The objective of this review is to evaluate the literature on medications associated with delirium after cardiac surgery and potential prophylactic agents for preventing it.Cumulative Index to Nursing and Allied Health, and EMBASE with the MeSH headings: delirium, cardiac surgical procedures, and risk factors, and the keywords: delirium, cardiac surgery, risk factors, and drugs. Principle inclusion criteria include having patient samples receiving cardiac procedures on cardiopulmonary bypass, and using DSM-IV-TR criteria or a standardized tool for the diagnosis of delirium.Articles were searched in MEDLINE, Fifteen studies were reviewed. Two single drugs (intraoperative fentanyl and ketamine), and two classes of drugs (preoperative antipsychotics and postoperative inotropes) were identified in the literature as being independently associated with delirium after cardiac surgery. Another seven classes of drugs  and three single drugs  have mixed findings. One drug (risperidone) has been shown to prevent delirium when taken immediately upon awakening from cardiac surgery. None of these findings was replicated in the studies reviewed.These studies have shown that drugs taken perioperatively by cardiac surgery patients need to be considered in delirium risk management strategies. While medications with direct neurological actions are clearly important, this review has shown that specific cardiovascular drugs may also require attention. Future studies that are methodologically consistent are required to further validate these findings and improve their utility. Diagnostic and Statistical Manual fourth, text-revised (DSM-IV TR) edition ))emergencance use , 7. Neveance use .et al. [et al. [et al. [et al. [et al. [et al. [Similarly, it is also difficult to establish the role of postoperative drugs on delirium with such observational designs. Even though delirium is defined by the DSM-IV-TR as having multifactorial etiology  the role of postoperative factors on delirium is frequently downplayed in studies because they are not commonly considered ‘predictors’ of delirium, despite the fact that they are potentially modifiable. For instance, Afonso et al. , Katznel [et al.  and Rede [et al.  did not  [et al. , Shehabi [et al. , and Tul [et al.  focused Other studies that have looked at the influence of drugs on delirium are randomized controlled trials (RCTs). These studies, which are more robust, are typically designed to investigate the prophylactic effectiveness of certain medications like dexmedetomidine or rivastigmine to prevent delirium in vulnerable individuals. Unlike observational studies, well-controlled RCTs can suggest that any observed differences in the rates of delirium are due to differences in drug administration.In this review, delirium after cardiac surgery is considered distinct from other types of postoperative deliria for a number of reasons. For one, different surgical populations often have different medication profiles and require different anesthesia techniques. Thus, the pharmacological triggers of delirium will vary depending on surgery. Secondly, the use of cardiopulmonary bypass (CPB) in cardiac surgeries requires special consideration since its use is associated with postoperative effects on neurological function and an increase in delirium . Lastly,The purpose of this article hence is to synthesize the evidence in the literature for drugs that have been shown to be associated with either a higher or a lower rate of delirium after cardiac surgery. We also discuss studies that have attempted to use certain drugs for strategic prevention of postoperative delirium.1. The DSM-IV-TR, which is the current edition of the manual as of this publication, was published in 2000; therefore, only studies that were published in 2000 onward were included in this review. Studies were excluded if they took place in a community setting, if delirium was not a specific outcome, if the diagnosis of delirium was based solely on a clinical diagnosis without the use of DSM criteria or a standardized tool, or if they were reviews or case reports. Studies were searched in MEDLINE (January 1948 through January 2011), Cumulative Index to Nursing and Allied Health , and EMBASE (1980-2011). MeSH headings that were searched included the following: delirium, cardiac surgical procedures, and risk factors. Keyword searches included: delirium, cardiac surgery, risk factors, and drugs. Reference lists of the articles that were retrieved were also searched for relevant citations. Articles were included only if they were published between January 2000 and December 2010, used DSM-IV-TR criteria or a standardized assessment tool  for the screening or diagnosis of delirium, involved more than one assessment of delirium in the postoperative period, included only adults, were written in English, were prospective, retrospective, or interventional in their designs, and included cardiac procedures requiring CPB, i.e., coronary artery bypass grafting (CABG), valve replacements, combination CABG-valve replacements, or heart transplantset al. [et al. [n = 284, 158; cardiac patients n = 9,272), and this gives the study considerable relevance for cardiac surgery despite the small proportion of the total sample size that were actually cardiac surgery patients. More importantly, when the rate of delirium was analyzed with respect to their primary factor of interest , they found that the type of surgery received did not affect the relationship that they found between preoperative statin use and postoperative delirium [et al. [It should be mentioned that the study by Redelmeier et al.  possesse [et al.  did incldelirium  .For the et al.,  and Hude [et al.  also quaet al. [From the studies that were evaluated, several drugs that patients were taking as outpatients prior to surgery, during surgery, and in postoperative intensive care emerged as being either significantly predictive or protective of postoperative delirium. In most studies, drugs that were identified to be significantly associated with delirium by univariate analysis were further analyzed by multivariate logistic regression to identify drugs that were independently associated with delirium. One study that took a rather different approach was by Katznelson et al. , who per1.Eight prospective observational studies, 5 randomized controlled trials, 1 retrospective observational study and 1 post-hoc analysis were selected for review, and these are summarized in Table 2 for a complete summary of the drugs that have been studied in relation to delirium after cardiac surgery.See Table IPreoperative use of psychiatric medications is frequently cited to be a risk factor for postoperative delirium . Howeveret al. [p < 0.001). This result was obtained by controlling for age, sex, social status, prior admissions, prior use of medications, all neuropsychiatric, cardiac, vascular and miscellaneous medications, and duration and type of surgery in their multivariable logistic regression model [Only one single study included preoperative antipsychotic use as a factor in their analysis. Redelmeier et al.  found thon model . No otheet al. [p = 0.01) [p ≤ 0.01), but also was reported to be highly predictive: patients who were taking SSRIs or tricyclic antidepressants and/or drugs with known anticholinergic effects were 5.12 times more likely to become delirious than patients who were not taking these drugs  [et al. [et al. [et al. [n = 287, 353), and they were able to acquire a much larger number of patients who were taking antidepressants in the preoperative period . Redelmeier et al. [p < 0.001). The work on antidepressants and delirium is more extensive, but likewise unconvincing due to small sample sizes and conflicting findings. Tully et al.  looked a = 0.01) . Despite = 0.01) . This co = 0.01) . A study [et al.  also inc [et al.  also inv [et al.  study far et al.  found thet al. [et al.’s [p < 0.001). Thus, the findings for the influence of preoperative benzodiazepine use on postoperative delirium are inconclusive and further work is required to reveal any relationship that may exist.Afonso et al.  includedet al.’s  multivarNo studies were found that included preoperative use of mood stabilizers, stimulants, anxiolytics or any other psychiatric drugs. et al. [p = 1.00). However, given that only four individuals in the entire cohort of 112 patients were taking opioids before surgery [et al. [et al. [Preoperative opioids have not been thoroughly investigated for their relationship to delirium. Only one study meeting inclusion criteria included this as a factor . Koster et al.  showed t surgery , this fi [et al.  and Tull [et al. . et al. [et al. [et al. [et al. [et al. [et al. [p = 0.10; p = 0.31 respectively). Though Tan et al. [n = 20 out of a total n = 53), the broad definition that they attributed to the variable “ other anticholinergic meds” means that additional studies are required for evidence on the effects of anticholinergic medications on postoperative delirium.Two studies evaluated the relationship between preoperative anticholinergic drug use and postoperative delirium, and neither found an association between anti-cholinergics and delirium. These studies by Tan et al.  and Tull [et al.  were bot [et al.  used the [et al.  included [et al. -31, it w [et al.  nor Tull [et al.  found a n et al.  did haveet al. [in vitro to have moderate anticholinergic activity at therapeutic doses [Interestingly, as noted above, when Tully et al.  grouped ic doses , it may ic doses ) to alloet al. [et al. [Studies that have looked at the influence of preoperative statin use on the outcome of delirium after cardiac surgery have produced contrasting findings: of the four studies that focused specifically on preoperative statin use, one study showed that it was protective against delirium , anotheret al.  was a pr [et al.  performeet al. [p < 0.001). To control for the broad range of surgeries that were included in this study, surgery type was included as a covariate in the analysis. This produced an OR = 1.12, with a 95% confidence interval of 0.99 – 1.27 (p = 0.07), meaning that surgery type had no effect on the relationship between statin use and delirium [et al. [et al. [Redelmeier et al.  found thdelirium . Redelme [et al.  then pro [et al. . It is p [et al. . Had the [et al.  also fou [et al. . et al. [p < 0.01) [On the other hand, the prospective study by Katznelson et al.  came to  < 0.01) . This re < 0.01)  as well  < 0.01) . et al. [et al. [et al. [et al. [Besides advanced age, one confounding factor that was not appropriately controlled for in neither the Katznelson et al.  nor the  [et al.  study wa [et al. , 36. The [et al. , for exa [et al. , a selec [et al. . n = 58 in Hudetz et al., [n = 113 in Burkhart et al., [Other studies that included statins or