulated programmatic activity by clinical discipline, region and country. We calculated the Spearman's rank correlation coefficient to estimate the association between programmatic activity and country–level disease burden.Of the 1856 programs assessed between January and June 2011, there were 380 global health residency training programs (20%) working in 141 countries. 529 individual programmatic activities  occurred at 1337 specific sites. The majority of the activities consisted of elective–based rotations. At the country level, disease burden had a statistically significant association with programmatic activity (Spearman's ρ = 0.17) but only explained 3% of the total variation between countries.There were a substantial number of US medical specialty global health programs, but a relative paucity of surgical and mental health programs. Elective–based programs were more common than programs that offer longitudinal experiences. Despite heterogeneity, there was a small but statistically significant association between program location and the global burden of disease. Areas for further study include the degree to which US–based programs develop partnerships with their program sites, the significance of this activity for training, and number and breadth of programs in medical specialty global health education in other countries around the world. United States (US) – based academic global health programs have more than quadrupled in number between 2003 and 2009 . These pThe rapid expansion of US global health programs has been multifactorial. Medical students and graduates are increasingly seeking to matriculate to residency and fellowship programs at academic centers which offer opportunities in global health. In one study, 92% of US surgical residents surveyed expressed interest in an international elective, and 82% noted they would prioritize a global health elective over any other . SimilarThis rapid growth has been largely uncoordinated between training institutions and, therefore, is at risk of not necessarily aligning training focus to optimize the experience with the global burden of disease . To dateWhile related work has examined the scope of US post–graduate medical specialty training in global health ,10 and tWe systematically collected information available on residency program websites of seven major US graduate medical education specialties. Our search aimed to identify the presence of global health–focused training type of activity, and geographic location of these global health programs.Clinical residency training programs including internal medicine, pediatrics, general surgery, obstetrics and gynecology, mental health, emergency medicine and family medicine were compiled from the official Accredited Council for Graduate Medical Education (ACGME) website . These pFrom January – June 2011, the following terms were entered (without punctuation) as separate queries using Google as a web search engine: “[Insert ACGME–listed program’s name] global health [Insert Clinical Discipline] residency.” The web page results were reviewed by one of several trained data abstractors  for the first 20 search results ,19. SearGlobal health training programs were evaluated for three types of programmatic activity: “elective–based rotations,” “research programs” or “extended curriculum–based field training.” Elective–based rotations were defined as clinical or educational activities of less than six weeks duration. Research programs required some component of data collection or human subjects approval. Extended curriculum–based field training experiences were defined as engagements greater than six weeks and/or including a designated course of study concentrating on pertinent principles in global health. If an activity did not fit the previous three classifications or could otherwise not be characterized, it was listed as “other.” Sites of programmatic activity were designated as country(ies) where any of the three above the programmatic activities occurred. To categorize these programmatic sites, we used the designated World Health Organization (WHO) list of countries and regions , specifyThe data were tabulated and summary descriptive statistics were used to compare program characteristics by region. Data from the 2004 WHO Global Burden of Disease assessment -25. DiseA total of 1856 ACGME residency programs were identified in internal medicine, pediatrics, obstetrics and gynecology (OB/GYN), general surgery, emergency medicine, family medicine, and psychiatry (Geographic location by country was available fully or in–part for 223 (59%) of the total 380 global health training programs identified which demonstrated programmatic activity in 141 countries in the world. Thirty–nine global health training programs referenced having both programmatic activity in specific countries as well as programmatic activity that was not assigned a specific country. One hundred and fifty–seven global health training programs did not specify the countries in which they were working. The 529 individual programmatic activities occurred at 1337 specific sites (2 = 0.03) (At the country level (n = 193), there was a statistically significant correlation between burden of disease and programmatic activity . Fitting a linear regression model, only a small proportion of the variance in programmatic activity could be explained . Importantly, though not within the scope of this study, a deeper analysis of activities within countries would add to our findings. South Africa and India, for example, have very disparate burden of disease within the country. Understanding the location of activities for each program within certain countries would continue to refine the response to burden of disease.The web based search protocol is limited in its sensitivity and will not capture global health activity of residencies which is not posted on their website ; activitFurther evaluation will need to be conducted to better understand any additional granularity by specialty and/or subspecialty, as well as the depth of partnership between a US academic program and partner site and the amount of knowledge transfer. Equally, further evaluation would help elucidate the challenges to developing programs and international partnerships which may include cultural and language barriers, financial constraints, differing priorities between partner institutions or unsustainability. It will be important to better characterize the type of clinical education and investigation in each location.Characterizing global health education among medical specialties in the US is the first step to standardizing global health training at this level in order to improve the experience for our trainees and to determine the extent to which US global health education reflects and addresses the global burden of disease. Identifying gaps in today’s global health education will guide global health training to reduce the morbidity and mortality caused by the diverse etiologies of global burden of disease. The impact and benefits of these programs on trainees and vulnerable populations will need to be better assessed to balance the distribution of programs with respect to geography and disease burden and to better understand how to shape global health programs in medical specialty education.


Hypertension induced by chronic administration of angiotensin II (AngII) is exacerbated by high‐salt intake. Previous studies have demonstrated that this salt‐sensitive component is due to increased activity of the sympathetic nervous system, suggesting an interaction of plasma AngII with sodium‐sensitive regions of the brain. This study tested the hypothesis that the salt‐sensitive component of AngII‐induced hypertension would be prevented by intracerebroventricular (ICV) administration of the sodium channel/transporter blocker benzamil. Male Sprague Dawley rats were instrumented to measure mean arterial pressure (MAP) by radio telemetry and for ICV administration of benzamil or vehicle and placed in metabolic cages for measurement of sodium and water intake and excretion. In rats consuming a high‐salt diet (2.0% NaCl) and treated with ICV vehicle, administration of AngII  for 13 days increased MAP by ~30 mmHg. ICV administration of benzamil (16 nmol/day) had no effect during the first 5 days of AngII, but returned MAP to control levels by Day 13. There were minimal or no differences between ICV vehicle or benzamil groups in regards to sodium and water balance. A lower dose of ICV benzamil administered ICV at 8 nmol/day had no effect on the MAP response to AngII in rats on a high‐salt diet. Finally, in contrast to rats on a high‐salt diet, AngII had negligible effects on MAP in rats consuming a low‐salt diet (0.1% NaCl) and there were no differences in any variable between ICV benzamil (16 nmol/day) and ICV vehicle‐treated groups. We conclude that the salt‐sensitive component of AngII‐induced hypertension is dependent on benzamil blockable sodium channels or transporters in the brain. Chronic intracerebroventricular infusion of benzamil at 16 nmol/day attenuates AngII–salt hypertension. This effect is not observed at a dose of 8 nmol/day. It has long been known that the severity of angiotensin II (AngII)‐induced hypertension in experimental animals is directly dependent on the prevailing level of salt intake  were purchased from Charles River Laboratories  and housed in small groups in a temperature‐ and light‐controlled room until the time of study. During this period rats were randomly placed on either a low‐ (0.1% NaCl) or high (2.0% NaCl)‐salt diet  with distilled water available ad libitum. Rats remained on these diets for the duration of the study. All procedures were approved by the University of Minnesota Animal Care and Use Committee and were conducted in accordance with the institutional and National Institutes of Health guidelines.