Bordetella parapertussis, is composed of two distinct clades that have specialized to different hosts: one to humans (huBpp), and the other to sheep (ovBpp). While huBpp and the other classical bordetellae can efficiently colonize mice, ovBpp strains are severely defective in their ability to colonize the murine respiratory tract. ovBpp genomic analysis did not reveal the loss of adherence genes, but substantial mutations and deletions of multiple genes involved in the production of O-antigen, which is required to prevent complement deposition on B. bronchiseptica and huBpp strains. ovBpp lacks O-antigen and, like O-antigen mutants of other bordetellae, is highly sensitive to murine complement-mediated killing in vitro. Based on these results, we hypothesized that ovBpp failed to colonize mice because of its sensitivity to murine complement. Consistent with this, the ovBpp defect in the colonization of wild type mice was not observed in mice lacking the central complement component C3. Furthermore, ovBpp strains were highly susceptible to killing by murine complement, but not by sheep complement. These data demonstrate that the failure of ovBpp to colonize mice is due to sensitivity to murine, but not sheep, complement, providing a mechanistic example of how specialization that accompanies expansion in one host can limit host range.The classical bordetellae are comprised of three subspecies that differ from broad to very limited host specificity. Although several lineages appear to have specialized to particular host species, most retain the ability to colonize and grow in mice, providing a powerful common experimental model to study their differences. One of the subspecies,  Listeria monocytogenes enters host cells via the binding of the bacterial protein internalin to human E-cadherin, but does not infect mice due to a single amino acid difference in mouse E-cadherin . Al. AlBorde is brkA ,14. It iBppov clade could provide additional insight into the adaption of other bordetellae sub-species to specific host populations. B. pertussis has lost the O-antigen locus, and is similarly specialized to a human host. Since the O-antigen is both energetically costly to make and a dominant antigen, the loss of O-antigen may have been beneficial to B. pertussis [Bpphu strains that circulate among humans have retained many genes in this large locus [Bpphu that is not required by B. pertussis. Previously, we have shown that loss of altered O-antigen can allow evasion of cross-immunity mediated by antibodies to O-antigen. Potentially contributing to their co-existence in the same ecological niche Bpphu has been previously shown to evade B. pertussis-induced immunity by shielding shared surface antigens behind its O-antigen. While Bppov strains are only found in sheep populations, B. bronchiseptica strains have also been isolated from sheep [Bppov strains to circulate in a B. bronchiseptica immune population. This suggests that inter-strain competition may be an important aspect of the evolution of this locus, and raises the interesting possibility that increased success within a single host may result in loss of ability to infect others.The loss of O-antigen within the ertussis . Howeverge locus ,32,33, iom sheep , and it Bppov lineage and suggests that the differing repertoires of complement resistance factors confer differing susceptibilities to complement of various hosts. As various complement activation pathways are critical aspects of both host immunity to disease and some autoimmune pathologies, understanding the molecular basis for ability of bacteria to either prevent complement activation or inhibit individual pathways is of substantial significance.In conclusion, these data reveal an immunological mechanism that explains the observed host specificity of the S1 FigB. parapertussisov strains Bpp5 and HI. Bacterial colonization was enumerated from the nasal cavity, trachea, and lungs of three to four mice per group at 0, 3, 7, 14, and 28 days post-inoculation. Error bars indicate standard deviation (SD). Dashed line indicates limit of detection.C57BL/6 mice were inoculated with (TIF)Click here for additional data file.S2 FigB. bronchiseptica strain RB50 (purple), B. parapertussishu strain 12822 (green) and B. parapertussisov strains Bpp5 (blue) and HI (red) in Stainer-Scholte media over time. (B) Doubling time of indicated strains based on growth during mid-log phase. Error bars indicate standard deviation (SD).(A) Growth of (TIF)Click here for additional data file.


Disrupted empathic processing is a core feature of psychopathy. Neuroimaging data have suggested that individuals with high levels of psychopathic traits show atypical responses to others’ pain in a network of brain regions typically recruited during empathic processing . Here, we investigated whether neural responses to others’ pain vary with psychopathic traits within the general population in a similar manner to that found in individuals at the extreme end of the continuum. As predicted, variation in psychopathic traits was associated with variation in neural responses to others’ pain in the network of brain regions typically engaged during empathic processing. Consistent with previous research, our findings indicated the presence of suppressor effects in the association of levels of the affective-interpersonal and lifestyle-antisocial dimensions of psychopathy with neural responses to others’ pain. That is, after controlling for the influence of the other dimension, higher affective-interpersonal psychopathic traits were associated with reduced neural responses to others’ pain, whilst higher lifestyle-antisocial psychopathic traits were associated with increased neural responses to others’ pain. Our findings provide further evidence that atypical function in this network might represent neural markers of disrupted emotional and empathic processing; that the two dimensions of psychopathy might tap into distinct underlying vulnerabilities; and, most importantly, that the relationships observed at the extreme end of the psychopathy spectrum apply to the nonclinical distribution of these traits, providing further evidence for continuities in the mechanisms underlying psychopathic traits across the general population.The online version of this article (doi:10.3758/s13415-015-0346-7) contains supplementary material, which is available to authorized users. Empathy is a multidimensional phenomenon that involves the capacity to resonate with and understand the affective states of others  to probe the neural bases of empathy  is indeed associated with reduced reactivity to emotional stimuli, whilst the lifestyle-antisocial dimension (characterized by impulsivity and irresponsibility) is associated with increased reactivity to emotional stimuli , excessive response times (two participants), incidental findings (one participant), and corrupted fMRI data due to excessive movement (one participant). Analyses of the residuals from the multiple regression models inspecting the relationships between