lipid-lowering agents as variables in their databases failed to find a significant association with postoperative delirium use in either direction , 11. Thi et al., ; total nBased on evidence from a systematic review, Kulik and Ruel  recommenAntihypertensive drugs taken in the preoperative period, other than drugs with direct cholinergic receptor interactions, have not been linked to delirium after cardiac surgery in any study that was reviewed. Diuretics, calcium channel-blockers (CCBs), angiotensin-converting enzyme inhibitors (ACE-Is), β-blockers, angiotensin receptor blockers (ARBs) and nitrates have all failed to show a relationship with delirium in the studies published thus far , 10, 24.IIet al. [p < 0.05). However, when Santos et al. [p-values ≤ 0.1 from univariate analysis, the use of pre-anesthetic diazepam was not identified to be an independently associated risk factor for delirium [One class of drugs commonly used during surgery that has been implicated in the development of delirium after cardiac surgery is the benzodiazepines and their derivatives. Specifically, Santos et al.  showed tp = 0.006) [p = 0.003) [et al. [et al. [Fentanyl is frequently used to provide sedation and analgesia during cardiac surgical procedures because of its fast onset, short duration of action, and minimal cardiovascular depressive effects. A post-hoc analysis  performe= 0.006) . When th= 0.003) . Importa= 0.003) . The ori [et al.  had anal [et al.  also didin vitro studies have been unable to replicate earlier findings demonstrating that fentanyl displays serum anticholinergic activity [et al. [et al. [The risk that fentanyl imparts is likely not due to its purported minor anticholinergic effects because recent activity , 31. It  [et al.  is media [et al.  reportedet al. [p = 0.01) [p < 0.05) [et al. [The anesthetic agent ketamine is commonly regarded as a “dissociative” drug and has been frequently linked with emergence delirium . Howeveret al.  to decre = 0.01) . There w < 0.05) . This le [et al.  to postuet al. [p = 0.36 for the day of surgery, and p = 0.46 for postoperative day 1), nor did the proportion of patients who were given morphine in the postoperative period (p = 0.70). Mean total doses of fentanyl received during surgery were also compared, but did not statistically differ between the groups [et al.’s [et al. [et al. [Another possible reason for why ketamine may be associated with a decreased rate of postoperative delirium may be because using ketamine reduces opioid consumption in the postoperative period during the first 48-hours after cardiac surgery, as it is able to serve as an adequate adjunct to analgesic management for pain from sternotomies . In Hudeet al. , the amoe groups . Howeveret al.’s  post-hoc [et al.  to calcu [et al.  were onlIIIet al. [In a review of clinical risk factors for delirium by Sockalingam et al. , four stet al. -44. Howeet al. [Within the cardiac surgery population, similar to preoperative use of opioids, postoperative use of opioids has not been shown to increase or decrease the rate of postoperative delirium. Specifically, two prospective studies found no statistically significant relationship between either average morphine-equivalent dose of opioids consumed over 3 postoperative days or opioid dose per kilogram of body weight and the incidence of delirium , 25. Hudet al.  were alsChoice of sedatives in the postoperative period may be critical for preventing postoperative delirium. The selective, centrally-acting α-2-adrenergic agonist, dexmedetomidine, has recently garnered interest due to its ability to provide adequate postoperative sedation and analgesia without producing excessive hypotension or the need for vasopressors, while reducing the risk of delirium after cardiac surgery . Unlike et al. [p = 0.088) [p = 0.040) [A randomized controlled trial by Shehabi et al.  compared= 0.088) . Rather = 0.040) . Thus byet al. [et al. [p < 0.001 for dexmedetomidine vs. propofol, and vs. midazolam) [et al. [et al. [In another randomized study by Maldonado et al. , postope [et al. , they fodazolam) . One pro [et al.  and Mald [et al.  is that et al. [et al. [et al. [et al. [et al. [et al. [One likely reason for the discrepancy between the rates of delirium associated with dexmedetomidine use reported by Shehabi et al.  and Mald [et al.  is due t [et al.  used a s [et al.  used for [et al. , the rat [et al.  may be u [et al. . et al. [p = 0.002). This was found to be one of the strongest independent predictors of delirium in this sample after using multivariate regression analysis. No other study in the context of cardiac surgery has yet reproduced this finding. While inotropes are commonly used in the postoperative period to maintain hemodynamic stability in cardiac surgery patients, only one study that met the inclusion criteria looked at their effects on delirium. Norkiene et al.  reportedet al. [p = 0.08, p = 0.05, p = 0.07 respectively). However, delirious and non-delirious individuals did have significantly different ejection fractions prior to surgery, with delirious individuals having significantly lower mean ejection fractions in the preoperative period (p = 0.005) [It is especially important, when considering the influence of inotropes on delirium, to consider if this association may be confounded by indication. The reason for this is because problems with cardiac contractility can affect cerebral perfusion, and perfusion abnormalities have been observed by Single Photon Emission Computed Tomography (SPECT) in the brains of older hospitalized delirious patients . With reet al.  study, t= 0.005) . Thus, iIVet al. [2 and serotonin 5-HT2 receptors, is the only agent that has been studied in the context of delirium after cardiac surgery for its role as a potential prophylactic agent. The reason this drug was selected for investigation is presumably because of its relatively long half-life, which can be up to 20-hours long in poor metabolizers, and this is due to the similar pharmacology of its active metabolite, 9- hydroxyrisperidone [As previously mentioned, preoperative use of antipsychotics was shown by Redelmeier et al.  to increet al. . The mosperidone . In its peridone . In the peridone . Unlike Despite these findings, the future use of risperidone for preventing delirium in cardiac surgery patients remains uncertain. Adverse effects of risperidone, such as hypotension, symptomatic orthostasis, and cardiac arrest, have been reported to be associated in particular with cardiovascular disease and its treatment , althouget al. [et al. [While it may seem contradictory for antipsychotics to be both beneficial and harmful for delirium , one ex [et al.  was like [et al. , 14, 22.et al. [Along with studies showing the potentially beneficial effects of taking preoperative statins, intraoperative ketamine, and postoperative dexmedetomidine, the cholinesterase inhibitor rivastigmine, has also been tested for its efficacy to prevent delirium after cardiac surgery. The rationale for this study was based on the “cholinergic deficiency” theory of delirium. This theory, which postulates that delirium is caused by insufficient levels of acetylcholine in the brain, is derived from the observations by Tune et al.  that shoIn a randomized, double-blind, prospective interventional study, short-term oral rivastigmine was administered to CPB patients the evening before their procedures, and was continued every 6 hours following surgery for 6 days . Intereset al. [et al. [et al. [et al. [et al. [et al. [et al. [et al. [Another, albeit less-detailed investigation of cholinesterase inhibitors was performed by Redelmeier et al. , who inc [et al.  found th [et al.  and Gamb [et al.  had rati [et al.  study we [et al.  failed t [et al. , 14, 22. [et al.  study wa [et al. , it may Two single drugs (intraoperative fentanyl and ketamine), and two classes of drugs (preoperative antipsychotics and postoperative inotropes) have thus far been identified to be independently associated with delirium after cardiac surgery. Specifically, preoperative antipsychotics, intraoperative fentanyl and postoperative inotropes are associated with higher rates of delirium, while intraoperative ketamine is associated with a lower rate of delirium. Additionally, the administration of one drug (risperidone) has been shown to be effective for preventing delirium after cardiac surgery. Another seven classes of drugs  and three single drugs  have mixed findings in relation to delirium after cardiac surgery.From the results of this review, it is clear that drugs taken perioperatively by cardiac surgery patients have either direct or indirect influence on the outcome of delirium. However, given the present state of delirium research, relatively little is known about how the large number of drugs administered to cardiac surgery patients before, during and after surgery contributes to postoperative delirium. Most of the studies that have recorded perioperative drug use are very broad in their approach and do not include analysis on specific drugs. In addition, the literature on delirium after cardiac surgery is heterogeneous and differs quite substantially in terms of designs, methodologies, definitions and diagnostic instruments, making it difficult to compare the results. For instance, investigators’ selection of covariates for their regression model could significantly change the outcomes and the conclusions that could be made. As for whether or not specific covariates should be consistently accounted for in future studies, investigators should be attentive to control for the factors of age, sex, and any clear confounders of indication; however, it is always important to select covariates based on results of current research. None of the findings on the drugs that have been reported to be associated with delirium, including the potentially prophylactic drugs, have been reproduced in the cardiac surgical population. For this reason, any general conclusions about the relationship of these drugs to postoperative delirium should be considered with these limitations in mind. Future studies on the relationship between perioperative drug use and postoperative delirium clearly are necessary; in particular, these should consider statistical solutions for taking into account factors that influence drug action within the individual, such as drug dose and efficiency of drug metabolism, as some studies that were reviewed obtained significant results only when drug doses were normalized to body weight. Although the evidence for the role of drugs in the etiology of postoperative delirium may not yet be completely conclusive, the data available to date indicate that this should be considered an important aspect of the management of cardiac surgery patients at risk for delirium throughout the course of care.