μL/h. Benzamil was initially dissolved in propylene glycol and then diluted with 0.9% saline. The pH of the final solution was adjusted to 7.4 with NaOH. All skin incisions were closed and rats were treated with antibiotics  and an analgesic . Upon recovery from anesthesia, rats were individually housed in metabolic cages with the telemetry receiver mounted adjacent to them for continuous monitoring of arterial pressure and heart rate. Rats were allowed 5 days for surgical recovery before initiating the experimental protocols.Rats were anesthetized with an injection of pentobarbital , prepared for surgery and given gentamicin  for antimicrobial prophylaxis. Surgery was performed using aseptic techniques on a heated pad. Following a midline abdominal incision, a telemetry transmitter  was placed into the abdominal cavity and its catheter was inserted into the abdominal aorta as previously described  filled with AngII was implanted as previously described  was treated with ICV benzamil at a dose of 16 nmol/day. The second group (N = 10) was treated with ICV vehicle. Twenty‐four‐hour food and water intake and urine output were measured gravimetrically and daily urine samples were taken for analysis of sodium concentration using a NOVA‐5+ sodium‐potassium analyzer . Twenty‐four‐hour sodium intake was calculated by multiplying the food intake by sodium content of food (2.0% = 0.35 mmol Na/g). Twenty‐four‐hour urinary sodium excretion was calculated as the product of urine flow and urine sodium concentration.Two groups of rats were studied in metabolic cages to measure daily sodium and water intake and excretion. The first group (N = 8) and ICV vehicle (N = 10).The objective of this protocol was to determine whether a lower dose of benzamil than that used in Protocol 1 was effective in attenuating AngII–salt hypertension. The protocol was identical to Protocol 1 with the exception that benzamil was administered at a dose of 8 nmol/day. Sodium and water intake and excretion were measured in both groups; ICV benzamil (N = 6) and ICV vehicle (N = 6). Sodium and water intake and excretion were measured in both groups.The objective of this protocol was to test the hypothesis that the effect of the higher dose of ICV benzamil on arterial pressure in rats administered AngII were dependent on rats consuming a high‐salt diet. This protocol was identical to Protocol 1 with the exception that rats consumed a low‐salt diet (0.1% = 0.018 mmol Na/g). Two groups were studied; ICV benzamil  and heart rate data were sampled over a 10‐sec period at 500 Hz every 4 min and stored for later analysis. Twenty‐four‐hour averages of MAP and heart rate, as well as sodium and water intake and excretion were plotted and analyzed by two‐way analysis of variance for repeated measures followed by the Holm–Sidak method for all post hoc comparisons . Statistical significance was set at Two separate protocols were conducted to investigate the effects of two doses of benzamil, 8 and 16 nmol/day, on cardiovascular and fluid balance responses to AngII in rats consuming a high‐salt diet. Each protocol included a vehicle control group. Since responses in vehicle‐treated rats were not statistically different between protocols, data from these groups were combined and are presented with both benzamil groups in Figs. Prior to AngII administration, control levels of MAP were similar in all three groups Fig. A. MAP inVariables for sodium balance are shown in Fig. Variables for water balance are shown in Fig. This protocol was conducted to determine whether ICV benzamil affected the arterial pressure response to AngII in the absence of a high‐salt diet. As seen in Fig. Daily water intake in rats consuming a 0.1% NaCl diet Fig. A was appThis study tested the hypothesis that chronic ICV administration of the sodium channel/transporter blocker benzamil would attenuate or prevent hypertension in the AngII–salt model in the rat. Several previous studies provided support for our hypothesis. First, the contribution of the sympathetic nervous system to AngII‐induced hypertension is amplified by a high‐salt diet . In contrast, salt loading in the DOCA‐salt model is achieved by giving rats 0.9% saline to drink, without access to water, which results in a 24‐h sodium intake of ~20 mmol/day  of benzamil may account for its efficacy in this study is unknown as is its location in brain autonomic pathways. Ion channels permeable to sodium, such as ENaC or acid‐sensitive ion channels (ASIC) are likely candidates  and organum vasculosum of the lamina terminalis (OVLT), which process and relay information downstream to sympathetic control neurons in the paraventricular nucleus of the hypothalamus (PVN) and rostral ventrolateral medulla (RVLM). We have recently reported that whereas electrolytic lesion of the SFO has minimal effects . This would decrease CSF sodium concentration and therefore activity of osmotically driven sympathetic activity . It has been proposed that ENaC in the choroid plexus control the level of sodium in hypothalamic tissue independent from other brain sites  to ultimately affect CSF sodium concentration. This would secondarily affect sodium‐sensitive neurons that subsequently drive sympathetic activity. Since benzamil has a low molecular weight (356.2 Da) and is lipophilic relative to other amiloride analogs  and brain site(s) at which benzamil acts are needed to possibly translate these findings into new therapies for the treatment of salt‐sensitive hypertension.The authors would thank Myraida Rodriquez for her technical assistance with these studies.None declared.


Newborn hearing screening is an established healthcare standard in many countries and testing is feasible using otoacoustic emission (OAE) recording. It is well documented that OAEs can be suppressed by acoustic stimulation of the ear contralateral to the test ear. In clinical otoacoustic emission testing carried out in a sound attenuating booth, ambient noise levels are low such that the efferent system is not activated. However in newborn hearing screening, OAEs are often recorded in hospital or clinic environments, where ambient noise levels can be 60–70 dB SPL. Thus, results in the test ear can be influenced by ambient noise stimulating the opposite ear. Surprisingly, in hearing screening protocols there are no recommendations for avoiding contralateral suppression, that is, protecting the opposite ear from noise by blocking the ear canal. In the present study we have compared transient evoked and distortion product OAEs measured with and without contralateral ear plugging, in environmental settings with ambient noise levels <25 dB SPL, 45 dB SPL, and 55 dB SPL. We found out that without contralateral ear occlusion, ambient noise levels above 55 dB SPL can significantly attenuate OAE signals. We strongly suggest contralateral ear occlusion in OAE based hearing screening in noisy environments. Audiometric testing in general is best carried out in a low noise environment. Indeed most clinical testing is done in sound attenuating booths, where background noise levels are typically below 20 dB SPL (for frequencies of audiometric interest). For performing behavioral (pure tone and speech audiometry) and physiological tests  the focus has been on maintaining a good signal to noise ratio for the test signals presented. The issue addressed in the present study pertains not to the test ear but to the contralateral ear that may or may not be occluded. In neonatal or newborn hearing screening with OAEs most protocols do not specify any occlusion or plugging of the nontest ear e.g., –11). How. How11])It is now well established that OAEs—discovered by Kemp in 1978 —are suppThe question posed in the present study is do ambient noise levels, typical of OAE screening environments, suppress OAEs in the test ear by stimulation of the contralateral, nonoccluded ear? In a sense the answer is already known in that numerous studies (as referenced above) have utilized contralateral sound stimuli to enable OAE suppression, which have stimulus levels that are similar to those of ambient noise. Furthermore, work including that by our own group  has cleaN = 12). Two OAE measurement methods were used. Transient evoked (TE) OAEs  and distortion product (DP) OAEs . In each of the 4 acoustic environments (described below) TEOAE and DPOAE measures were repeated 3 times with and without occlusion of the contralateral ear. The ear canal was occluded with a standard memory foam earplug, and a circumaural headphone shell was also worn to achieve a combined attenuation greater than 40 dB. We measured TEOAEs to click stimuli (ILO88 default mode) and quantified using the average dB response. DPOAEs were measured in the form of a DPgram; 2f1-f2 signal levels as a function of f2 frequency  with normal audiograms and robust OAEs . OAE recordings were made in each individual ear ((i) Control experiments were carried out in a sound attenuated booth  with ambient sound levels below 25 dB SPL (100 Hz–16 kHz). (ii) Experiments were also made in the open laboratory environment, where ambient noise level was approximately 45 dB SPL. (iii) A study was made in noise-augmented environment in which white noise generation was adjusted to give an overall ambient noise level of 55 dB SPL. (iv) A recorded babble/shopping mall sound sample was used to provide a 55 dB SPL ambient noise that was more dynamic in character than the white noise augmented environment. In other words this background noise had significant temporal and spectral fluctuations. All acoustic signal levels were measured in free field at the level of the subject's head using a calibrated  sound meter (Larson Davis 831) with half-inch condenser microphone (PCB Piezotronics). We used a linear (nonweighted) mode with a 100 Hz–16 kHz bandwidth.t-test, after confirmation of normal data distribution with Kolmogorov and Smirnov analysis.For each acoustic condition, TEOAE and DPOAE signals with and without plugging of contralateral ear are compared with a two tailed, paired Student's P values of paired t-test results are listed. The lower panels show comparisons in sound environments with noise levels at 45 dB SPL and in (white) noise and babble noise augmented environments (55 dB SPL). In the 45 dB SPL environment three subjects have statistically significant differences in OAE level with versus without opposite ear plugging. In the 55 dB SPL ambient noise environments all but one subject show significant differences between TEOAE levels with and without opposite ear occlusion. P values for the paired t-test are mainly low hinting of an effect. Indeed an analysis of pooled results graphed in P < 0.0001) of the 55 dB SPL environmental noise.There has been some considerable attention paid to the issue of ambient noise in environments in which OAE screening tests are carried out. The main concerns however have related to the test ear rather than the contralateral ear. Thus there is concern about the signal-to-noise ratio in the test ear that has to be high for getting a valid OAE response , 38. TheIn the present study, we have tested the hypothesis that moderate levels of environmental noise can suppress OAE responses by activation of the olivocochlear efferent system. In the present study a level of 55 dB SPL has a significant effect. Given that most hospital ward and clinic environments have ambient noise levels higher than 55 dB SPL we conclude that, unless the untested ear is occluded, there will almost certainly be a suppression effect. It should be noted that clinical diagnostic OAE testing is almost always carried out in a low noise environment, typically in a sound attenuating booth. Here the problem of contralateral ear stimulation is negligible. However, in neonatal hearing OAE screening the availability of a sound booth or even a quiet environment is not a reality. It has been suggested that the olivocochlear efferent system is not fully matured or operational in a neonatal human subject, and therefore the precaution of occluding the contralateral ear is unnecessary. It has been reported that in some species efferent innervation is one of the final stages of cochlear maturation –41. In tThe results of this present study indicate that with a 55 dB ambient noise OAE levels can be attenuated by as much as 3 dB. It could be argued that such small attenuations will be of little significance in a screening test. However, it should be noted that this level of ambient noise is very low compared with that in a typical NICU or hospital clinic environment. Furthermore, 3 dB is a significant level change when the original OAE signal level may be of a similar order of magnitude. Will small OAE attenuations make a difference in a pass/refer (fail) screening paradigm? We suggest that it will definitely lead to more false positive results, and that means increasing parent anxiety and further healthcare costs.In OAE screening tests, a nonoccluded contralateral ear will be stimulated by ambient environmental noise. Noise levels above 55 dB SPL can significantly suppress OAEs in the test ear and lead to false positive results. Such inaccuracy can be avoided by occlusion of the contralateral ear canal.