neural responses and psychopathic traits revealed one extreme outlier. This participant was excluded, leaving 46 participants in the analyses . According to the G*Power software , lifestyle-antisocial scores varied between 15 and 47 , and the two scales presented a correlation coefficient of r = .66 (p < .001), thus presenting a distribution similar to previously reported distributions from larger samples of adults from the general population  with blood oxygenation-level-dependent (BOLD) contrast were acquired in a single run of 9 min. The T2* EPI sequence was based on Weiskopf, Hutton, Josephs, and Deichmann  and usedwww.fil.ion.ucl.ac.uk/spm) in MATLAB. The first five and last two volumes were discarded. The data were realigned to the sixth volume, normalized to the Montreal Neurological Institute template (resampling to a voxel size of 2 × 2 × 2 mm), and smoothed with an 8-mm full-width-at-half-maximum Gaussian filter. The data were high-pass filtered at 128 s to remove low-frequency drifts, and the statistical model included an AR(1) autoregressive function to account for autocorrelations.The EPI data were analyzed using SPM8  and fixation (15 s), modeled as boxcar functions convolved with a canonical hemodynamic response function. The six realignment parameters were also modeled as effects of no interest. At the first level, pain > no-pain and no-pain > pain contrasts were created. These contrast images were entered into second-level analyses, in which both SRP dimensions were entered either separately or simultaneously as covariates in multiple regression models. Relationships between the total SRP scores and BOLD response were also examined.p < .001 , with cluster-level family-wise error (FWE) correction. Region-of-interest (ROI) analyses were conducted in four a priori ROIs . The first three were taken from Lockwood et al. (http://marsbar.sourceforge.net) was used to calculate average contrast estimates across bilateral ROIs and to conduct t tests at a standard statistical threshold of p < .05  = 5.76, p < .001; pain: M = 767.11, SD = 106.62; no pain: M = 738.10, SD = 104.52]. We found no significant differences in percentage error rates between the conditions .Mean reaction times (RTs) and percentage error rates were calculated. Consistent with previous studies , whilst affective-interpersonal traits presented an at-trend negative association . That is, when holding the other dimension constant, higher levels of affective-interpersonal traits were associated (at trend level) with fewer errors during the pain than during the no-pain condition, whilst higher levels of lifestyle-antisocial traits were associated with increased error rates in the pain than in the no-pain condition. There were no significant associations with the difference in RTs for the pain relative to the no-pain condition, and no significant bivariate associations between total SRP score or either dimension of psychopathic traits and the mean RT/percentage error rate differences between conditions .On the basis of previous studies showing that the unique variances associated with affective-interpersonal and lifestyle-antisocial traits present opposing associations with emotional reactivity . ROI analyses for the main effect of pain > no-pain also revealed the predicted pattern of significant BOLD response in the bilateral AI  and IFG , but not in midCC  and ACC . Additionally, entering the difference (pain > no-pain) in error rates and the difference in RTs between conditions as predictors of BOLD response in two SPM models also showed that BOLD response in all ROIs presented significant positive relationships with differences in error rates  and differences in RTs  between the pain and no-pain conditions, with the exception of the IFG, whose association was at trend .The results from the whole-brain analyses for the main effect of pain > no-pain are displayed in Table t(43) = 1.87, p = .03], IFG , and midCC , and was at trend in ACC . That is, when holding levels of lifestyle-antisocial behavior constant, increased levels of affective-interpersonal traits were associated with a decrease in neural responses to others’ pain in these regions. After controlling for affective-interpersonal traits, the unique variance associated with lifestyle-antisocial traits was positively related to differential BOLD response in AI , IFG , midCC , and ACC . That is, when holding levels of affective-interpersonal traits constant, increased levels of lifestyle-antisocial behavior traits were associated with an increase in neural responses to others’ pain in these regions.On the basis of previous studies showing that the unique variances associated with affective-interpersonal and lifestyle-antisocial traits show opposing associations with emotional reactivity .To exclude the potential confounds of trait anxiety and cognitive ability, we included trait anxiety and estimated IQ as additional covariates in follow-up regression models. Including these variables did not change the pattern of results  = 0.27, p = .39; IFG, t(44) = 0.72, p = .24; midCC, t(44) = 0.80, p = .21; ACC, t(44) = 0.04, p = .97], lifestyle-antisocial traits , and total psychopathy score .To test whether these opposing results were genuine suppressor effects, we inspected the bivariate associations between psychopathic dimensions and total score and differential BOLD response in three separate regression models. These analyses revealed weaker and largely nonsignificant bivariate associations between neural responses in our ROIs and affective-interpersonal traits [AI, For completeness, due to previous research linking amygdala dysfunction to psychopathic traits, we inspected whether neural responses in amygdala varied as a function of psychopathic traits. No significant associations were found.Neuroimaging studies have shown that the observation of other people experiencing distress, in particular pain, elicits robust activation in AI, IFG and midCC/ACC . An increased error rate in the pain condition is thought to result from increased reactivity to the emotional content of the stimuli  and consequent interference in task performance (hand/feet judgment)  in AI, IFG, midCC, and ACC. After shared variance with lifestyle-antisocial traits was removed, affective-interpersonal traits (characterized by a lack of consideration for others’ well-being) presented negative associations with neural responses in AI, IFG, and midCC, which is consistent with the characteristic lack of arousal to others’ distress and the general blunted affect associated with this set of traits. In contrast, after removing the variance associated with affective-interpersonal traits, lifestyle-antisocial characteristics (marked by poor inhibitory control) were positively associated with responses in these regions, consistent with evidence showing that these traits are associated with hyperreactivity to emotional stimuli and poor emotional and behavioral regulation in both extreme and typical samples Below is the link to the electronic supplementary material.