Schwannoma  is a common, histologically distinctive, benign, usually encapsulated, peripheral nerve tumor of Schwann cell origin. Schwannomas can appear anywhere in the body, but are more frequently reported in the head and neck with an incidence of 25–48% in maxillofacial region. Resorption of bones due to schwannoma is rarely noticed in maxillofacial region. We hereby present a case report of schwannoma in a 35–year-old female, causing resorption of zygomatic arch along with review of literature. Schwannoma  is a slow-growing, benign neoplasm derived from Schwann cells, which are sheath cells that cover myelinated nerve fibers. Schwannomas may be encapsulated and can appear anywhere in the body, but are more frequently located in the head and neck.–5 Most cA 35-year-old female presented at our department complaining of swelling in right facial region since 2 years. There was no history of pain, paresthesia or limitation in mouth opening. During the examination, a firm mass, measuring 5 × 3 × 2 cm in size, was observed in right zygomatic region. The mass was bound to a part of zygoma .in toto [A submentovertex view of skull showed resorption of zygomatic arch . Under gin toto . Beneathin toto . During An oval, sharply demarcated, encapsulated, firm nodule measuring 3 cm in diameter was submitted for histopathologic examination. The cut surface was yellowish white and smooth. Microscopic analysis revealed that the tumor mass was composed of interlacing fascicles of compact spindle cells with twisted nuclei . The nucOral and maxillofacial peripheral nerve tumors include schwannoma, neurofibroma, nerve sheath myxoma, palisaded encapsulated neurinoma, mucosal neurinoma associated with multiple endocrine neoplasia III, traumatic neuroma and granular cell tumor.There are three mechanisms by which schwannomas may involve a bone: (1) a tumor may arise centrally within a bone, (2) a tumor may arise within a nutrient canal and produce canal enlargement, or (3) a soft tissue or periosteal tumor may cause secondary erosion and penetration into a bone.–15 This Schwannomas most often occur in the fourth and fifth decade of life with a 1.6:1 female predilection. The duration of symptoms varies from a few months to a few years. A majority of these tumors have a long duration because of their lack of symptoms and slow growth.et al.[et al.[A review of the English literature revealed three cases similar to ours with regard to clinical and radiological features. In 1954, Bruce describeet al. and Sciuet al. reportedl.[et al. reported1-weighted images, enhancement of the solid component of the tumor after administration of contrast medium, heterogeneity on T2-weighted images, and multiple target signs due to a central collagen area (some patients).[et al.[et al.[et al., based on the pre-operative CT and MRI findings, a malignant tumor derived from the sublingual gland was suspected. Intraoperatively, adhesion of the mass to circumferential regions was not observed, but nerves penetrated into the mass at several places. Based on operative findings, the mass was thought to be a tumor derived from the lingual nerve. Almeyda et al.[en bloc”. Even with advancement in imaging techniques, the diagnostic dilemma remains.[et al.,[Radiographically, schwannoma is commonly unilocular and associated with bone resorption. It may r2528atients). MRI findatients). Yamazaki).[et al. reportedl.[et al. reportedl.[et al. Only a fl.[et al. In the cda et al. reported remains. MRI has  remains. In the c.[et al., the ultret al.[et al.[Although schwannomas originate from the nerve tissue, locating the nerve of origin exactly can be impossible. Direct relation with a nerve can be demonstrated in only approximately 10–50% of the cases.2840–43 T28et al. stated tet al. Arda et l.[et al. presenteFor the differential diagnosis, neurofibroma, granular cell tumors, lipoma, fibroma, leiomyoma, rhabdomyoma, nerve sheath myxoma, adenoma, neuroma, granular cell tumor, neurothekeoma and perineurioma should be considered.314647 Th3146In conclusion, we have reported here a rare case of schwannoma with secondary erosion of the zygomatic arch. The tumor may have originated from a branch of infraorbital nerve and may have extended into the zygomatic arch, creating a bony defect.


However, this dose corresponds to what would have been absorbed by a bee in an entire day of foraging. In the context of this study, the difference between acute and sub-chronic exposure is critical. Furthermore, it is already well-established that physiological and behavioral effects vary significantly depending on whether the same dose is applied in one treatment or in many treatments over a longer period of time. For example, a human tobacco smoker inhales on average between 10.5 and 78.6 mg of nicotine per day without any immediate lethal consequences (Benowitz et al., Henry et al. apply the thiamethoxam insecticide in an acute manner and claim that the dose used for oral treatment (i.e., 1.34 ng.beemhf value by 17.5–20.4%.The model presented by Henry et al.  is basedThe ecological relevance of Henry et al.'s study is compromised by four main methodological issues. The daily range of thiamethoxam exposure is incorrectly estimated, the applied dose is uncommonly encountered, thiamethoxam is applied in an acute rather than a sub-chronical manner and the use of an incorrect formula falsely inflates the bees' homing failure rate. It is also important to acknowledge that Henry et al.'s  study re


Echinostoma (Echinostomatidae) with 37 collar spines that comprise the so-called ‘revolutum’ species complex, qualify as cryptic due to the interspecific homogeneity of characters used to differentiate species. Only five species were considered valid in the most recent revision of the group but recent molecular studies have demonstrated a higher diversity within the group. In a study of the digeneans parasitising molluscs in central and northern Europe we found that Radix auricularia, R. peregra and Stagnicola palustris were infected with larval stages of two cryptic species of the ‘revolutum’ complex, one resembling E. revolutum and one undescribed species, Echinostoma sp. IG. This paper provides morphological and molecular evidence for their delimitation.The digenean species of R. auricularia, 357 R. peregra and 577 S. palustris were collected in seven reservoirs of the River Ruhr catchment area in Germany and a total of 573 R. peregra was collected in five lakes in Iceland. Cercariae were examined and identified live and fixed in molecular grade ethanol for DNA isolation and in hot/cold 4% formaldehyde solution for obtaining measurements from fixed materials. Partial fragments of the mitochondrial gene nicotinamide adenine dinucleotide dehydrogenase subunit 1 (nad1) were amplified for 14 isolates.Totals of 2,030 Echinostoma spp. of the ‘revolutum’ species complex. A total of 14 partial nad1 sequences was generated and aligned with selected published sequences for eight species of the ‘revolutum’ species complex. Both NJ and BI analyses resulted in consensus trees with similar topologies in which the isolates from Europe formed strongly supported reciprocally monophyletic lineages. The analyses also provided evidence that North American isolates identified as E. revolutum represent another cryptic species of the ‘revolutum’ species complex.Detailed examination of cercarial morphology allowed us to differentiate the cercariae of the two revolutum’ group of Echinostoma.Our findings highlight the need for further analyses of patterns of interspecific variation based on molecular and morphological evidence to enhance the re-evaluation of the species and advance our understanding of the relationships within the ‘ Echinostoma Rudolphi, 1809 (Echinostomatidae) with 37 collar spines that comprise the so-called Echinostoma ‘revolutum’ complex, qualify as cryptic , E. echinatum  and E. jurini , the North American E. trivolvis  and the African E. caproni Richard, 1964, were considered valid in the most recent revision of the group using for species delimitation a single morphological feature of the larval stages , the specificity towards the first intermediate host , the ability to infect avian or mammalian hosts (or both) and geographical range on a global scale (continents) [E. echinatum has not been formally described and justified in a taxonomic publication and is not recognised as valid [see 6 for details]. However, recent molecular studies have demonstrated a higher diversity within the ‘revolutum’ species complex. Thus one African species, Echinostoma deserticum Kechemir et al., 2002, and a yet unidentified species from New Zealand were distinguished based on molecular data [E. trivolvis was found to represent a species complex [Echinostoma spp. have also been obtained. E. revolutum was recorded in Australia [Echinostoma paraensei Lie & Basch, 1967 in Australia and South America [E. cf. robustum in North and South America [The digenean species of rd et al. for a retinents)  , E. miyagawai Ishii, 1932, E. robustum Yamaguti, 1935, E. bolschewense , E. nordiana , E. friedi Toledo et al., 2000 [E. revolutum[E. friedi (GenBank AJ564379).However, in contrast with the wealth of sequences gathered recently from North America, which have revealed high diversity (six cryptic lineages) within the ‘hinostoma,11, datal., 2000 -22, sequrevolutum,12-14 anRadix auricularia , Radix peregra  and Stagnicola palustris  were infected with larval stages of two species of the Echinostoma ‘revolutum’ complex of cryptic species, one resembling E. revolutum sensu stricto (s.s.) and one undescribed species . Here wsee also , Kostadio [et al. and Detwl.