The persistent excess in adverse outcomes by ethnicity highlights the need for improved public health responses. Evidence suggests that indigenous populations have suffered disproportionately from past influenza pandemics. To examine any such patterns for Māori in New Zealand, we searched the literature and performed new analyses by using additional datasets. The Māori death rate in the 1918 pandemic  was 7.3× the European rate. In the 1957 pandemic, the Māori death rate  was 6.2× the European rate. In the 2009 pandemic, the Māori rate was higher than the European rate . These findings suggest some decline in pandemic-related ethnic inequalities in death rates over the past century. Nevertheless, the persistent excess in adverse outcomes for Māori, and for Pacific persons residing in New Zealand, highlights the need for improved public health responses. Evidence suggests that indigenous populations have been disproportionately affected more by influenza pandemics than other population groups. In the most detailed review to date for the Spanish influenza pandemic (1918–1920), Mamelund  and to some extent for Pacific populations residing in this country.We searched the literature (Medline and Google Scholar) for relevant publications relating to New Zealand up to December 1, 2010. Search terms used were combinations of influenza and Māori/Pacific and New Zealand. The bibliography of a key text  were obtained from an electronic dataset (Roll-of-Honor) covering all deaths in these personnel during World War I (WWI) . This daMilitary personnel were classified as having Māori ethnicity if they: had a first, second, or surname in the Māori language; had a parent with a Māori language name; were buried in a Māori cemetery or had a memorial in such a cemetery; or had a iwi  affiliation listed in the Cenotaph database covering NZEF personnel  who served in the NZEF as detailed in the Cenotaph database. This denominator sample was then adjusted further to replace  those who died in the prepandemic period. Ethnicity coding was then performed as for the numerator data.A validation study was performed for the method of ethnicity coding for Māori; this study involved a University of Otago colleague with local history expertise (Dr George Thomson) who independently classified the ethnicity of WWI participants in a rural area in which he had performed historical research. The results indicated that the coding system we have used was underascertaining Māori ethnicity . Of note, however, is that the rural locality used in this validation study had a relatively high Māori population in the pre-WWI era, and intermarriage between Māori and New Zealand European persons was relatively common. As such, the underascertainment found would be a worst-case assessment if applied to New Zealand in general. In contrast, all of those classified as Māori by our coding system were also classified as Māori by Dr Thomson .In addition to considering Māori mortality rates in official data identified in our literature search, we undertook an additional analysis of an online national database for deaths in New Zealand . Furthermore, some persons with Māori surnames may not have been Māori . Also, a proportion of the total New Zealand mortality rate would have included Māori deaths because the most common 7 surnames on the Māori electoral roll (2006) are actually names of European origin that Māori have commonly adopted over the past 150 years . The latter factor is likely to dominate. Thus, our analysis is likely to have underestimated the true pandemic-related Māori mortality rate.Anonymized mortality data were obtained from an official mortality review group that was charged by the New Zealand government with identifying deaths caused by pandemic (H1N1) 2009  was 7.3× the rate for the rest of the population . This woThe analysis of the effect of 2 pandemic waves among New Zealand military personnel found a substantially higher mortality rate among Māori personnel  than for European military personnel . The ratIn this pandemic, the Māori mortality rate  was 6.2× the European rate . In our A national serosurvey after wave 1 of the pandemic found that Māori had evidence of higher seroprevalence of antibodies to the pandemic (H1N1) 2009 virus but not at statistically significant levels   compared with Europeans and others  (Intensive care unit (ICU) admissions were also significantly higher for Māori and Pacific persons compared with Europeans  than the rate for other New Zealanders  . SimilarNone of the work on these 3 pandemics systematically analyzed risk factors for adverse outcomes of pandemic influenza on Māori. Nevertheless, in 1918 the high rate of illness and death among adult caregivers is thought to have limited capacity to provide basic care for others, contributing to relatively high total Māori mortality overall , morbid obesity (56%), and respiratory disease (49%)  appears to have declined over the 3 pandemics. However, the persistently poorer health outcomes of Māori during the 2009 pandemic is of continuing concern and is compatible with other evidence for persisting inequalities in major health risk factors (Other possible factors for poorer pandemic influenza outcomes in indigenous populations (The results for Māori are compatible with the findings for Pacific persons serving in the military in 1918 and living in New Zealand in 2009 . Like MāThe relatively higher mortality rate from pandemic influenza for Māori military personnel in 1918 indicates that the excess pandemic effect was even seen among relatively fit young men. One possible explanation for this pattern comes from a large study of Australian soldiers in 1918, which suggests that one’s previous experience with respiratory pathogens was an important protective factor in the pre–antimicrobial drug era (Concurrent disease incidence is a plausible risk factor in the 1918 pandemic for Māori soldiers and the civilians in 1918, given the much higher rates of other infectious diseases such as tuberculosis (New Zealand data made it possible to describe health outcomes by ethnicity for pandemics from 1918 onwards. Integrated national-level data collection systems for notifications, hospitalizations and deaths also facilitated such comparisons for the 2009 pandemic.A limitation of the 1918 data identified was the incomplete ascertainment of pandemic-related deaths among Māori, caused partly by incomplete death registrations in this population (Māori deaths occurring during 1957 may have also been underestimated because ethnicity classification at this time was based on funeral director assessments. We acknowledge the limitations of using the language of surnames as part of ethnicity coding and the likelihood of underestimating the mortality rates for Māori; practical alternatives for analyzing such historical data are lacking.To identify risk factors for these ethnic disparities, analytic epidemiologic methods are needed, such as case–control studies of the 1918 military personnel for which there are detailed archival data and hospitalization records for 2009. Such studies need to include risk factors for influenza infection as well as possible risk factors for adverse outcomes, e.g., low socioeconomic position, household crowding, smoking, obesity, preexisting chronic diseases, the lack of prior seasonal influenza vaccination or pneumococcal vaccination, and poorer access to healthcare. Indeed, further detailed work is underway on the ethnic gradient for influenza for 2009 in New Zealand by some of us with Māori health colleagues.,Although further research is desirable, enough is now known about health inequalities in nations with indigenous peoples for government agencies and health care workers to pursue specific interventions. For example, in New Zealand, interventions should continue to raise the social and economic well-being of Māori, i.e., improve housing, reduce smoking, control obesity, improve management of diabetes, increase immunization rates, and improve access to health care services. Fortunately, many such interventions are part of New Zealand health sector activity and range from national-level smoking cessation campaigns to more local community-level programs such as a Let’s Beat Diabetes program. Other policy development is occurring, with new and substantive tobacco control measures recommended by a Māori Affairs Select Committee in late 2010 (Analysis of multiple health data sources indicates large reductions in absolute mortality rates from pandemic influenza for Māori and European New Zealanders and is suggestive of some decline in relative ethnic health inequalities for pandemic mortality over the past century. However, the persistent Māori excess in hospitalizations and deaths for the 2009 pandemic highlights the need for additional research to clarify contributing factors. There remains an ongoing need for societal and public health action to reduce known risk factors for influenza infection and adverse health outcomes for indigenous populations such as Māori.