Primary cardiac lymphoma (PCL) is a rare subset of non-Hodgkin’s lymphoma involving the heart and/or pericardium with no or minimal evidence of extracardiac involvement at presentation. Distant relapses have infrequently been observed.We report two cases of this disorder that showed isolated central nervous system (CNS) relapse. Diagnosis by endomyocardial biopsy was consistent with diffuse large B-cell lymphoma. After immunochemotherapy they achieved complete remission (CR). Eight and five weeks after, isolated CNS relapses were observed respectively. The first patient was treated with high-dose methotrexate (HD-MTX) and high-dose cytarabine, resulting in a second CR. She then went onto receive autologous stem-cell transplantation but unfortunately died shortly after because of infection. The second patient received systemic CNS prophylaxis with HD-MTX, and later she was treated with an induction chemotherapy strategy with evidencing of progressive disease after two courses of treatment. She was subsequently initiated on a salvage therapy with cytarabine, followed by whole-brain radiotherapy, and autologous stem-cell transplant (ASCT), finally achieving a complete remission.Isolated CNS relapse is a very uncommon pattern in PCL and a standard approach to treatment is not yet well established. Nevertheless, the importance of CNS evaluation, using magnetic resonance imaging (MRI) and lumbar puncture, in patients with PCL should be considered, and further studies are recommended to determine the appropriate management of this complication. A 54-year-old woman presented to another hospital in January 2011 with a one-month history of dyspnoea. Her electrocardiogram (ECG) was in sinus rhythm with low-voltage QRS intervals. Six months later, the patient presented with worsening heart failure symptoms. Evaluation by echocardiogram and cardiac magnetic resonance imaging (MRI) showed a reduction of systolic left ventricular function. Laboratory findings revealed elevated markers for myocardial injury and hypereosinophilia. To exclude Loeffler endocarditis, the patient underwent an endomyocardial biopsy. However, the histology revealed a myocardial localisation of diffuse large B-cell lymphoma (DLBCL). Staging by full-body computed tomography (CT) scan, positron emission tomography (PET)/CT, and bone marrow biopsy did not show extracardiac involvement of lymphoma. Common laboratory and serologic tests were unremarkable, and in particular the patient was human immunodeficiency virus (HIV) negative.The patient was diagnosed with a primary cardiac lymphoma (PCL) and received chemotherapy with etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (VACOP-B) in combination with rituximab for 12 weeks. No prophylaxis for central nervous system (CNS) dissemination was performed. After treatment, she achieved a complete remission (CR).Two months after completion of chemotherapy, the patient presented with a three-day history of headache and vomiting. A MRI examination of the brain, revealed an infiltrating lesion slightly hyperintense on T2 weighted images adjacent to the fourth ventricle . Cerebro2 every two weeks for two cycles plus six doses of Ara-C at 2 g/m2 every 12 hours. The patient achieved second CR (She received chemotherapy with high-dose methotrexate (HD-MTX) in combination with high-dose cytarabine (HD-Ara-C): MTX dose of 3 g/mecond CR  and was A 59-year-old woman presented to another hospital in April 2013 because of one month history of dyspnoea and chest pain. A transthoracic echocardiogram showed a mass twisting between the right atrium and ventricle . With th2 administered every two weeks for four cycles.The diagnosis was a PCL, and she was transferred to our institution in a critical condition. The patient was treated with a CHOP-like regimen: R-ACOD  every 21 days for eight cycles. Based on our previous experience, we performed a lumbar puncture and a CT scan of the brain which were normal. Nevertheless, we decided to administer CNS prophylaxis with systemic HD-MTX at a dose of 1.5 g/mAfter the first course of treatment, the patient noted an improvement in her cardiac symptoms. A transthoracic echocardiogram, cardiac MRI, CT scan, and PET/CT demonstrated complete disappearance of disease after four cycles of chemotherapy.One week later, the patient presented with headache and motor symptoms. The brain MRI showed two enhancing lesions surrounded by oedema, respectively located in the left frontal and frontoparietal regions . A lumba2 every two weeks for two cycles) for CNS relapse of lymphoma. However, the follow-up brain MRI after two courses of HD-MTX revealed progressive disease. Therefore, HD-MTX in combination with cytarabine was initiated as salvage therapy without improvement of CNS disease. Whole-brain radiotherapy was than performed with a CR. This patient was then consolidated with ASCT.She received induction chemotherapy with HD-MTX  should be excluded . Thus, dPCL should be treated like other aggressive lymphomas arising in other primary sites. In most cases of PCL, lymphoma cells originate from the B-lymphocyte lineage, being DLBCL the most common subtype of PCL . AnthracAfter the addition of rituximab to standard chemotherapy in patients with systemic DLBCL, the incidence of CNS relapse appears to have decreased .In a retrospective study of 197 cases of PCL, CR was achieved in 59% of patients who were treated by any modality, and 12 patients showed relapse before one year. According to this largest review of PCL to date, there was no case showing CNS recurrence ; howeverUsually, CNS relapse is rare in DLBCL; the strongest evidence for high-risk of CNS relapse according to anatomical sites of involvement is for testicular, breast, and involvement of the epidural space. Recent guidelines recommend the use of CNS prophylaxis with directed therapy  for patients with high-grade NHL presenting risk factors . Many stGiven the fact that the first patient had a CNS relapse, we believe that the administration of prophylactic treatment to reduce the risk of CNS relapse was then considered as a logical management strategy for the second patient.2 if systemic chemotherapy is to be used as CNS prophylaxis [The Southwest Oncology Group (SWOG), in an attempt to decrease the CNS relapse rate in diffuse aggressive lymphomas, conducted a prospective trial whereby patients were randomly assigned to receive one of four treatments for CNS prophylaxis. The early occurrence of CNS events suggests that these patients had subclinical disease at initial diagnosis. As such, strategies to better detect and treat patients with subclinical CNS disease at diagnosis was anticipated to result in a decrease in the incidence of CNS relapse  but no dphylaxis . Neverthphylaxis . Moreovephylaxis . These, We suggest that in patients with PCL, an individual patient’s circumstances may dictate an alternative approach because CNS relapse is likely to occur even if there is not a failure of control of systemic disease. Thus, a routine evaluation of CNS should be performed by brain magnetic resonance imaging and lumbar puncture.In conclusion, studies are recommended to determine the real risk of CNS involvement in PCL, refining the predictors of risk of CNS involvement, and identifying those patients who may benefit from CNS-directed therapy according to more precisely tailored therapeutic protocols.