[et al. to the rR. auricularia, 357 R. peregra and 577 S. palustris were collected during 2009–2012 in seven reservoirs of the River Ruhr catchment area : Baldeneysee ; Harkortsee ; Hengsteysee ; Hennetalsperre ; Kemnader See ; Sorpetalperre ; and Versetalsperre . Seven distinct samples of R. peregra  were collected in five localities in Iceland: Lakes Family Park  and Nordic House  in Reykjavik; Opnur ; Raudavatn ; and Helgavogur, Lake Myvatn  in May and August 2012. Snails were collected randomly with a strainer or picked by hand from stones and floating vegetation along the shore at several sampling sites at each reservoir. In the laboratory, snails were labelled and placed individually into beakers with a small amount of lake water, and kept under a light source for up to 5 days to stimulate emergence of cercariae. Thereafter, snails were measured, dissected and examined for prepatent infections.Totals of 2,030 et al.[R. peregra and R. ovata  have recently been treated as junior synonyms of R. balthica  we used the name R. peregra following the molecular studies of Bargues et al.[et al.[Cercariae were examined and identified live using the data from the keys of Faltýnková et al.,25 and oet al.,18-22. Det al.. Upon pret al.. Althouges et al. and Huňol.[et al. which prnad1) were performed in 25 μl reactions using Ready-To-Go-PCR Beads  containing ~2.5 units of puReTaq DNA polymerase, 10 mM Tris–HCl (pH 9.0), 50 mM KCl, 1.5 mM MgCl2, 200 mM of each dNTP and stabilisers including BSA, 10 mM of each PCR primer, and 50 ng of template DNA. The following PCR primers were used: forward NDJ11  amplifications of partial fragments of the mitochondrial gene nicotinamide adenine dinucleotide dehydrogenase subunit 1 ( JB11 in ) 5′-AGA PCR amplicons were purified using Qiagen QIAquick™ PCR Purification Kit  and sequenced directly for both strands using the PCR primers. Sequencing was performed on an ABI Prism 3130xl automated sequencer using ABI Big Dye chemistry  according to the manufacturer’s protocol. Contiguous sequences were assembled and edited using MEGA v5 [nad1 sequences for Echinostoma spp. (see Table Newly-generated and published 6 generations via 4 simultaneous Markov Chain Monte Carlo chains (nchains = 4) with a sampling frequency of 100. The first 25% of the samples were discarded (sump burnin = 2500) as determined by the stationarity of lnL assessed with Tracer v. 1.4 [BI log-likelihoods were estimated with default prior probabilities and likelihood model settings  over 10r v. 1.4 ; the remr v. 1.4 . GeneticEchinostoma spp. in the snail populations sampled in three of the seven reservoirs in the River Ruhr drainage in Germany and in two of the five lakes in Iceland  but occasionally higher values were registered  37 collar spines with an arrangement 5-6-15-6-5  were identified as E. revolutum based on cercarial morphology and especially the presence of 12 small para-oesophageal gland-cells with long ducts, located between pharynx and ventral sucker [R. peregra from Iceland and six ex R. auricularia from Germany, further referred to as Echinostoma sp. IG (indicating the origin of the isolates i.e. Iceland and Germany) exhibited slight differences from the isolates identified as E. revolutum as follows: (i) collar spines with blunt  of Kostadinova et al.[Echinostoma sp. IG formed a strongly supported reciprocally monophyletic lineage, basal to Echinostoma spp., which also incorporated the sequence for an isolate from Wales (UK) provisionally identified as Echinostoma cf. friedi by Kostadinova et al.[Echinostoma spp. analysed  (p-distance range 18.9-19.1%).Both NJ and BI analyses resulted in consensus trees with similar topologies . On theva et al.. The isoE. revolutum and those obtained from natural infections in Lymnaea elodes and Ondatra zibethicus (L.) in North America by Detwiler et al.[revolutum’ species complex.Unexpectedly, the European isolates of er et al. formed tEchinostoma revolutum of Morgan and Blair [Echinostoma friedi of Marcilla et al.  based on an isolate of this species recently described by these authors [i.e. Echinostoma robustum sensu Detwiler et al.[E. robustum from North America exhibited a complex structure suggesting the existence of at least three species  [Echinostoma spp. of the ‘revolutum’ species complex parasitising L. stagnalis and Radix spp. are conspecific or represent as yet undiscovered cryptic species. We believe that ‘reciprocal illumination’ sensu Hennig [revolutum’ complex of cryptic species.However, the distinguishing features are difficult to detect and/or subject to variation (reviewed in Kostadinova and Gibson ). For exvá et al. also pron Europe ,24, infed, 1805) ,37-45. Fu Hennig  of morphEchinostoma sp. IG was found to be conspecific with an isolate from Wales (UK) provisionally identified as Echinostoma cf. friedi by Kostadinova et al.[et al.[nad1 gene of Detwiler et al.[E. robustum (U58102) and E. friedi (AY168937) reveals that they are found within the same monophyletic clade and thus do not qualify as distinct species according to a phylogenetic definition. Additionally, they are genetically similar  is genetically very similar to E. robustum”. Our results clearly indicate that the sequence for E. friedi from its type-locality in Spain  and for the European isolate labelled as E. revolutum (AF025832) of Morgan and Blair [i.e. substantially lower than that (i.e. 18.9-19.1%) between the lineage containing E. cf. friedi (AY168937) of Kostadinova et al.[E. revolutum  by Morgan and Blair [et al.[E. friedi of Marcilla et al. (AJ564379) but have mislabelled it (as AY168937).va et al.. The linl.[et al.) and thier et al.. These ai AY16893 reveals nd Blair ,13 repreva et al. and the i AY16893 reveals nd Blair ,13. We br [et al. have in et al.[E. robustum of the isolates of the ‘Australian-German’ clade of Echinostoma spp. of Morgan and Blair [E. friedi should await examination of a larger number of molecularly characterised natural isolates of the European species of the ‘revolutum’ complex since our knowledge on cryptic diversity in this group is still limited. This suggestion is supported by the discovery of two genetically distinct, geographically separated lineages of E. revolutum: E. revolutum s.s. from Europe and E. revolutum of Detwiter et al.[Kostadinova et al. indicatend Blair , but sugnd Blair ,12,13 aner et al. from Norer et al. appears er et al.,47.revolutum’ group of Echinostoma.The results of our study suggest that further analyses of patterns of interspecific variation based on a combination of molecular and well-documented morphological data would enhance the re-evaluation of the species and advance our understanding of the relationships within the ‘The authors declare that they have no competing interests.CS, MS and KS obtained the samples. CS, AF, MS and SG undertook the morphological study. SG carried out the sequencing and phylogenetic analysis. CS, SG, AF and MS prepared the first draft of the MS. KS, BS and AK conceived and coordinated the study and helped to draft the MS. All authors read and approved the final manuscript.


Current Biology, different combinations of the present authors used repetitive transcranial magnetic stimulation (rTMS) to disrupt activity in human superior parietal cortex, and reported seemingly contradictory results When faced with ambiguous sensory input, conscious awareness may alternate between the different percepts that are consistent with the input. Visual phenomena leading to such multistable perception, where constant sensory input evokes different conscious percepts, are particularly useful for investigating the processes underlying perceptual awareness  Rather than being combined into a single percept, the incompatible images compete and perception alternates between each monocular view every few seconds. Carmel et al.et al.et al.et al.A different kind of bistability arises in structure-from-motion perception. For example, a field of moving dots can be seen as a sphere that rotates clockwise or counterclockwise A. Here tet al.et al.et al.et al.'s To resolve this apparent contradiction, we first revisited the brain-structure/percept-duration correlation reported by Kanai et al.Having established that the structure of posterior For the same bistable stimulus, disruption of posterior SPL slowed perceptual switching These findings imply that further research on separate functions residing within the SPL is required in order to develop an understanding of visual awareness. One promising theoretical approach to guide such research may be found in hierarchical Bayesian network theory The present findings resolve an intriguing contradiction et al.Finally, a further twist to the story comes from a recent study by Zaretskaya


Body size can vary throughout a person's lifetime, inducing plasticity of the internal body representation. Changes in horizontal width accompany those in dorsal-to-ventral thickness. To examine differences in the perception of different body axes, neural correlates of own-body-size perception in the horizontal and dorsoventral directions were compared using functional magnetic resonance imaging. Original and distorted  images of the neck-down region of their own body were presented to healthy female participants, who were then asked whether the images were of their own body or not based explicitly on body size. Participants perceived body images distorted by −10% as their own, whereas those distorted by +30% as belonging to others. Horizontal width images yielded slightly more subjective own-body perceptions than dorsoventral thickness images did. Subjective perception of own-body size was associated with bilateral inferior parietal activity. In contrast, other-body judgments showed pre-supplementary motor and superior parietal activity. Expansion in the dorsoventral direction was associated with the left fusiform gyrus and the right inferior parietal lobule, whereas horizontal expansions were associated with activity in the bilateral somatosensory area. These results suggest neural dissociations between the two body axes: dorsoventral images of thickness may require visual processing, whereas bodily sensations are involved in horizontal body-size perception. Somatosensory rather than visual processes can be critical for the assessment of frontal own-body appearance. Visual body thickness and somatosensory body width may be integrated to construct a