A blinded study was undertaken to determine whether XMRV or MLV-like virus could be detected in peripheral blood from 40 adult subjects divided into three groups: severely ill with CFS, recovered from CFS, and a control group lacking a CFS diagnosis at any time. All patients in the“severe CFS” group currently meet Fukuda criteria. “Recovered CFS” subjects had scores on the SF-36 survey instrument that were significantly lower than the healthy control group, according to Hotelling’s T2 test. Blood was collected in EDTA tubes and cDNA and DNA made from PBMCs. Plasma was incubated with LNCaP cells that were subsequently passaged. Nested PCR with USB Hot-Start IT FideliTaq was performed with gag primers. Any PCR products of expected sizes were sequenced. Samples were tested for mouse contamination with primers to IAP and/or mouse mitochondrial DNA. gag sequences were detected in both severe and recovered CFS subjects’ blood as well as in some healthy controls. gag sequences could be amplified from genomic DNA from LNCaP cells of some subjects after 4 or 6 subcultures following incubation with certain subjects’ plasma, indicating the presence of infectious virus in blood. All gag sequences detected in this cohort were more similar to the MLV-like sequences reported by Lo et al. (2010) than to the XMRV sequences reported by Lombardi et al. (2009). Detection of gag sequences in whole blood genomic DNAs that were negative for mouse IAP and mitochondrial DNA provides strong evidence for infection of humans with MLV-like viruses.


To The Editor: Barchi et al. report a case of simultaneous pandemic (H1N1) 2009 influenza and HIV infection  or for the nurse who was exposed to the patient’s urine. Occupationally acquired HIV infection in a health care provider after an ocular splash with urine has, to our knowledge, never been reported and, if these test results are for the worker, would represent a novel source of transmission. Precision with respect to the source of these samples and results is critical to reader understanding.Additionally, the reported negative Western blot results demonstrated p24 and p41 bands; this test result would be considered positive by Centers for Disease Control and Prevention–endorsed interpretive criteria  (Finally, diagnosing acute HIV infection can be challenging. Although the elevated initial CD4 lymphocyte percentage and viral load are suggestive of recent HIV infection ( In Response: In reply to Kuhar and Henderson (


To evaluate the incidence and mechanism of mitral regurgitation [MR] as a complication in the evolution of myocardial infarction [MI]. Patient population: 95 patients diagnosed on the basis of clinical, electrocardiographic and coronary-angiographic data with coronary artery disease [CAD] with a history of MI with haemodynamically significant MR (>/=grade II).• All patients were treated in accordance with standard therapy for CAD and heart failure• 56 Patients with PTCA of the obstructed coronary artery• 28 Patients treated with CABG out of these 19 patients with mitral valvuloplastyCriteria for exclusion from the study: patients with organic MR  or with myxomatous mitral valve prolapse.Transthoracic echocardiography [TTE] for all patients and transoesophageal echocardiography for 75 patients.Sixty eight patients had grade II MR and twenty seven grade III MR. The aetiology of MR was:• Papillary muscle rupture – 1 patient• Papillary muscle ischaemia (inferior or posterior MI) – 15 patients• Dilatation and remodeling of left ventricle [LV] – 58 patients (13 out of these 58 patients had LV aneurysms)• Mixed mechanism (papillary muscle ischaemia and LV dilatation) – 21 patientsMR appears frequently in the evolution of patients with MI, even in patients subjected to a standard line of treatment. Echocardiography is a very important tool for the evaluation of severity and more importantly, that of aetiology. Understanding of the mechanism of MR offers the possibility to find a correct treatment option and where necessary, an optimal surgical intervention.


EHP, researchers report preliminary evidence of an association between two birth defects and a mother’s residential proximity to natural gas wells at the time of birth.More than 15 million Americans are now estimated to live within one mile of a natural gas well drilled since 2000.“Studies like this underscore the need for more representative and comprehensive research on workers and communities to understand their exposures and potential health risks,” says Aubrey Miller, a senior medical advisor at the National Institute of Environmental Health Sciences.Researchers led by Lisa McKenzie at the Colorado School of Public Health estimated exposure to natural gas development for nearly 125,000 Colorado women. They used an “inverse distance weighting” method in which they determined the density of natural gas wells within a 10-mile radius of each mother’s home at the time she gave birth, with greater weighting for wells nearer the home. Then they compared proximity to gas wells between mothers who had adverse birth outcomes—including three types of birth defects, preterm birth, and term low birth weight—and those who did not.Among 59 cases of neural tube defects, prevalence was twice as high among babies of mothers in the highest exposure group—a group of 19 women with more than 125 wells per mile within a 10-mile radius of the home—compared with babies of unexposed mothers. However, there was no evidence that neural tube defects were increased among the 13 babies of mothers classified as having low or medium exposure.Among 1,823 cases of congenital heart defects, prevalence was 30% higher among babies of mothers in the highest exposure group, compared with babies born to unexposed mothers. In contrast to neural tube defects, however, the likelihood of a congenital heart defect increased steadily with increasing exposure. Congenital heart defects are the most common type of birth defect, affecting about 8 of every 1,000 newborns in the United States.There was no association observed between proximity to natural gas development and having babies with an oral cleft. In addition, babies whose mothers experienced the highest exposures to natural gas wells were slightly less likely to be born prematurely or at a low birth weight. However, the association between proximity to gas wells and improving birth weights diminished when the researchers accounted for elevation. “Higher elevations are associated with lower birth weights, while most natural gas drilling in Colorado occurs at low elevations,” McKenzie explains.,Although low levels of maternal folic acid—a B vitamin found in green leafy vegetables—is an established risk factor for neural tube defects,“The study certainly raises legitimate concerns, given that there are plausible mechanisms for many of the chemicals that are used in natural gas development,” says Kenneth Spaeth, medical director of the Occupational and Environmental Medicine Center at North Shore University Hospital inNew York, who was not involved in the study.The authors suggest that exposure to benzene from the wells is one such plausible explanation for their findings. However, they did not identify or measure specific pollutants that may have been present at natural gas wells or specific activities occurring at the sites, so it is not possible to know which chemicals and/or other environmental stressors—if any—explain the associations. It’s also possible that some other risk factor not associated with wells, such as mothers’ folic acid consumption or level of prenatal care, could have influenced the results.“Our findings are far from representing a causal effect,” says McKenzie. Her plans for future research include interviews with study mothers to get more information about their pregnancy and place of residence during the first trimester, a critical period for birth defect formation. She also plans to obtain more detailed information on specific activities taking place at well sites during the first trimester.