CRF explained 73% of the variance in the association between MVPA and clustered cardio-metabolic risk and attenuated this association to non-significance. After mutual adjustment for MVPA and ST, CRF was the most important risk factor for a higher clustered cardio-metabolic risk . In conclusion, because of the mediating role of CRF, lifestyle-interventions need to be feasible yet challenging enough to lead to increases in CRF to improve someone’s cardio-metabolic health.We aimed to study the independent associations of sedentary time (ST), moderate-to-vigorous physical activity (MVPA), and objectively measured cardiorespiratory fitness (CRF) with clustered cardio-metabolic risk and its individual components . We also investigated whether any associations between MVPA or ST and clustered cardio-metabolic risk were mediated by CRF. MVPA, ST, CRF and individual cardio-metabolic components were measured in a population-based sample of 341 adults  between 2012 and 2014. MVPA and ST were measured with the SenseWear pro 3 Armband and CRF was measured with a maximal exercise test. Multiple linear regression models and the product of coefficients method were used to examine independent associations and mediation effects, respectively. Results showed that low MVPA and low CRF were associated with a higher clustered cardio-metabolic risk ( According to the World Health Organization, noncommunicable diseases were responsible for 38 million (68%) of the world’s deaths in 2012 . MoreoveEvidence from cross-sectional studies –10, longBased on the temporal associations of ST and MVPA with CRF , 27, it The aim of the current study was to examine the independent associations of objectively measured ST, MVPA and CRF with clustered cardio-metabolic risk and individual cardio-metabolic risk factors. Furthermore, the mediating effect of CRF on the relation between MVPA or ST and clustered cardio-metabolic risk was analysed. We hypothesized that objectively measured high CRF, high MVPA, and low ST were independently associated with a favourable cardio-metabolic risk profile. Moreover, we hypothesized that CRF is a potential mediator for the association of MVPA or ST and clustered cardio-metabolic risk.This cross-sectional study is part of a Flemish longitudinal study of which the sampling procedure is previously described in detail by Matton et al. . ParticiObjective measurement of physical activity and ST was obtained with a SenseWear Pro 3 Armband , which is proven valid for measuring daily energy expenditure under free-living conditions . Partici2peak) was measured directly with breath-by-breath respiratory gas exchange analysis, using a Cortex MetaLyzer 3B analyzer  and was defined as the highest 20-s value during the exercise test  * 100%; resulting in an effect of 73%, meaning that CRF explained 73% of the total variance in the association between MVPA and CMRS , variable definitions, or study populations. For example, physical activity is often defined differently  for clustered cardio-metabolic risk. This study also highlights some important associations between ST, MVPA and CRF, and certain cardio-metabolic risk factors. Furthermore, our findings suggest that the risk related to low MVPA is substantially mediated by CRF. Therefore, when designing interventions for reducing cardio-metabolic risk, apart from an increase in MVPA and decrease in ST, an increase in CRF will have to be the additional goal. Consequently, exercise programs need to be feasible yet challenging enough to lead to increases in CRF.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


The fixed-dose combination of Efavirenz/Emtricitabine/Tenofovir is a first-line agent for the treatment of HIV; however few cases have reported hepatotoxicity associated with the drug. We report a case of Efavirenz/Emtricitabine/Tenofovir-associated hepatotoxicity presenting mainly with hepatocellular injury characterized by extremely elevated aminotransferase levels, which resolved without acute liver failure or need for liver transplant referral. Drug-associated hepatotoxicity has been well defined in the literature. The fixed-dose Efavirenz/Emtricitabine/Tenofovir (EFV/FTC/TDF) (Atripla) is a first-line agent for the treatment of HIV but has rarely been associated with acute hepatotoxicity. We present a case of EFV/FTC/TDF-associated hepatotoxicity in a young, healthy male with HIV.3 with an undetectable viral load and similar values were found during his admission. The patient had been on a combination therapy of FTC, ritonavir, and atazanavir; however, he expressed interest in changing to a one-pill, once-a-day combination. Two months prior to admission, the patient was started on a new antiretroviral regimen of EFV/FTC/TDF. He was taking no other medications; however, he admitted to drinking at least eight shots of hard liquor at a party a few days prior to presentation. He denied any fevers, chills, sore throat, chest pain, shortness of breath, jaundice, rash, or diarrhea.A 24-year-old Hispanic male with a history of vertically acquired HIV presented for evaluation of right upper quadrant pain and nausea for three days. He was diagnosed with HIV at the age of four and followed routinely in the HIV clinic. His CD4 count in February 2014 (four months prior to admission) was 