whole-body representation. Height is essentially stable throughout adulthood, but the other dimensions can vary. Although body width and thickness are in the same transverse direction in two dimensions for upright posture, body thickness differs from width in several ways: it is generally less than width (except for the feet), and viewing the body from the side is relatively infrequent when compared with viewing the body from the front. Accordingly, the dorsoventral view of thickness may require precise and fine visual processing. Visual perception of own-body width has been examined in normal subjects and in patients with eating disorders  body image, rather than the real body image, is associated with enhanced activity in the inferior parietal lobule (IPL) and fusiform gyrus  participated in this study. The mean body mass index was 19.5 ± 1.3 kg/mColor photographs of the participants' own bodies (neck to knees) were used . ParticiParticipants were informed that their own and others' neck-down body images would be presented. Participants were asked to judge whether the presented image was of their own body or not by pressing two buttons on a four-button response pad with the right hand. They were also informed that all other participants wore an identical suit and that they were photographed in an identical posture to make the images indiscernible except for body size. Participants were instructed to judge the images based on body size. The buttons for self or others were counterbalanced between participants. E-prime software  was used to control the presentation of stimuli and to record responses.Each image was presented for 1 s, with a mean interstimulus interval of 7 s . The order of images was pseudo-randomized. After the experiment, participants were informed that all of the images they were shown were of their own original and distorted body, and they were asked whether they had noticed this.All brain images were acquired using a 3-T Siemens Trio magnetic resonance imaging (MRI) scanner . Functional images were obtained using a gradient-echo EPI sequence with the following parameters: 36 axial slices in the AC–PC plane; 2000 ms TR, 30 ms TE, 90° flip angle, 192 × 192 mm FOV, 3 × 3 mm in-plane resolution, 3-mm slice thickness, and no gap; the first six images were discarded. A T1-weighted anatomical scan of each participant was also obtained . Four-hundred and eighty-six scans were acquired for each participant.spm8 software package . Individual slices of a functional volume were temporally corrected for differences in acquisition time with reference to the middle (18th) slice. To correct for head motion, functional images of each participant were realigned with reference to the first image. Anatomical images were co-registered with the first functional images and normalized to the Montreal Neurological Institute (MNI) brain template. Functional data were then normalized using the same transformation parameters with a voxel size of 3 mm × 3 mm × 3 mm, smoothed in the spatial domain . Functional data were analysed using an event-related design. A general linear model was applied for each of the two orientations by five sizes and self–other judgments; the analysis was modeled using the canonical hemodynamic response function and its temporal derivative for each event type. Subjective ‘self’ and ‘others’ body perceptions associated with faster response times (RTs) were further analysed using parametric modulation. Random effects analysis was performed. Global scaling was not applied. Statistical parametric maps were generated for each contrast of the t-statistic on a voxel-by-voxel basis. These t-values were then transformed into z-scores in the standard normal distribution. The threshold of significance was set at P < 0.001, and more than 10 continuous voxels were reported. This threshold was uncorrected for multiple voxel-wise comparisons to balance the trade-off between Type I and Type II errors  was used for image rendering.Preprocessing and data analysis were performed using the t-tests were conducted.To examine the brain regions involved in the perception of horizontal expansion, weightings of 0.7, 0.9, 1.0, 1.1 and 1.3 were applied to horizontal −30%, −10%, original, +10% and +30% images, respectively, and contrasted with weightings of 1.0 for each of the five dorsoventral images. For dorsoventral expansion, weightings of 0.7, 0.9, 1.0, 1.1 and 1.3 were used for −30%, −10%, original, +10% and +30% dorsoventral images, respectively, and contrasted with weightings of 1.0 for each of the five horizontal images. The two contrasts were calculated for each participant, and one-sample t-tests. Those subjective own- and other-body judgments associated with faster RTs were also analysed.Neural responses to subjective own-body perception vs. that of other-body perception  based on individual responses were also examined using one-sample Mean responses for original and distorted images are shown in anova [two orientations  × five body sizes ] for own-body judgment  revealed no differences between directions , but significant differences between sizes . Post hoc analyses (Ryan's method) showed that −10% distortions were judged as own-body more often than +30% , +10%  and −30%  distortions. Original images were judged as own-body more often than both +30% and +10% distortion images .A 2 × 5 anova for mean RTs showed no effect of image orientation , suggesting no difference in task difficulty between width or thickness. However, the anova did reveal significant differences between sizes , and post hoc analyses revealed faster responses for +30% distortions than for −10%, −30% and original images .A two-way After the experiment, the participants were asked whether they had noticed that all images were of their own body, with no other bodies presented. Most participants (eight out of 11) were sure that other bodies had been presented. Three participants reported that they had suspected as much mid-way through the test; however, they were not convinced, and their performance was similar to that of the other participants.z-coordinate of activity in the right SI was 50, while the z-coordinate for activity in the left SI was 70  for other than own-body perception. No effects of faster RTs on own-body perception were observed.Faster RTs were associated with activation of the right insula (MNI coordinates: 34, −6, 16; The neural mechanisms involved in the perception of body size were found to differ between the horizontal and dorsoventral directions. Perceiving wider bodies induced greater activity in somatosensory areas, whereas the perception of deeper bodies resulted in enhanced activity in the higher visual and posterior parietal areas. Bodily sensations could contribute more to frontal body appearance than visual processes. In addition, when compared with other-body judgment, own-body judgment yielded dissociated neural activity in the posterior parietal area. Therefore, body representation in the brain may be a perceptive and cognitive integration of distributed components.et al., et al., et al., et al., et al., et al., Greater activity in the SI and SII was observed for body width rather than for dorsoventral thickness. Familiar frontal views of body images may induce bodily sensations. Moreover, somatosensory representations may contribute to slightly greater own-body judgments (Frassinetti et al., et al., et al., et al., et al., et al., The area of the fusiform gyrus found to be associated with perceiving dorsoventral body thickness in this study may be the body-selective area, namely, the FBA (Peelen & Downing, vice versa. The differences between horizontal and dorsoventral images found in this study may be derived from viewpoint differences. Body images rotated by 0–45° induced repetitive neuronal reduction in the right FBA, whereas those rotated by 60° were processed differently (Taylor et al., et al., et al., The dorsoventral image is orthogonal to the horizontal image and et al., et al., Consistent with other lesion and neuroimaging studies, we observed posterior parietal cortex involvement in body perception. The right parietal cortex is associated with the conscious perception of the body, whereas left parietal activity is involved in monitoring action (Daprati et al., et al., et al., In patients with anorexia nervosa, alterations in IPL activity have been reported (Pietrini et al., et al., et al., et al., et al., et al., The sense of body ownership has been studied using illusory tactile attribution to visual body-like objects, and sensorimotor inputs can facilitate visual attribution of body ownership associated with the premotor cortex (Petkova et al., et al., et al., et al., et al., We observed that slightly slimmer body images were most acceptable as own-body images in this study. On the contrary, distorted images of the hand appear to be less accepted if they depict a shrunken view than if they depict an enlarged view (Pavani & Zampini, et al., Visual size can vary depending on distance and angle. Therefore, the size of a person's own body in the mirror is a relative feature. Our finding of moderate underestimation of own-body size may be derived from these factors. Although binocular disparity is essential for depth perception, the close proximity of one's own body under direct vision may prevent the utilization of visual depth information. However, somatosensory information is more robust, even though it is not as precise as vision. Blocking somatosensory information with anesthesia induces the sensation of swelling both in large and small body parts (Gandevia & Phegan, et al., et al., et al., et al., Although gender differences in brain anatomy (Luders & Toga, In conclusion, the neural substrates involved in the processing of frontal and side views of identical body images differ in the human cortex. Visual and somatosensory processes and their integration may construct a whole-body representation and may be responsible for the dissociation of own-body perception from other-body perception.