Besides its classical function of bone metabolism regulation, vitamin D exhibits multiple biological targets mediated by its nuclear hormone receptor, the vitamin D receptor (VDR) Holick, , 2011b. At least one billion people have hypovitaminosis D worldwide Holick, . Even ifThe high prevalence of hypovitaminosis D in elderly population is also explained by the choice of the threshold defining hypovitaminosis D, which may vary between 10 and 30 ng/mL.Vitamin D status is usually estimated by measuring serum 25OHD Holick, . In geneThe second method for calculating reference values of 25OHD is to define hypovitaminosis D as 25OHD levels for which there are some adverse health effects. These reference values are called “health-based reference values.” There is an international consensus to use this kind of threshold in the case of 25OHD  and brain by crossing the blood–brain barrier via passive diffusion and additional specific carriers in the cerebral capillaries or the blood–CSF barrier in the plexus choroideus  contributing to the conception and design, or analyzing and interpreting data; (2) drafting the article or revising it critically for important intellectual content; and (3) approving the final version to be published.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


P < 0.001) and (2) the sensory feedback threshold for closed‐loop control was lowered (P < 0.010). Altered postural control was predominantly associated with increased co‐contraction of leg muscles. Body sway and leg and neck muscle co‐contraction correlated with the severity of subjective anxiety (P < 0.050). Alterations in postural control diminished if there were nearby stationary contrasts in the visual surrounding or if subjects stood with eyes closed. The performance of a cognitive dual task also improved impaired balance. Visual heights have two behavioral effects in vHI subjects: A change occurs in (1) open‐ and closed‐loop postural control strategy and (2) co‐contraction of anti‐gravity leg and neck muscles, both of which depend on the severity of evoked fear at heights.Fear of heights occurs when a visual stimulus causes the apprehension of losing balance and falling. A moderate form of visual height intolerance (vHI) affects about one third of the general population and has relevant consequences for the quality of life. A quantitative evaluation of balance mechanisms in persons susceptible to vHI during height exposure is missing. VHI‐related changes in postural control were assessed by center‐of‐pressure displacements and electromyographic recordings of selected leg, arm, and neck muscles in 16 subjects with vHI while standing at heights on an emergency balcony versus standing in the laboratory at ground level. Characteristics of open‐ and closed‐loop postural control were analyzed. Body sway and muscle activity parameters were correlated with the subjective estimates of fear at heights. During height exposure, (1) open‐loop control was disturbed by a higher diffusion activity  during the experience of fear at heights. Visual heights have two behavioral effects in vHI subjects: A change occurs in (1) open‐ and closed‐loop postural control strategy and (2) co‐contraction of anti‐gravity leg and neck muscles, both of which depend on the severity of evoked fear at heights. Individual responses to visual stimulation of heights vary within a continuum ranging from physiological visual height imbalance to acrophobia, the severest end of the spectrum  versus standing at ground level (laboratory). Stimulus‐ and attention‐dependent changes in postural control were evaluated by a comprehensive stance protocol, including different visual feedback conditions and cognitive dual tasks. Postural behavior was analyzed by means of CoP amplitude variables  and SDA. Accompanying EMG was performed to evaluate associated changes in muscle activity levels and muscle cocontraction patterns. The major question was whether these subjects apply different strategies of postural control and patterns of anti‐gravity muscle innervation during free stance at ground level or when exposed to heights.Sixteen subjects  who had reported lifetime vHI participated in the study. A detailed questionnaire was used to enquire about vHI  and afterward while standing in the laboratory. The experimental protocol for both measurements comprised six postural tasks during which each participant was instructed to stand quietly for 30 s: (1) Eyes open, line of gaze toward the horizon (EO); (2) eyes open, line of gaze toward a given object at ground level, that is, ↓ 45° head flexion in the pitch plane (EOHF); (3) eyes open, line of gaze toward the sky, that is, ↑ 45° head extension in the pitch plane (EOHE); (4) eyes closed (EC); (5) eyes open while performing a cognitive dual task (naming items from a given category) (EODT); and (6) eyes closed while performing a cognitive dual task (naming items from a given category) (ECDT). At the end of the protocol the first task  was repeated to evaluate potential training and compensatory effects  and a report of any accompanying somatic symptoms and compensatory behavior. Furthermore, the impact of vHI on daily routine and quality of life was evaluated.Static postural behavior was measured on a stabilometer platform  with a sampling frequency of 100 Hz. The CoP trajectories in anterior–posterior (AP) and medial–lateral (ML) directions were calculated and filtered using a second‐order low‐pass Butterworth filter with a cutoff frequency of 10 Hz to eliminate low‐amplitude measurement noise  at a sampling frequency of 1500 Hz. To evaluate activity levels and co‐contraction of the leg, arm, and neck musculature, the following three muscle pairs were selected: (1) tibialis anterior and soleus for the leg  was estimated by fitting an ellipse covering 95% of the planar CoP displacement (Duarte and Zatsiorsky RMS (mm) and range (mm) were calculated for AP and ML directions. The sway area  and Dl (mm2s−1) were determined by linear fits to the diffusion plot. In most cases, the linear fit to the short‐term region included data ranging from 0.1 to 0.5 s; the linear fit to the long‐term region included data ranging from 2 to 5 s. In some cases fitting regions were manually altered to maintain good‐quality linear fits of the data. The critical point coordinates Δtc (s)  and <Δr2>c (mm2)  were obtained from the intersection point of the linear fits to the short‐ and long‐term regions  was calculated for each pair following the approach proposed by Falconer and Winter  procedure .The effects of each dependent variable were analyzed using a three‐way repeated measurement analysis of variance (ANOVA) and a Bonferroni post hoc analysis with height stimulus , stance condition , and CoP displacement direction (AP vs. ML direction) as factors. Significant interaction effects were further decomposed into simple main effects. Pearson's correlations were performed to evaluate (1) the influence of muscle activity and co‐contraction on the CoP variables and (2) the influence of subjectively rated anxiety on the EMG and posturography outcomes during height exposure. The resulting ANOVA results are given in Subjectively rated anxiety while standing on the balcony averaged 4.6 ± 2.5 . Among the accompanying somatic symptoms, instability of stance/gait was most frequently reported (64%) followed by inner agitation (57%), to‐and‐fro vertigo and trembling (both 43%), queasy‐stomach feeling (36%), weakness in the knees (29%), fearfulness and sudden sweating (both 21%), palpitations and light headedness (14%). The most common compensatory behavior was thinking about a safe grip (57%), avoiding looking down (43%), staying close to the building walls (29%), and considering withdrawing from the experiment (21%). A total of 36% of the participants indicated that aside from typical triggering situations, vHI had no disturbing impact on their daily routine. On the other hand, 64% reported that in typical triggering situations vHI led to compensatory behavior with relevant consequences for their quality of life.None of the examined CoP parameters showed any significant training effects for the duration of the experiments. Sway ranges were greater during height exposure. Under the condition EOHF, ranges were generally smaller than for the condition ECDT. In contrast, CoP RMS and sway area did not differ significantly between the different height situations. RMS was generally smaller while standing under the condition EOHF compared to the conditions EOHE and ECDT. Both sway ranges and RMSs were higher in AP than in the ML direction.Ds during height exposure. Decomposing the significant interaction effect revealed that increased Ds was only present for the conditions EO and EOHE, but comparable for all other stance conditions. While standing on the balcony, Ds was decreased under the condition EOHF compared to all other conditions except EODT. In contrast, Dl results were in the same range for both height situations and all stance conditions. Overall, Hs was similar for the different height stimuli and stance conditions. Hl was smaller during height exposure, but did not differ between stance conditions. Critical point analysis revealed smaller Δtc during height exposure. Decomposing the significant interaction effect revealed that shortened Δtc was only present under the conditions EO and EOHE, but comparable for all other stance conditions. <Δr2>c was comparable between both height situations, but was generally decreased under the condition EOHF compared to the conditions EODT and ECDT. Ds, Dl, as well as <Δr2>c were generally higher in AP than in the ML direction  The alterations in postural control measures and (2) the associated changes in muscle activity parameters.Ds has been associated with an increase in postural instability, that is, a less tightly regulated and less damped postural control system (Collins and De Luca tc during height threat significantly shortens the effective range of the steady‐state open‐loop regime and thereby lowers the temporal primary feedback threshold. A decreased critical time has also been linked to an increased stiffness of the postural control system (Peterka Sway ranges increased in vHI subjects while quietly standing at heights in accordance with previous studies on healthy subjects (Alpers and Adolph  Peterka . During  Peterka . LimitedAlmost all observed significant alterations of balance behavior were associated with the subjective estimates of fear at heights. This suggests that the degree of manifestation of altered postural control and the amount of anxiety experienced during height threat are mutually linked in vHI subjects, leading to a vicious circle of fear, perception, and instability (Schaeffler et al. Altered postural control during height exposure was linked to specific changes in muscle activity parameters. Increased leg muscle activity predominantly accompanied alterations in the steady‐state open‐loop control and positively correlated with subjective estimates of fear at heights. Raised leg muscle co‐contraction observed in vHI subjects was mediated by a parallel downgrade of soleus activity and upgrade of tibialis anterior activity and in conformance with previously reported changes in leg muscle activity in healthy subjects standing under height threat (Brown and Frank This study provides first insights into the characteristic changes in postural control strategy in persons susceptible to vHI during height exposure. These changes appear to be predominantly linked to enhanced co‐contraction of anti‐gravity muscles. Two distinct sources of postural imbalance were identified: Both a critical distance to stationary surroundings in the visual environment and the anxiety evoked by height threat appear to trigger inadequate balance strategy in vHI subjects. The specificity of the observed alterations in balance control of these subjects shows a notable conformance with recently found changes in postural behavior in patients with phobic postural vertigo (Wuehr et al. The authors thank Judy Benson for copyediting the manuscript.None declared.