563 cells/mmUpon admission, the liver enzymes were found to be elevated with an aspartate aminotransferase (AST) level of 1663 IU/L and an alanine aminotransferase (ALT) level of 1793 IU/L . EFV/FTCThe clinical condition of the patient and his liver chemistries continued to improve and obviated the need for liver biopsy or referral to a liver transplantation tertiary center. His hospital course lasted seven days and he was seen in outpatient clinic three weeks following discharge at which point repeat liver profile testing revealed an ALT of 55 IU/L and an AST of 33 IU/L. After discharge his highly active antiretroviral therapy (HAART) was changed to TDF, rilpivirine, and FTC and then to a combination of cobicistat, elvitegravir, FTC, and TDF. His liver profile remained normal several months thereafter.The fixed-dose combination of EFV/FTC/TDF is a first-line agent for the treatment of HIV; however few cases have reported hepatotoxicity associated with the drug . HepatotOur patient presented with remarkably elevated transaminases, pointing to a pattern of hepatocellular injury rather than the more commonly associated pattern of cholestasis. He did not have a long-standing history of alcohol abuse but he had been drinking more heavily the few days prior to admission. The association of hepatotoxicity due to alcohol binging and Atripla remains unclear. This patient's liver toxicity was most likely caused by EFV/FTC/TDF and though some patients have required liver transplant, our patient recovered after four weeks of stopping the medication. In cases of severe hepatic decompensation due to suspected HAART etiology, a close collaboration of the gastroenterologist and the HIV specialist is important and recommended.


We report a case of a 58-year-old Japanese man with epithelioid-type MPM, with a left chest wall protruding tumor, who underwent extrapleural pneumonectomy and chest wall resection. Postsurgical pathology showed that surgical margins were free of mesothelioma cells. Positron emission tomography taken 5 years after surgery showed no recurrence at any site, suggesting that long-term survival could be dependent on margin-free tumor resection or that specific MPM subgroups have lower malignant potential, leading to improved survival.The online version of this article (doi:10.1186/s13019-014-0176-7) contains supplementary material, which is available to authorized users. Chemotherapy, immunotherapy, irradiation, hyperthermia, and surgery have all been applied for malignant pleural mesothelioma (MPM); however, presently, with the exception of surgery, the outcomes of these treatments are unsatisfactory. The benefit of extrapleural pneumonectomy (EPP) for MPM has been controversial since data from the MARS feasibility trial were published . HoweverTM, Chugai Pharm. Co. Ltd., Tokyo, Japan) was administered twice  intrathoracically to promote adhesion between the visceral and the parietal pleura. We decided to perform EPP on consultation with the patient, following a diagnosis of clinical T3N0M0 stage III MPM based on the International Mesothelioma Interest Group classification.A 58-year-old Japanese man was admitted with left chest pain. He worked in the electrical industry for 40 years. Chest radiography revealed left pleural effusion and a 6-cm diameter protruding tumor on the anterior chest wall. A needle biopsy pathologically confirmed epithelioid-type MPM. Computed tomography revealed direct intercostal invasion of mesothelioma between the first two ribs Figure . PreoperTwo weeks after OK-432 infusion, EPP plus mediastinal lymph node dissection, combined with chest wall resection, including the first two ribs, the pericardium, and the diaphragm, was performed via a sigmoid incision of the fifth intercostal space. The pericardium and the diaphragm were reconstructed using polytetrafluoroethylene Blood loss and the duration of surgery were 1085 g and 490 minutes, respectively. Histological analysis showed that, the mesothelioma cells reached the fascia of the major pectoral muscle invading the intercostal muscles and partially destroying the ribs. However, pathological investigation confirmed that all the surgical margins were tumor-free. In addition, microscopic findings showed the aggregation of inflammatory cells, lymphocytes, plasma cells, and histiocytes with the mesothelioma cells  has been suggested as a more feasible alternative that would confer substantial survival benefit. Lang-Lazdunski et al. [Some reports indicated that trimodality improves long-term survival . HoweverThe patient here demonstrates long-term, recurrence-free survival following EPP, with combined resection of a chest wall-invading T3 tumor, for MPM. Our case findings suggest that long-term survival could be dependent on margin-free tumor resection and that even in advanced cases, some patients with a subgroup of MPM that has lower malignant potential may have a better prognosis than others.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.YY, HM and HH are the doctors for the general thoracic surgery. YY wrote the article. YY and HM performed the surgery and assisted the post operative care. HH is the consultant of performing the study. MK assessed the pathological findings. All authors read and approved the final manuscript.