CDKN2A germline mutation. This review is designed to depict several of the hereditary pancreatic cancer syndromes with particular attention given to the clinical application of this knowledge into improved control of pancreatic cancer.Pancreatic cancer’s high mortality rate equates closely with its incidence, thereby showing the need for development of biomarkers of its increased risk and a better understanding of its genetics, so that high-risk patients can be better targeted for screening and early potential lifesaving diagnosis. Its phenotypic and genotypic heterogeneity is extensive and requires careful scrutiny of its pattern of cancer associations, such as malignant melanoma associated with pancreatic cancer, in the familial atypical multiple mole melanoma syndrome, due to the  It is estimated that in the United States during 2009, 21,050 males and 21,420 females will be diagnosed with pancreatic cancer (PC), giving a total of 42,470. Its mortality is estimated at 18,030 men and 17,210 women giving a total of 35,240. Its mortality closely approximates its incidence [PC’s high lethality rate results from its aggressive metastasis coupled with its low probability for diagnosis at an early stage when surgery would have promising curative results. The best prospects for a cure, center on its early detection. Ideally, tests would enable its diagnosis in asymptomatic individuals, because once clinical signs and symptoms of malignancy have manifested, patients may already have a significant tumor burden . At thiset al. [Poley et al.  studied et al. [Chu et al.  reviewedet al. .A study from Johns Hopkins involved 38 asymptomatic high-risk patients, 37 of whom had familial PC (two or more first- and/or second-degree relatives with PC) and one had Peutz-Jeghers syndrome, each of whom was screened by EUS. Findings showed abnormal EUS exams which were then followed by EUS-FNA, CT, and ERCP. Findings disclosed six individuals with definitive pancreatic lesions . A total of 29 individuals had abnormalities on EUS. Findings disclosed an overall yield of significant masses to be 5.3% (2/38). Noteworthy was a single ductal adenocarcinoma, which was not detected by either the follow-up CT or ERCP evaluations .Our purpose is to update the genetic epidemiology of PC in the interest of advancing progress in its early diagnosis, screening, and management.Review of the epidemiology of PC depicts a disease whose risk correlates with increasing age; only rarely are PC affecteds younger than 25 and it is even relatively uncommon in those younger than 45 years . There iet al. [et al. [The genetic epidemiology of PC is exceedingly heterogeneous. For example, Zerón et al.  discuss et al. . Blackfo [et al.  note tha [et al. .et al. [Chu et al.  note thaet al. .et al. [While young age of onset is a hallmark of many hereditary cancer syndromes, the implications of young-onset in familial PC (FPC) family members remains elusive. Brune et al.  studied There has been a recent groundswell of knowledge about hereditary forms of cancer, although its translation into the clinical setting has been problematic. For example, a comprehensive history of cancer in a family, often the linchpin to this effort, has been insufficiently recorded in many patients’ medical records, thereby compromising its clinical significance . Obstaclet al. [Shi et al.  emphasizCDKN2A mutation in the familial atypical multiple mole melanoma-pancreatic cancer (FAMMM-PC) prone syndrome [Many high-risk patients can benefit immensely from genetic counseling. This becomes of extreme importance when a cancer-causing germline mutation has been identified in a family, such as the syndrome ,17,18. Set al. [Real et al.  stressedet al. [Hruban et al.  postulatet al. [Hruban et al.  note thaet al. .et al. [Hruban et al.  also notet al. [Sipos et al.  note thaet al. [MSH2 germline mutation. Interestingly, the patient’s adenocarcinoma of the colon and IPMN of the pancreas revealed identical immunohistochemical staining profiles showing loss of expression of MSH2 and MSH6 proteins with high levels of MSI. The authors concluded that “…The immunohistochemical staining and microsatellite instability patterns of the adenocarcinoma of the colon and IPMN provides strong evidence to support the consideration of IPMN as part of the spectrum of lesions found in LS.Sparr et al.  discuss Numerous case-control studies have described families with two or more first-degree relatives with PC which fit a familial category . When suCDKN2A for the FAMMM syndrome, mismatch repair (MMR) for Lynch syndrome, TP53 for Li-Fraumeni syndrome, APC for familial adenomatous polyposis, and BRCA2 for the hereditary breast-ovarian cancer syndrome, indicate that the PC is part of each disorder’s cancer spectrum. Landi [et al. [Landi  has descm. Landi  has alsom. Landi  notes th [et al.  provide et al. [6 SNPs. Findings disclosed that “…pancreatic cancers contain an average of 63 genetic alterations, the majority of which are point mutations. These alterations defined a core set of 12 cellular signaling pathways and processes that were each genetically altered in 67 to 100% of the tumors. Analysis of these tumors’ transcriptomes with next-generation sequencing-by-synthesis technologies provided independent evidence of the importance of these pathways and processes…” These genetically altered core pathways and regulatory processes only became evident when the coding regions of the genome were analyzed in depth. Furthermore, “…Dysregulation of these core pathways and processes through mutation can explain the major features of pancreatic tumorigenesis.” Jones et al. [CDKN2A, SMAD4, and TP53 tumor suppressor genes and in the KRAS oncogene have been identified in this lethal cancer. They emphasize that these discoveries, important in comprehending the natural history of PC, spurred efforts for developing improved diagnostic and therapeutic opportunities, since the vast majority of human genes have not been analyzed in this particular cancer. Recognizing that all human cancers are primarily genetic disorders, their plan is to identify additional genes and signaling pathways in the hope that this effort will guide future research on PC. They concluded that the key to understanding the pathogenesis of PCs rests on an appreciation of a core set of genetic pathways and processes. Importantly, they identified 12 partially overlapping processes that are genetically altered in the great majority of PCs; nevertheless, the pathway components that are altered in each tumor vary widely. For example, two of the tumors each contained mutations of a gene involved in the TGF-β pathway, one being SMAD4 and the other being BMPR2. Interestingly, these two tumors each contained mutations of genes involved in most of the other 11 core processes and pathways, but the genes altered in each tumor were largely different. However, from the practical standpoint Jones et al. [Jones et al.  performes et al.  indicates et al.  indicateet al. [BRCA germline mutations. Al-Sukhni et al. [BRCA2 germline mutations with PC has been well established. However, the role of its BRCA1 counterpart mutations is less clear. Their study disclosed that the loss of heterozygosity at the BRCA1 locus “…occurs in pancreatic cancers of germline BRCA1 mutation carriers, acting as a ‘second-hit’ event contributing to pancreatic tumorigenesis.” They concluded that BRCA1 germline mutations may be considered for PC screening. Similar results were found among BRCA1-prone families by Lynch et al. [Wang et al. , when coi et al.  note thah et al. .et al. [Couch et al.  have recet al. [BRCA2 gene.Hiripi et al.  discuss et al. were the first to describe pancreatic cancer as an integral lesion in the FAMMM syndrome [CDKN2A germline mutation was described within these families [Lynch syndrome ,18,36,37families ; malignaCDKN2A germline mutation which is believed to be the pathogenic causal mutation for the syndrome in this family. CMM indicates melanomas and it is noteworthy that the proband had 13 melanomas. CDKN2A germline mutation. Of keen interest is that she did not have any evidence of the FAMMM phenotype comprised of multiple atypical nevi. However, her father (III-2) had the FAMMM phenotype, two melanomas, a sarcoma, and he died of esophageal cancer. He was a nonsmoker and not a consumer of alcohol. It is noteworthy that the proband’s paternal lineage showed four cases of pancreatic cancer as evidenced in II-7, II-9, II-10, and the proband’s paternal great‑grandfather (I-4). The yellow stars indicate the presence of pancreatic cancer.CDKN2A mutation as did two of the siblings . Importantly, the proband’s mother had melanoma and died of pancreatic cancer.et al. [Gargiulo et al.  note thaet al. [Kastrinos et al.  studied PALLD, the gene that encodes the protein palladin, in PC is controversial. More research is clearly needed. The heterogeneity of hereditary and familial forms of PC must be considered, given the possibility that the palladin protein may be involved in some forms of PC but not in others.The issue of the role of PALLD) was identified by Pogue-Geile et al. [PALLD gene is located. This subject is reviewed by Klein et al. [et al. “…implicated an oncogenic function for palladin after finding overexpression of PALLD mRNA in pancreatic cancer tissues.” However, Klein et al. note that since the Pogue-Geile et al. paper was published, subsequent investigations failed to find evidence linking palladin to familial PC. Furthermore, Klein et al. note that investigators have failed to evaluate the full sequence of PALLD in patients with familial PC in order to determine if sequence variants in PALLD might be contributing to PC susceptibility. Given this background, Klein et al. sequenced the entire coding region of PALLD in 48 individuals with familial PC. Importantly, they did not find any deleterious mutations and were not able to show evidence to implicate mutations in PALLD as a cause of familial PC.The palladin gene ; the protein was found to be overexpressed in a rare inherited form of PDA. It is also overexpressed in a number of sporadic pancreas tumors as well as in premalignant precursors . For exall lines , resultsll lines . Goicoec [et al. , comment [et al.  note thaet al. [PALB2 which may be a PC susceptibility causative germline mutation. A study by Slater et al. [PALB2 mutations might be causative for familial PC in a small subset of European families, especially in those also manifesting breast cancer. More research is clearly needed.Recently, Jones et al.  identifir et al.  suggestset al. [miR-200a and miR-200b, but this expression did not affect SIP1 expression, since “…the SIP1 promoter is silenced by hypermethylation and in these cancers E-cadherin is generally expressed. Both miR-200a and miR200b were significantly elevated in the sera of pancreatic cancer and chronic pancreatitis patients compared with healthy controls (P ≤ 0.0001), yielding receiver operating characteristic curve areas of 0.861 and 0.85, respectively…” These authors concluded that most PCs display hypomethylation in concert with overexpression of miR-200a and miR-200b silencing of SIP1 promoter methylation and retention of E-cadherin expression. Of major clinical importance is their suggestion that elevated serum levels of miR-200a and miR-200b in the majority of patients with PC might harbor diagnostic potential.Li et al.  discuss PancPRO is the first risk prediction model for PC which is based upon findings from one of the largest registries of familial PC enabling accurate risk assessment . It has et al. [et al. [There are few biomarkers which enable high sensitivity and specificity for early diagnosis of PC. Kim et al.  have sho [et al.  investigCreating hypotheses for reducing PC morbidity and mortality is clearly an exceedingly difficult task. The most promising areas seem to be in improved imaging or in new gene probes.et al. [Decker et al.  have recet al. ). The roet al. [et al. [et al. [The most sensitive imaging modality for the diagnosis of PC is probably endoscopic ultrasound (EUS), though there is poor interobserver agreement on EUS interpretations . Kimmey et al.  reported [et al.  showed t [et al.  describe [et al.  have deset al. [et al. [et al. [Others have tried to find diagnostic clues through analysis of pancreatic juice. Yan et al.  looked a [et al.  analyzed [et al.  found saet al. [In conclusion, Chu et al.  note thaet al. . The medet al. . Clearlyet al. [Chu et al.  call attet al. . In addiet al. ,63. Moreversus relative encouragement when detected early, particularly in a stage I disease? One answer, from our perspective, rests upon the need to focus heavily upon individuals at inordinately high risk for PC when based upon environmental and genetic factors and their interaction. Such patients will then be the ones who will be candidates for innovative approaches to safe screening measures and, in turn, they will be high order candidates for molecular genetics, pathophysiology, pathology, and environmental modification, and genetic investigations.Why are we addressing statistics on the one hand that are discouraging, as in the case of PC’s late diagnosis with metastatic spread,


Dear Editor,et al.[Prolonged exposure to acid and bile induces chromosome abnormalities that precede malignant transformation of benign Barrett’s epithelium”, which has been published in the recent issue of Molecular Cytogenetics. Barrett’s esophagus results from gastroesophageal reflux and harbors an increased risk for the development of esophageal adenocarcinoma  [in vitro approach the authors modeled the effect of gastroesophageal reflux on immortalized Barrett’s esophagus cells [et al. found that intermittent exposure of BAR-T cells to acid and bile for 18 to 78 weeks caused a spectrum of genetic abnormalities typical for cancer development, including polyploidy, loss of chromosomes and the development of transformed clones. In addition, the genetic changes evoked by acid and bile exposure format the target protein receptors for tumor stimulating growth factors, i.e. epidermal growth factor (EGF), which are known to promote the growth of gastrointestinal cancers [With interest we read the article by Bajpai et al., entitleer risk) ,3. Usingus cells . Bajpai  cancers . In contBarrett’s esophagus, when compared to ablation and post-ablational proton pump inhibitor (PPI) therapy, which solely changes the pH of the reflux, but not the reflux per se[Conceptually, Barrett’s esophagus results as the consequence of a complex neurohumoral response of the esophageal mucosa to gastroesophageal reflux including acid and bile ,3. Thus,ux per se.et al.[Given that the genetic abnormalities assessed by Bajpai et al. can be vet al.,6,7 and et al.. Therefoet al. and endoet al.,4,6,7. Tet al.,5. In coet al.. Endoscoet al.,6,7. TakSincerely,Reza Asari, Martin Riegler, Sebastian F. Schoppmann.