We regret any confusion or inconvenience this error may have caused.In the article "A Common Denominator: Calculating Hospitalization Rates for Ambulatory Care–Sensitive Conditions in California," the citation for reference 12 was incomplete. The correction was made to our website on October 17, 2011, and appears online at


Cardiac magnetic resonance imaging (MRI) has emerged as a prime player in the clinical and preclinical detection of ischemic heart disease (IHD) as well in the prognosis assessment by offering a comprehensive approach for all spectrums of coronary artery disease (CAD) patients. The aim of this review is to provide the reader a state–of–the art on how the newest cardiac MRI techniques can be used to study IHD patients.In patients with suspected/stable CAD, functional and perfusion imaging both at rest and during vasodilatatory stress /dobutamine stress can accurately depict ischemic myocardium secondary to significant coronary artery stenosis.In patients with acute MI, MRI is a robust tool for differentiating and sizing the jeopardized and the infarcted myocardium by using a combination of functional, edema, perfusion and Gd contrast imaging. Moreover, important prognostic factors like myocardial salvage, the presence of microvascular obstruction (MVO), post reperfusion myocardial hemorrhage, RV involvement and infarct related complications can be assessed in the same examination.In patients with chronic ischemic cardiomyopathy, the role of the MRI extends from diagnosis by means of Gadolinium contrast scar imaging to therapy and prognosis by functional assessment and viability testing with rest and dobutamine stress imaging.In all the circumstances mentioned, MRI derived information has been proven valuable in every day clinical decision making and prognosis assessment. Thus, MRI is becoming more and more an accepted alternative to other imaging modalities both in the acute and chronic setting. In the last 2 decades magnetic resonance imaging (MRI) has emerged as a prime player in the clinical and preclinical detection of IHD as well in the prognosis assessment . The jeopardized myocardium (myocardium at risk) refers to the myocardium in the perfusion territory of the involved artery distal to the critical lesion.After the acute coronary occlusion, the time frame of events in the myocardial reperfusion injury” [4]. The main feature of this complex phenomenon is the presence of microvascular obstruction (MVO) with a complete lack of tissue perfusion, despite successful epicardial recanalization.Urgent restoration of epicardial flow, which is the cornerstone of modern therapeutic strategies in acute MI, aims to salvage the jeopardized but viable myocardium in the myocardium at risk. Despite the beneficial effects of reperfusion, the process of cell death may continue during the first hours of reperfusion, a phenomenon called “stunned myocardium” which may take days to weeks to normalize, though it can be reversed with inotropic agents [5].Prolonged post–ischemic contractile dysfunction of the myocardium salvaged by reperfusion defines the “hibernating myocardium” is used to describe viable myocardium in a state of persistent but potentially reversible dysfunction secondary to a chronic coronary artery stenosis with impaired myocardial blood flow [6].Finally, the term “anatomic imaging with visualization of CAD and on the other hand, ischemia imaging with evaluation of the consequences of CAD to the heart, particularly myocardial perfusion and function and depiction of irreversible myocardial damage. Due to its superiority over MRI, cardiac computed tomography is used nowadays for mere visualization of coronary artery stenoses, cardiac MRI being primarily focused on the assessment of the ischemic consequences of CAD [9].Currently available cardiac MRI techniques are able to fulfill the aims of imaging in IHD patients: on one hand, In clinical practice, by using a comprehensive MRI approach, the above information can be obtained within a single examination taking not more than 30–45 minutes.dynamic cine MRI (b–SSFP) sequences provide a non–invasive, accurate and reproducible alternative to conventional echocardiography for calculating ventricular volumes and function and visualizing regional wall motion and contraction patterns. Thus, cine MRI should be considered as a fast and robust imaging modality for both daily clinical routine and research purposes [11]. With techniques as real–time non–gated cine sequences, problems like the presence of atrial fibrillation or the incapacity for breath holding are now mostly overcome.ECG gated and acquired during breath holds, Fig. 1).For volumetric and functional ventricular analysis, the heart is typically studied in different cardiac imaging planes. Hereby the ventricles are completely encompassed by a set of contiguous images , in at least one direction which is usually the short–axis. Contouring of endo– and epicardial borders of this stack of images at end-diastole and end–systole provides global functional parameters   or quantitatively . In order to have consensus between readers and imaging modalities, the standardized 17–segment model as proposed by the American Heart Association is usually used .Further, for a more comprehensive approach of CAD patients, evaluation of cardiac function and myocardial contractility can be performed both at rest and under stress conditions , i.e. Myocardial tagging MRI techniques non–invasively create tag or grid lines on the myocardium, allowing to analyze regional myocardial deformation 2– or 3 dimensionally throughout the cardiac cycle, and to calculate myocardial strains .14].A better characterization of the mechanisms of normal/impaired myocardial contraction is thus achieved but due to the elaborative post–processing, the clinical use of myocardial tagging MRI is currently limited . T2–relaxation time is linearly correlated to the percentage of free water, and edema is visible on T2–weighted MR sequences in infarcted myocardium as bright areas (hyper–intense). In acute MI patients, it is accepted that the bright myocardium on T2–weighted imaging reflects the myocardium at risk. Abnormalities are most evident in the acute and sub–acute phase of MI and slowly fade away due to processes of infarct healing with scar formation and resorption of infarct-related myocardial edema and inflammation [16]. Thus, in addition T2–weighted imaging distinguishes between a fresh and a healed MI [17]. It should be emphasized that other conditions such as acute myocarditis or transplant rejection may equally present focal or diffuse myocardial edema [18]. T2–weighted MR sequences, equipped with inversion techniques to null the signal of fat and blood (will appear dark) , are now most commonly used for edema imaging [19].Increased free water in the infarcted myocardium changes tissue magnetization properties (i.e. prolongs proton T1– and T2–relaxation) when compared to normal myocardium, and this change is related to the duration of ischemia . This small molecule diffuses rapidly after intravenous injection into the interstitial space (strictly extracellular), and is eliminated by renal clearance. Due to differences in pharmacokinetics and distribution volume between normal and infarcted/scarred myocardium, the latter appears bright (enhanced) compared to normal myocardium which appears dark.Up to date, the paramagnetic gadolinium–chelated contrast agents Gadolinium contrast agents are not infarct specific; as such, myocardial enhancement is non-specific, while the location and pattern of enhancement give important information regarding the underlying etiology.inversion–recovery T1–weighted sequence, which achieves an increased contrast between normal and pathological tissue (dark vs. bright). Using this technique, infarcted myocardial tissue weighting as low as 1 gram can be visualized (vs. 10 grams with SPECT) like, for example, in papillary muscle necrosis or peri–procedural myocardial damage [22].Currently, in the routine clinical setting, MI imaging after Gd administration is done by an acute MI results in a time–varying infarct enhancement. Infarct–related factors and contrast agents or MRI sequences characteristics contribute to the “observed” enhancement. Among the infarct related factors a hyperemic response after reperfusion (increased delivery of Gd) and an increased myocardial distribution volume due to interstitial edema and myocyte disruption (intracellular diffusion of contrast agent) will increase Gd concentration in the infarcted area, while an incomplete coronary recanalization with a poor collateral circulation and the presence of MVO will act the opposite [25].Administration of Gd contrast agents in Ce–MRI is a robust, well–validated and accurate tool to depict myocardial necrosis in the acute setting of MI. Following administration of contrast material, infarcted myocardium is visible as a time–varying enhancement (bright) distinguishable from normal myocardium (dark). However, one should comprehend that extracellular contrast agents are neither specific nor avid for myocardial necrosis.chronic CAD patients, myocardial enhancement in