The distinction between treatment effect and recurrent brain malignancy has been a controversial topic for quite some time, with various proponents and opponents for the various cross-sectional neuroimaging modalities. The goal of this manuscript is to provide the latest information on positron emission tomography (PET) molecular imaging, offer other options within the realm of molecular imaging, and to let the reader’s ultimate decision regarding follow-up imaging be made on a case-by-case basis based upon available resources and user experience.Delineation between treatment effect and tumor recurrence is an exceedingly important decision in the era of more focused, targeted therapy, whether anti-angiogenic, immunologic, or radiotherapy. The consequences of an incorrect assessment are obvious, leading to unnecessary treatment and morbidity, delayed treatment, or shortened survival. Various modalities have been proposed to follow such lesions after initial treatment: MRI, MRS, brain PET, and brain single photon emission computed tomography (SPECT). Only molecular imaging (PET and SPECT) will be discussed in this article.A radiographically negative scan cannot exclude microscopic disease.Molecular imaging depends on specific substrate metabolism by tumors. If the particular tumor cannot metabolize or concentrate the substrate, false negative scans will occur.False positive scans can occur when substrates are metabolized or concentrated by cells related to non-neoplastic processes, such as inflammation or infection.Molecular imaging is distinguished from anatomical imaging in that it requires intact intra- and extra-cellular architecture, whereas anatomical imaging only requires an intact structure. Cancer begins at a cellular level, and thusly, microscopic changes precede macroscopic changes. No imaging modality can replace a microscopic diagnosis, but current technology attempts to model a microscopic process non-invasively. This has inherent implications of:These implications lead to the paradigm of follow up imaging after initial diagnosis and treatment: how to separate cases of residual/recurrent disease from treatment response. The optimal imaging algorithm has not been clearly delineated.Positron emission tomography with or without inline computed tomography (CT) imaging has largely overtaken clinical SPECT imaging of the brain for functional and oncological purposes. The increased resolution of PET  and shorter acquisition times 10 min) have significant advantages over SPECT imaging. At our institution, brain PET has largely replaced brain SPECT for both oncologic and neurologic indications. Previously, the number of PET cameras limited the availability to PET imaging, but currently, most tertiary medical centers have access to PET imaging (0 min havl-tyrosine (FET), 18-F-fluoro-dopamine (F-DOPA), 18-F-flouro-thymidine (FLT), and 11-C-methionine (MET); however, these are only approved under an Investigational New Drug (IND) application in the United States and are not commercially available for routine clinical use outside of a research protocol. The main topic of this article will be the use of 18-F-FDG-PET/CT.Positron emitting isotopes are limited in the United States, as only 18-F-fluoro-de-oxy-glucose (FDG), 11-C-choline, and 18-F-sodium fluoride (NaF) are currently approved by the FDA for routine clinical use. Sodium fluoride is a bone imaging agent, and 11-C-choline is only approved for prostate cancer imaging in the United States. Promising agents include O-2-18-F-flourorethyl-Flouro-deoxy-glucose is structurally very similar to glucose, with the number 2 hydroxyl group substituted with F-18. It becomes a charged particle and is excreted mainly via the kidneys. However, tumor cells are unable to distinguish FDG from glucose and transport it through the cell membrane into the intracellular space, where it is phosphorylated by hexokinase into FDG-6-phosphate. Due to the polarity as well as faulty cellular enzyme machinery, FDG-6-phosphate becomes trapped within cancer cells and undergoes positron emission radioactive decay, thus localizing its distribution within the body and organs, specifically the brain in this discussion. Hence, cancer cells will concentrate FDG, although to varying degrees, often related to the degree of de-differentiation of the tumor. Increasing levels of FDG uptake associated with higher grades of gliomas has been well documented . HoweverSingle photon emission computed tomography (SPECT) has been utilized for several decades in nuclear medicine imaging. It allows for tomographic rather than planar images and improves diagnostic accuracy. It, however, has limitations of spatial resolution and long imaging times. Spatial resolution is approximately 1 cm under ideal conditions and imaging times can be up to 45 min per acquisition. Both of these can limit its usefulness in the setting of distinguishing between tumor recurrence and post-treatment changes. However, for facilities without access to PET imaging, brain SPECT can still provide useful information, as SPECT gamma cameras are more widely accessible than PET scanners. Currently, the only clinically available brain SPECT agent for use in this setting in the US is Thallium-201 chloride. Previous studies have suggested relative robust accuracy with Th-201 ; howeverMolecular imaging in the setting of detecting recurrent disease and delineating treatment effect is an evolving topic, with multiple promising, newer agents being evaluated, particularly, PET tracers. The future of imaging in this setting is likely going to be a combination of multiple modalities with possibly multiple radiotracers. Serial imaging is likely to be important as well. Further research is underway to define the optimal imaging protocols. Ultimately, at this time, determining the most accurate modality is up to the reader, who must determine the best compromise, given what resources are available and his or her comfort level in interpreting the radiographic findings, but the author’s opinion is that molecular imaging is the best single imaging modality at this time, with combined multimodality imaging soon to become the top choice, particularly when radiotracers only currently used for research become available for widespread clinical use.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The Guest Associate Editor Pamela Zyman New declares that, despite being affiliated to the same institution as author Stephen Chiang, the review process was handled objectively and no conflict of interest exists.