Exposure to extreme altitude presents many physiological challenges. In addition to impaired physical and cognitive function, energy imbalance invariably occurs resulting in weight loss and body composition changes. Weight loss, and in particular, loss of fat free mass, combined with the inherent risks associated with extreme environments presents potential performance, safety, and health risks for those working, recreating, or conducting military operations at extreme altitude. In this review, contributors to muscle wasting at altitude are highlighted with special emphasis on protein turnover. The article will conclude with nutritional strategies that may potentially attenuate loss of fat free mass during high altitude exposure. It is well-documented that weight maintenance above 5000 m is extremely difficult, if not impossible, in free living adults. A number of explanations have been proposed including anorexia, elevated basal metabolic rate, body water loss, and altered satiety hormones. However, the majority of studies support that altitude-induced weight loss is largely a function of negative energy balance secondary to inadequate energy intake ,7,8,9. EOf particular concern is the composition of weight loss. Above 5000 m fat free mass (FFM) accounts for as much as 60%–70% of weight loss ,8,9. Lesi.e., caloric restriction and low protein intake) on protein turnover as influenced by protein synthesis and protein degradation. Nutritional strategies that may potentially attenuate loss of FFM during high altitude exposure are reviewed.Currently, there is limited research on the mechanisms of muscle wasting at altitude. In this review potential contributors to muscle wasting at altitude are discussed with a special emphasis on the independent effects of hypoxia and concurrent altitude-related nutritional issues  ,24. Doubi.e., sea level), FFM comprises approximately 25% of body weight loss [i.e., increased protein) [i.e., high altitude) FFM comprises as much as 60%–70% of weight loss [et al. [vastus lateralis cross-sectional area in 14 mountaineers following eight weeks above 5000 m. Further, on an ascent of Mt. Shishapangma (8046 m), subjects lost 1.9 kg FFM compared to 0.9 kg fat mass [et al. [Caloric restriction induces weight loss which is generally a mix of water, fat and FFM. With caloric restriction under normoxic conditions (ght loss . This caprotein) ,31,32,33protein) . Howeverght loss ,34. In s [et al.  found a et al. [et al. [There are some studies that support a greater loss of fat mass (FM) than FFM at high altitude. However, differences may be due to altitude attained and limitations of measurement techniques. Fulco et al.  compared [et al.  compared [et al. . Further [et al.  and has  [et al. . HoweverMuscle wasting is a well-documented occurrence with chronic high altitude exposure. Skeletal muscle is of particular importance given it contains the majority of body proteins and comprises almost half of human body weight . As suchet al. [et al. [et al. [vs. three-fold increase in MPS). Similarly, in a comparison of subjects who were either flown or walked to 4559 m, those walking had a 35% increase in fractional synthetic rate compared to those not walking [Perhaps the largest contributor to muscle wasting at altitude is hypoxia. Evidence suggests that hypoxic exposure may impair MPS through downregulation of mTOR by the hypoxia-induced REDD1 gene . Of partet al.  also fou [et al.  found a  [et al.  exposed  walking . However walking  suggestiet al. [et al. [i.e., calories and protein) may potentiate the problem. Therefore, targeting diet and nutrient intake may be a more practical approach to influencing MPS at altitude.Limited research suggests that muscle proteolysis may also be affected with hypoxic exposure. Using a rat model, Chaudhary et al.  examined [et al.  reported [et al. ,46, nutret al. [et al. [As previously discussed, a primary contributor to weight loss at altitude is low energy intake. Energy status influences MPS. Thus it is likely subcaloric intake contributes to both impaired MPS and increased proteolysis at altitude. This effect is exacerbated in combination with hypoxia as demonstrated by Favier et al.  who expoet al. . Sea levet al. . Converset al. . Howeveret al. . In the  [et al.  demonstret al. [et al. [As a consequence of low energy intake, protein intake is also compromised with high altitude exposure. Protein intake, particularly the branched-chain amino acids (BCAA), is critical for the regulation of MPS . Severalet al.  found no [et al.  similarl [et al. .Regarding high altitude protein supplementation studies, data is limited. In rats supplemented with 10, 20 or 40 g of protein for 26 days at 6000 m, protein supplementation did not prevent the decrease in muscle growth . In ski et al. [et al. [et al. [et al. [Targeting two primary areas of nutrition may be useful to improve FFM retention at altitude: caloric intake and protein intake. Of these two areas, only the latter would seem practical and feasible. As demonstrated in previous studies, weight maintenance is extremely difficult at progressively higher altitudes above 5000 m. Butterfield et al.  was able [et al.  was able [et al.  found th [et al.  providedGiven the present body of research, increasing protein intake at altitude would appear a logical choice to aid retention of FFM. However, there are many limitations to this approach. At altitude increasing protein intake may not be feasible or practical. In a recent trek to Everest base camp, trekkers supplemented with protein were able to maintain a protein intake of only 1.1 g protein/kg/day  which isLeucine is a branched-chain amino acid that is not only a substrate for the synthesis of new proteins but is critical in mTOR cell signaling and muscle protein synthesis regulation ,65,66. LThe above information presents the possibility of a unique application of leucine to muscle wasting at altitude. Metabolite profiling in yeast cells has shown dramatically low levels of cellular leucine secondary to downregulation of amino acid permeases (leucine transporters) under hypoxic conditions . Furtheret al. [Under normoxic situations where high quality meal protein and energy intakes are sufficient, supplemental leucine would not be expected to exert a stimulatory effect upon protein synthesis. Glynn et al.  demonstret al. . It is wi.e., altitude), or when the muscle is resistant to stimuli , small amounts of protein enriched with leucine may enhance the MPS feeding response. In a study investigating the effects of 25 g whey protein (3 g leucine) compared to 6.25 g whey protein enriched with a leucine content equivalent to 25 g of whey (0.75 g leucine + 2.25 g leucine) and 6.25 g whey protein (0.75 g leucine), both whey and low dose whey + leucine increased MPS similarly 1–3 h post-feeding. However, the higher dose whey protein was more effective at sustaining increased MPS following resistance-exercise [i.e., higher leucine) (40 g whey) was found to induce the greatest stimulus in MPS following resistance exercise [The majority of research supports the amount of 20–25 g of high quality protein ingested at one time as the maximal dose for subsequent MPS stimulation. In situations where it is not possible to ingest sufficient protein  endurance exercise increased MPS by 33% compared with 10 g EAA (1.87 g leucine) although both increased Akt and mTOR phosphorylation 30 min post-exercise. Coffey et al. [Sea level studies suggest leucine may also be of benefit when ingested during exercise. Although studies have investigated the effects of leucine ingested post-exercise, few have examined the effects of leucine during exercise. Pasiakos et al.  demonstry et al.  reportedet al. [vs. −0.8 kg). In addition, Schena et al. [Three studies have examined the effects of branched chain amino acids (BCAA) and leucine on body composition at altitude. Bigard et al.  examineda et al.  investiga et al. . The altChronic high altitude exposure is associated with significant weight loss primarily comprised of FFM. Loss of FFM has negative consequences related to decreased physical performance and increased risk of illness and injury. Studies have demonstrated at lower elevations that when subjects are provided with sufficient food and perform limited activity, energy balance can be maintained. As altitude progresses, weight maintenance becomes virtually impossible. Hypoxia, negative energy balance, and insufficient high quality protein limit the body’s ability to synthesize protein secondary to inhibition of the mTOR pathway and perhaps accelerated proteolysis via upregulation of the UP system. Although this could be viewed as a favorable adaptation in the context of survivability, it is not in terms of performance and health. Increasing caloric and protein intake is difficult at high altitude due to feasibility and perturbations in appetite regulation. Therefore, the most practical strategy to improve FFM retention at altitude may be in the form of supplemental leucine. Clearly more research is needed in this area to determine the exact mechanisms related to altitude-induced muscle wasting, protein requirements and effectiveness of leucine for the retention of FFM during both acute and long-term high altitude exposure.