areas of dysfunctional myocardium corresponds closely to fixed defects on thallium SPECT, and areas of flow–metabolism matched defects on FDG–PET scans, histologically representing scarred or fibrotic tissue [27]. This technique is nowadays routinely used to depict infarct–related myocardial scarring and is helpful to differentiate dilated cardiomyopathy from LV dysfunction related to CAD, and to predict functional recovery post–coronary revascularization [28] .It is proven that in anatomic and ischemic imaging (rest and stress). Due to long acquisition times and lack of robustness, clinical use of cardiac MRI for non–invasive coronary plaque detection is nowadays of limited value. Despite this, substantial progress has been made in myocardial ischemia assessment, making this technique an attractive and valuable alternative to stress echocardiography and radionuclide pharmacological stress perfusion imaging (i.e. SPECT imaging).As already mentioned above, cardiac MRI offers a comprehensive non–invasive imaging approach to the broad chronic CAD spectrum patients, by being able to combine both Compared to stress echocardiography, MRI provides reliable image quality not limited by the adequacy of the acoustic window. Per stress level, images can be easily acquired in standardized (repeatable) planes, and easily compared on an off–line workstation reducing operator–dependency.29].Compared to SPECT, MRI is able to give similar information about myocardial perfusion with superior spatial resolution, no radiation exposure, and in a single examination. Moreover, the superior spatial resolution of MRI permits to visualize smaller, subendocardially located perfusion defects not infrequently missed by SPECT .At present this technique has been well validated, showing similar or better accuracies when compared to routinely used techniques such SPECT imaging [“first–pass” of contrast in one or more coronary artery perfusion territories. Semi–quantitative or quantitative methods have become available mainly for research purposes. A relatively simple semi–quantitative method that has been validated against coronary flow reserve measurements is the assessment of the myocardial perfusion reserve (MPR) or MPR index. MPR index is defined as the ratio of regional myocardial blood flow after induced vasodilatation to that under resting conditions [33]. For example, Rieber et al., found that by using fractional flow reserve in addition to the degree of stenosis on coronary angiography as reference modality, a MPR index cut–off value of 1.5 was able to distinguish between hemodynamically relevant and non–relevant coronary lesions with a sensitivity of 88% and specificity of 90% [34]. After PCI with stent implantation or CABG surgery, a significant improvement in MPR index was reported, thus providing information on the success of interventional revascularization procedures [35].Regarding data analysis, in daily clinical practice stress–induced perfusion defects are usually visually assessed by looking at the presence of subendocardial or transmural hypo–intense (dark) rim during the It must be noted that first–pass perfusion is prone to dark–rim artifacts  and these artifacts may interfere with depiction of subendocardial ischemia.36]. Similar to dobutamine stress echocardiography, a stepwise dose increment of dobutamine is used in order to differentiate the precise nature of the ischemic substrate, i.e., stunned, ischemic, hibernated, necrotic/scarred myocardium [38].Although it is possible to perform exercise testing in an MR environment using a specific MR–compatible ergometer (supine bicycle), functional stress testing is usually performed during dobutamine (± atropine) administration .With respect to adverse effects, studies have shown that high–dose functional stress imaging in an MR environment can be considered as safe and feasible in patients with suspected or known CAD [40]. Two studies have demonstrated the higher accuracy (86.0% vs. 72.7%) of high–dose stress dobutamine MRI compared to high–dose dobutamine stress echocardiography in detecting patients with significant CAD [42]. Patients with poor acoustic windows benefit the most from MRI stress testing.The advantage of stress function MRI over echocardiography rests in superior image quality, with high spatial and temporal resolution and better inter– and intra–observer agreement [visual analysis of new or worsening WMA’s using a high–dose dobutamine/atropine regimen and a 16 (or 17) segment model [12] .The most commonly used approach in ischemia functional stress studies is 43].This yields good sensitivities (83–96%) and specificities (80–100%) for detection of significant CAD . Although angiographic criteria were assessed to estimate more accurately the jeopardized myocardium, for example by using the Bypass Angioplasty Revascularization Investigation Myocardial Salvage Index (BARI), there is need for imaging techniques that can directly and accurately depict this area at risk [46].Edema imaging by T2-weighted sequences is at present one of the most appealing techniques to non–invasively assess the myocardium at risk [47]. This can be determined retrospectively, i.e. post–reperfusion, by T2–weighted edema imaging, with abnormalities present at least one week after the acute event [16]. Abdel–Aty et al., recently showed that edema imaging depicts acute ischemic injury within the first 30 minutes after onset of ischemia, before the onset of irreversible myocardial injury  [47]. Since the development of myocardial edema is an early feature in acute coronary syndromes, adding T2–weighted imaging to the MRI exam in unstable angina or MI patients, may serve as a very useful diagnostic marker in the emergency department [48].Fig. 7).As mentioned above, edema imaging is not MI specific and in the acute setting of cardiac–related chest pain, patients with Tako–Tsubo cardiomyopathy and acute myocarditis may show also myocardial edema  or using an automated quantification approach [66]. Several ce–MRI based studies have shown that increased infarct transmurality is related to lack of inotropic reserve and impaired recovery of contractile function, and is associated with more pronounced post–infarct wall thinning, aneurysm formation and adverse ventricular remodeling [69]. In patients with healed infarcts and ventricular dysfunction, scar transmurality as determined by ce–MRI, predicts functional recovery post–revascularization and patient survival [63].Microvascular obstruction or No–Reflow. Even with early, successful and sustained restoration of coronary flow in the culprit coronary artery, between 5 and 50% of STEMI patients show lack of restoration of blood flow at myocardial level. This no–reflow phenomenon is secondary to microvascular obstruction (MVO) and has a complex, multifactorial pathogenesis including: distal embolization, ischemia–reperfusion injury, and individual coronary microcirculation predisposition to injury [70]. No reflow increases with the duration of ischemia time, is related to more severe myocardial damage and is independently associated with lack of functional recovery, adverse ventricular remodeling and worse patient outcome [74].70]. Ce–MRI has become the preferential technique for MVO depiction and has been validated against pathologic studies using specific staining (thioflavin–S). On ce–MRI no reflow is visualized as a central or subepicardial, hypo–intense, dark region within the enhanced, bright area of infarcted myocardium and is clearly distinguishable from completely reperfused infarcts presenting as homogeneous enhancement .No–reflow can be assessed during primary PCI with Thrombolysis In Myocardial Infarction (TIMI) flow grade and myocardial blush grade (MBG) post–reperfusion, by ST–segment elevation resolution early post–reperfusion, and can be better quantified by noninvasive imaging techniques such as myocardial contrast echocardiography and ce–MRI [75]. Beyond 2 days, the progress causing no–reflow expansion most likely stabilizes and persists at least till 9 days post–infarction [76].Studies using early ce–MRI have shown a progressive increase in size for the hypo–intense region corresponding to no reflow (up to 3–fold) during the first 48 hours, suggesting progressive microvascular damage after reperfusion .To appreciate the extent of MVO, post–reperfusion intramyocardial hemorrhage  [78]. Hemorrhagic myocardium has a typical heterogeneous appearance on T2–weighted MRI (edema imaging) due to formation of hemoglobin breakdown products containing iron and their paramagnetic effects. This heterogeneous appearance is visualized as a hypo–intense core with a peripheral hyperintense rim, while, non–hemorrhagic infarcts present as areas with homogeneously increased signal intensity in the myocardium at risk [79]. In a study of 98 patients with reperfused STEMI’s, we found intra–myocardial hemorrhage in 25% of patients [80]. Patients with hemorrhagic infarcts had a lower pre–TIMI flow, higher cardiac enzymes, larger infarct size and greater infarct transmurality, larger no–reflow zone, and a lower myocardial salvage index. Intra–myocardial hemorrhage was an independent predictor