We have recently described an Epigenetic-Senescence-Signature that facilitates prediction of the state of cellular aging by analysis of DNAm at six CpG sites , but this has not yet been proven over subsequent passages and with MSCs isolated under good manufacturing practice (GMP) conditions.Tracking of replicative senescence is of fundamental relevance in cellular therapy. Cell preparations – such as mesenchymal stromal cells (MSCs) - undergo continuous changes during culture expansion, which is reflected by impaired proliferation and loss of differentiation potential. This process is associated with epigenetic modifications: during MSCs were isolated from human bone marrow and GMP-conform expanded for up to 11 passages. Cumulative population doublings (cPDs) and long-term growth curves were calculated based on cell numbers at each passage. Furthermore, 32 cryopreserved aliquots of these cell preparations were retrospectively analyzed using our Epigenetic-Senescence-Signature: DNAm-level was analyzed at six specific CpGs, and the results were used to estimate cPDs, time of culture expansion, and passage numbers. Overall, predicted and real parameters revealed a good correlation, particularly in cPDs. Based on predicted cPDs we could reconstruct long-term growth curves and demonstrated the continuous increase in replicative senescence on molecular level.Epigenetic analysis of specific CpG sites in the genome can be used to estimate the state of cellular aging for quality control of therapeutic cell products. Yet, cells undergo tremendous changes during long-term culture: they enlarge, acquire flat “fried-egg” morphology, lose differentiation potential, and ultimately stop proliferation ,2. This xpansion . Furtherxpansion ,7. This xpansion .in vitro[in vitro culture [Analysis of senescence-associated beta-galactosidase  activity is the most widely used biomarker for replicative senescence in vitro. We obsein vitro, althougin vitro,12. Furt culture  but this culture -16. Analin vitro culture [Culture expansion of MSCs is associated with senescence-associated DNA-methylation (SA-DNAm) changes at specific sites in the genome which become either hyper-methylated or hypo-methylated ,18. Thes culture . Yet, th2. After the initial passages cultures were split into parallel subcultures, cultivated for several passages and in some cases subcultured for a second time  and cultivated as described before . In brieGRM7 and CASR) and four CpGs become hypo-methylated . DNAm values of each sample were then used for linear regression analysis to predict cPDs, passage number and days of in vitro culture. An online-calculator is provided under: http://www.molcell.rwth-aachen.de/dms/. It needs to be noted that the genes associated with the six relevant CpGs are not expressed in MSCs [Thirty-two cryopreserved samples, which correspond to various passages of the three donors, were then analyzed using the Epigenetic-Senescence-Signature to estimate the state of cellular aging. In our previous work, we did not analyze many subsequent passages from the same cell preparation and harvested DNA directly from cells in culture. DNA was now isolated from cryopreserved vials without taking cells into culture and then bisulfite-converted. SA-DNAm of the six relevant CpGs was analyzed in a blinded manner by pyrosequencing as described in detail before  ,24. In b in MSCs . In fact in MSCs ,25 but t in MSCs ,21. Thus in MSCs  – it is in vitro culture and passage numbers correlated well with real parameters, although they were slightly overestimated , affect also the epigenetic state of cells in culture ,28. Our MSCs: Mesenchymal stromal cells; SA-β-Gal: Senescence-associated beta-galactosidase; cPDs: cumulative population doublings; DNAm: DNA methylation; SA-DNAm: Senescence-associated DNA-methylation; iPSCs: induced pluripotent stem cells; GMP: Good manufacturing practice; BM: Bone marrow.RWTH Aachen has applied for a patent application for the “Epigenetic-Senescence-Signature”. WW is involved in the company Cygenia that provides this service to other researchers. SM & PdW are employed by Cardio3 Biosciences; RJ has been employed by Cardio3 Biosciences. Apart from this, the authors have no competing interest for this study.AS analyzed the data and revised the manuscript. SM collected the data, participated in the analysis of the data and the writing of the manuscript. CMK collected and analyzed the data. RJ participated in the design of the study. PW participated in the design of the study and the writing of the manuscript. WW carried out the design of the study and the writing of the manuscript. All authors read and approved the final manuscript.


The number of RNA-Seq studies has grown in recent years. The design of RNA-Seq studies varies from very simple  to very complicated . Most of these publically available RNA-Seq studies are deposited in NCBI databases, but their metadata are scattered throughout four different databases: Sequence Read Archive (SRA), Biosample, Bioprojects, and Gene Expression Omnibus (GEO). Although the NCBI web interface is able to provide all of the metadata information, it often requires significant effort to retrieve study- or project-level information by traversing through multiple hyperlinks and going to another page. Moreover, project- and study-level metadata lack manual or automatic curation by categories, such as disease type, time series, case-control, or replicate type, which are vital to comprehending any RNA-Seq study. Here we describe “MetaRNA-Seq,” a new tool for interactively browsing, searching, and annotating RNA-Seq metadata with the capability of semiautomatic curation at the study level. High-throughput gene expression studies are pivotal in functional biology and genomics research . Until lhttp://metarnaseqdb.screensifter.com/.The importance of biocurating biological databases was realized in recent years , 12. TexThe metadata for RNA-Seq studies from multiple resources at NCBI were retrieved using the NCBI entrez direct utility . ScriptsThe MetaRNA-Seq web tool provides enhanced utilization of metadata for RNA-Seq studies in NCBI resources with semiautomatic curation, restructures the presentation, and allows convenient browsing of all of the details in a single window with a study-level search. MetaRNA-Seq currently has metadata information for 1508 human RNA-Seq studies and is updated every quarter. The main web interface of MetaRNA-Seq is shown in In contrast to the NCBI SRA interface, which by default provides an experiment-level view of the results of a search query, MetaRNA-Seq presents a study-level browsing and filtering mechanism. All RNA-Seq studies are presented in a table in the MetaRNA-Seq web interface. The table contains important columns, such as study accession, name, title, number of samples, number of experiments, number of runs, and average number of reads and bases. The table is filtered based on the search. The studies table can be sorted by double clicking any column. Study details appear for any selected project, including title, name, abstract, material, method, bioproject description, GEO design, and summary. This table of RNA-Seq