Similarly as we did in 2010, please, find below our annual overview of the published papers in the International Journal of Cardiovascular Imaging in the year 2011. We believe that we have received again very interesting papers over the last year, which we have subdivided over the well-known areas, i.e. X-ray angiography, intravascular imaging, echocardiography, nuclear cardiology, magnetic resonance imaging, and computed tomography. In 2011 we published two Topical issues, one on QCA, IVUS and OCT in interventional cardiology , and one on Transcatheter Valvular Interventions . In addition, the Asian Society of Cardiovascular Imaging published two ASCI Special issues with Adjunct Editor YH Choe and Guest Editors BW Choi, H Sakuma and J Lee, the first one being Vol. 27, no. 5 the second one Vol. 27, Suppl 1.The second volume in 2011 was a Topical issue on QCA, IVUS and OCT in interventional cardiology. In the QCA section a number of important developments in this field were presented, starting with an overview on angiographic imaging and scoring techniques by Ng et al.  have appCosta et al.  reportedAl-Hay et al. describe the efficacy and safety of the Amplatzer septal device for percutaneous occlusion of Fontan fenestration in  in a retIntravascular ultrasound (IVUS) and Intravascular optical coherence tomography (IOCT) are two catheter-based intravascular imaging technologies. IVUS has played a pivotal role in the evolution of interventional cardiology, allowing a better comprehension of coronary artery disease (CAD) as well as technique and device improvements. IOCT, a near-infrared light-based technology, was more recently introduced and has 10 times the spatial resolution of IVUS and a very high contrast between lumen and vessel wall contour, since images are obtained in a virtual blood free environment. These improvements enable for the first time in vivo direct characterization of metrics like fibrous cap quantification and stent coverage. IVUS radio frequency derived technology facilitates plaque composition interpretation and quantification, which consequently can be applied in a wide range of research activities. We are presenting here selected publications that exemplify not only research potential, but also clinical applications of these technologies.The International Journal of Cardiovascular Imaging received in the year 2011 several interesting contributions focused on the evaluation of vascular response following drug-eluting stent implantation as well as scaffold assessment. Chamié et al.  evaluateGarcìa-Garcìa et al.  performeThe assessment of coronary bifurcation lesions by IVUS was extensively reviewed by Costa et al. ; practicFinally, a special highlight to the paper by Tu et al.  who perfIn summary intravascular methods have been applied in a wide range of indications from plaque characterization to device evaluation. Most of the papers published in 2011 in the International Journal of Cardiovascular Imaging are focused in a variety of research applications of these methods. Considering the robustness achieved by these methods and continuous evolution we expect, for the upcoming years, more papers with emphasis in clinical applications of these methods in particular their potential impact in patient care.Just like last year, The International Journal of Cardiovascular Imaging received in 2011 several interesting contributions dedicated to conventional echocardiography but also to emerging ultrasound techniques including intravascular ultrasound, stress echocardiography, tissue Doppler imaging, strain analysis and three-dimensional echocardiography .In this era of modern technology, we sometimes forget the value of ‘basic’ techniques applied in a continent with a huge cardiovascular morbidity and mortality: Africa. Mocumbi et al.  discusseThe prognostic value of dobutamine stress echocardiography (DSE) for risk stratification of patients aged ≥80 years is not clearly defined. Innocenti et al.  obtainedP < 0.001) when compared with athletes (−15.2 ± 3.6 %) and control subjects (−16.0 ± 2.8 %). This technique could offer a unique approach to quantify global as well as regional systolic dysfunction, and might be used as new additional tool for the differentiation between physiologic and pathologic left ventricular hypertrophy. Simsek et al. [Sachdeva et al.  evaluatek et al.  evaluatek et al.  measuredk et al.  measuredChen et al.  evaluateIn a special focus issue, the role of intravascular ultrasound (IVUS) was reviewed by several authors. Costa et al.  discussetranscathether valvular interventions. Multi-modality imaging is of paramount importance during the selection process of patients, the implantation of the valve and during follow-up. The role of conventional echocardiography but also the role of three-dimensional transoesophageal echocardiography during the implantation of the MitraClip device or during the implantation of percutaneous aortic valves was highlighted by Maisano and Siegel [Finally, the last issue of the Journal was dedicated to emerging technology: d Siegel , 36.In 2011 several excellent papers were published in the field of nuclear cardiology. In this overview we highlight a selection of these papers.Cell therapy is an interesting therapeutic option in heart failure patients as it potentially improves contractility and restores regional ventricular function. However cell therapy remains complex and, next to determining the best cell type, the optimal delivery strategy, the bio-distribution and the survival of implanted stem cells after transplantation needs to be elucidated. Van der Spoel et al.  presenteSPECT myocardial perfusion imaging is commonly used for comprehensive interpretation of metabolic PET FDG imaging in ischemic dysfunctional myocardium. Nkoulou et al.  evaluateP = 0.08). LV volumes were also significantly lower when evaluated by gated SPECT as compared to MRI. In 4 patients (21 %) the LVEDV index was considered normal by gated SPECT and increased by MRI if MRI-derived normal values were used. No differences in LVEF were found between gated SPECT and MRI when MRI-derived LVEF was below 40 %. However, gated SPECT showed lower LVEF when MRI-derived LVEF was over 40 % .Sipola et al.  prospectThe authors concluded that LV volumes are lower by GSPECT as compared to MRI and that no direct comparisons can be made between methods in follow-up studies. The authors also suggest that abnormal gated SPECT results should be confirmed by another imaging modality, such as MRI, if these findings have therapeutic consequences. These findings were also discussed in an editorial comment by van der Wall et al. . They poP < 0.05). However, only 1.9 % of adenosine SPECT studies were terminated due to brady-arrhythmias with 1 patient requiring aminophylline. These findings indicate that denervation super-sensitivity can persist late after cardiac transplantation. As a result, adenosine induced brady-arrhythmias may occur more frequently than in non-transplant patients, but these arrhythmias are generally short-lasting and benign.In patients after cardiac transplantation, denervation super-sensitivity to adenosine is well described, particularly early after transplant. Al-Mallah et al.  now repoP < 0.05). However, in these patients with documented obstructive CAD, the prevalence of a positive stress test was comparable between both groups . From these data it can be concluded that the higher burden of CAD observed in AF patients is not associated with a higher burden of myocardial ischemia.Atrial fibrillation (AF) has been linked to the presence of underlying coronary artery disease (CAD). Nucifora et al.  evaluatePatients with ischemic cardiomyopathy can show varying degrees of LV remodeling after cardiac surgical revascularization. Skala et al.  directlyThere were a number of papers relating to the evaluation of patients with ischemic heart disease by cardiac magnetic resonance (CMR) in 2011. Lubbers et al.  examinedDelayed contrast enhanced CMR was found to be useful for differentiating cardiac tumors from thrombi in a small series of stroke patients . Late gaFernández-Golfín et al.  found siContrast enhanced whole-heart MRA at 3 T was found to be useful for assessing coronary venous anatomy . Normal Metz et al.  found thAs in previous years, a large number of very high quality, original articles on cardiac CT have been published in 2011. Many of these studies focused on the expanding role of coronary CT angiography (CTA) beyond the detection of lumen stenosis alone. Wang et al. showed the incremental value of dual-energy CT to assess significance of coronary lesions, comparing this technique with quantitative catheter based angiography and SPECT , 66. OthThe journal also published several important epidemiologic papers in different clinical cohorts. Lee et al.  reportedTwo important studies focused on the presence of coronary artery disease in patients with a zero calcium score. Ergun et al.  reportedRadiation dose remained a hot topic in 2011, and the journal has published several manuscripts related to efforts of exposure reduction , 76. UsiThe journal has also published a number of interesting meta-analyses. Abdulla and colleagues evaluated 10 coronary CTA studies  for the purpose of determining the risk of major adverse events . During Beyond coronary imaging, a special issue of the journal focused on imaging in the context of transvascular interventions for valvular and other structural heart disease , 89–98.