of adverse LV remodeling regardless of the initial infarct size. It should be emphasized that intra–myocardial hemorrhage has a close and intricate relation with MVO. On the one hand, the degree of microvascular injury underlies extravasation of red blood cells and on the other hand, intra–myocardial hemorrhage may worsen tissue turgor and aggravate the severity and extent of MVO.Reperfusion injury and microvascular damage, in their most severe form, can be associated with significant interstitial extravasation of red blood cells, i.e. Right ventricular (RV) infarction, usually an expression of a biventricular acute MI is characterized by a faster and better functional recovery than LV due to a more favourable oxygen demand/supply profile for the former [81]. Lack of RV recovery, however, is associated with persistent hemodynamic compromise and high mortality rate [82]. MRI is increasingly being used to study RV ischemic injury in MI patients, though assessment of reversible and irreversible ischemic injury in a thin and trabeculated RV wall is challenging . Despite some limitations, MRI has contributed not only to a better depiction but also to a better understanding of RV ischemic injury. It has become clear that current established techniques for RV infarct detection, such as clinical investigation, ECG with right precordial leads, and echocardiography underestimate the true incidence of RV ischemic injury in acute inferior LV infarcts, with RV inferior wall enhancement in approximately 50% of patients. Moreover, RV ischemic injury is not limited to inferior infarcts but is often found in anterior LV infarcts as well [83]. Taking into account that up to 30% of the RV free wall is perfused by the LAD coronary artery, a considerable portion of the RV myocardium is at risk in LAD infarcts. Fortunately, the RV myocardial salvage post–reperfusion is large and the resultant RV infarct size small [84]. In a recent study we found at 4–month follow–up post–infarction a significant decrease in extent and frequency of RV myocardial enhancement [83]. Potential explanations include volume shrinkage due to infarct healing but other mechanisms such as acute, temporary enhancement of the reversibly injured portion of the jeopardized myocardium should be equally considered.65].In the past, a great deal of knowledge about ECG changes in acute coronary syndromes and IHD was based on pathologic correlations in animal work and autopsy studies. Ce–MRI has allowed a reassessment and reinterpretation of our common understanding of the ECG [87].First, regarding Q waves and transmurality, several MRI studies have shown that the primary determinant of the presence of a Q–wave is the total size of the underlying infarction rather than its transmural extent [88][88]. Importantly, the lateral LV territories are electrically silent and therefore may present with little ECG alteration [89]. Recently, a multi–specialist team has defined a new terminology of the LV walls and proposed a new ECG classification of Q–wave myocardial infarction based on cardiac MRI and angiographic correlations [90].Second, ECG–derived estimates of infarct size correlate at best, only modestly with ce–MRI, overestimating small infarcts and underestimating large infarcts . MI associated pericarditis can also be depicted by late ce–MRI showing bright, enhanced pericardium with or without pericardial fluid [95]. MRI may be occasionally helpful in detecting rare complications such as ventricular septal defects or intramural dissecting myocardial hemorrhage [96].High–spatial resolution 3D ce–MRI techniques offer improved detection for peri–procedural necrosis after successful PCI and coronary bypass surgery and can help for a better understanding of its underlying mechanisms [98]. MRI yields promise to accurately depict subtle myocardial damage related to other procedures like trauma, chest compression and external defibrillation [99] .Looking at treatment–related complications, ce–MRI can depict chronic ischemic cardiomyopathy have single or multivessel CAD and dilated, dysfunctional ventricles containing a mixture of different ischemic substrates  in the same/different perfusion territory. Viability assessment is of utmost importance in deciding whether a patient may benefit from a revascularization procedure, with the aim of improving regional and global ventricular function, negative remodeling, symptoms, exercise capacity and long term prognosis [100].Patients with viability assessment, MRI has emerged as one of the preferential techniques by combining information about wall thickness and myocardial contractility reserve, used also by echocardiography, with the noninvasive visualization of even subtle amounts of myocardial scar formation [101]. Viability imaging with MRI is only part of a more comprehensive approach which involves evaluation of ventricular volumes and global function, visualization and quantification of associated valvular heart disease , and depiction of complications such as ventricular aneurysms or thrombus formation [92].Among the different tools available for 102].A first approach is the measurement of segmental end–diastolic wall thickness (EDWT). The degree of wall thinning secondary to MI healing and scar formation is related to the degree of infarct transmurality. This approach appears very sensitive (95%), but not specific (41%) for prediction of functional recovery, indicating that thinned myocardium (< 6mm) has a low likelihood to improve function after revascularization and accurately reflects scar tissue. While a substantial percentage of segments with preserved wall thickness do not improve in function following revascularization, probably due to the presence of subendocardial infarctions, thinned myocardial segments may undergo a process of “reverse remodeling” after successful myocardial revascularization with recovery of function and regain in regional wall thickness . Dobutamine stress MRI for viability testing has good specificity (83%) but moderate sensitivity (74%), values that are in line with those of dobutamine echocardiography [102].A second approach is the Contrast–enhanced MRI, the third approach, detects scar tissue but not viability. In brief, the likelihood of improvement in regional contractility after revascularization decreases progressively as the transmural extent of enhancement before revascularization increases. 78% of dysfunctional segments without enhancement showed improved contractility postrevascularization, compared to 2% of dysfunctional segments with scar tissue extending >75% of the LV wall in a study by Kaandorp et al. This technique had an excellent sensitivity (95%) but a low specificity (45%) [104]. The low specificity is related to subendocardial infarcts in which it is unclear whether the non–enhanced subepicardial myocardium contains normal, viable or jeopardized myocardium.integrated use of MRI techniques may improve diagnostic accuracy. Kaandorp et al. proposed to start with ce–MRI to depict myocardial scarring and determine the transmural extent. Then, in segments with an intermediate extent of scar tissue , in which the likelihood of recovery is uncertain, dobutamine stress MRI may be used to differentiate between those with versus those without contractility reserve [104].Because none of the above approaches is perfect in neither predicting nor excluding functional recovery after revascularization, an 105].Any clinical perspective about an imaging technique should involve its role in patient prognosis assessment and management. There is growing evidence that cardiac MRI is an increasingly important tool in the management of cardiovascular disease . Moreover, in patients without a history of MI but with clinical suspicion of CAD, the presence of myocardial enhancement even in small amounts, reflecting ischemia-related myocardial scarring, carries an increased risk for future major adverse cardiac events [64].In patients with unstable angina patients, adenosine stress perfusion MRI is a more accurate predictor of future cardiac events than traditional cardiac risk factors [108]. Moving forward to acute MI, in STEMI patients, MRI has become the reference technique for infarct sizing. Moreover, because of its unique capability for characterization of the infarct and jeopardized myocardium MRI is a valuable tool in the assessment of other factors associated with a poor prognosis, besides infarct size) [109]. These include MVO, post–reperfusion myocardial hemorrhage, the peri–infarct area, and myocardial salvage [110]. Also in patients with NSTEMI, persistent MVO is an independent predictor of major cardiac events [111].In low to intermediate risk ischemic cardiomyopathy patients with severely reduced LVEF, the extent of myocardial enhancement is associated with increased mortality or the need for cardiac transplantation. In a study involving 857 consecutive patients with and without LV dysfunction and a median follow–up of 4.4 years, myocardial enhancement using a myocardial scar index  was a strong and independent predictor of all cause mortality/cardiac transplantation [63].In Sources of Funding: none.Disclosures: none.