studies also provides manual annotation details for the RNA-Seq study if that study is annotated using the MetaRNA-Seq annotation interface. In addition, the MetaRNA-Seq interface provides hyperlinks to NCBI SRA or PubMed if the user needs additional information about a study.Suggestion: Cell Lines - -> Yes: Cell line derived from Merkel Cell Carcinoma (10 samples) Confidence: 25%” and hint text “Suggestion: Tissue - -> Yes: FFPE Merkel Cell Carcinoma (16 samples), FFPE Basal Cell Carcinoma (6), FFPE Normal skin (6), FFPE Squamous Cell Carcinoma (2) Confidence: 40%,” respectively  improve experimental settings by comparing different platforms under similar experimental conditions, (2) compare whole transcripts of different cell lines, tissues, diseases, and experimental conditions  to select the most suitable conditions for newly designed experiments, and (3) estimate the number of samples and number of biological and technical replicates needed to obtain significant and relevant data. However, NCBI database interfaces are unable to provide the study-level search and comparisons required by the end user. Using annotated studies with the guided search function provided by MetaRNA-Seq is strongly recommended to supplement NCBI RNA-Seq metadata resources. The annotation capabilities provided in MetaRNA-Seq can be utilized by end users to support the community and improve the search process in subsequent sessions. MetaRNA-Seq can easily be turned into a crowd sourcing-based annotated resource. Currently, the interface provides all of the annotation details for the studies with annotation completed by all biocurators, as the number of biocurators is limited to our lab at the time of writing this paper. In the future, if the number of biocurators increases or if multiple biocurators handle a single study, manual annotation study details can be presented based on crowd statistics. MetaRNA-Seq currently presents the metadata for RNA-Seq studies ofThe NCBI provides many options for finding RNA-Seq data. However, the large amount and complex nature of RNA-Seq data that can be retrieved using NCBI data resources present difficulties for researchers. An annotated resource of RNA-Seq metadata is needed to better serve the community. A tool such as MetaRNA-Seq can be a great resource for both annotating and browsing RNA-Seq metadata, and it can provide better tools for more effective data interrogation. Enhanced access to RNA-Seq metadata could also potentially allow the creation of a customized RNA-Seq metadata database and has the potential to be turned into a crowd sourcing-based annotated resource for the benefit of the research community.


Additionally, we were able to investigate the TCR richness and clonality in samples pre- and post-treatment in a clinical single agent cetuximab trial.T cell receptor (TCR) recognition of tumor antigen is essential for effective antitumor immunity. The immune system`s ability to respond to a broad spectrum of antigens requires a sophisticated selection of various TCR. So far, little is known about the role of TCR richness and clonality in the immune response to the EGFR-specific mAb, cetuximab. Therefore, we investigated differences in TCR sequences between HPVi(1-pi), pi is the proportion of sequence i relative to the total sequences. The clonality is defined as 1-H/log(S). The maximum available number of samples from the same patient was 4, containing pre- and post-treatment PBMC and pre- and post-treatment TIL. Paired comparisons (pre vs. post) were done using the Wilcoxon Signed Rank tests. Comparisons between two independent groups  were accomplished with Wilcoxon Rank Sum tests.TCR genotyping was performed and quantified by Adaptive Technologies, Inc . Richness (S) was defined as total number of unique productive sequences. The Shannon Index is defined as H=-log∑p+ and HPV- patients did not significantly differ in clonality and richness pre- and post-treatment in either PBMC or TIL. However, cetuximab therapy significantly increased the richness of unique sequences in PBMC (p=0.0002). Most importantly, the responder group had a higher increase of richness post-treatment in PBMC. The difference reached a p-value of 0.03 post-treatment. On the contrary, this increase was not observed in TIL, which appeared to be more focused after cetuximab therapy.Using a cohort of neoadjuvant, single-agent cetuximab treated HNSCC patients, 56 samples were analyzed for global TCR diversity. HPVTCR clonality and richness for PBMC and TIL seem to be independent from the patient's HPV status in HNSCC. Intriguingly, an increase in richness of TCR sequences in the periphery (PBMC) but a focusing in TIL was associated with an improved treatment response, suggesting an influence of peripheral quantity on intratumoral TCR quality.


Various psychiatric populations are currently investigated with resting state fMRI, with the aim of individualizing diagnostics and treatment options and improving treatment outcomes. Many of these studies are conducted in large naturalistic samples, providing rich insights regarding disease-related neural alterations, but with the common psychopharmacological medication limiting interpretations of the results. We therefore investigated the effects of common noradrenergic and anti-dopaminergic medications on local and global resting state activity (rs-activity) in healthy volunteers to further the understanding of the respective effects independent from disease-related alterations. Within a randomized, double-blind, placebo-controlled crossover design, we investigated 19 healthy male subjects by resting state fMRI after the intake of reboxetine (4mg/d), amisulpride (200mg/d), and placebo for 7 days each. Treatment-related differences in local and global rs-activity were measured by the fractional amplitude of low frequency fluctuations (fALFF) and resting state functional connectivity (rs-FC).fALFF revealed alterations of local rs-activity within regions of the core noradrenergic pathway, including the locus coeruleus under reboxetine, correlated with its plasma levels. Moreover, reboxetine led to increased rs-FC between regions within this pathway, i.e. the locus coeruleus, tectum, thalamus, and amygdala. Amisulpride modulated local rs-activity of regions within the dopaminergic pathway, with the altered signal in the putamen correlating with amisulpride plasma levels. Correspondingly, amisulpride increased rs-FC between regions of the dopaminergic pathway comprising the substantia nigra and putamen.Our data provide evidence of how psychopharmacological agents alter local and global rs-activity within the respective neuroanatomical pathways in healthy subjects, which may help with interpreting data in psychiatric populations. A variety of investigations conducted with task-related functional magnetic resonance imaging (fMRI) have provided insight into altered brain functioning and divergent neural activations in patients with psychiatric disorders compared to healthy controls. However, this modality is not easily implemented in clinical routines due to its complexity and dependency on the subject`s motivation and performance. Resting state fMRI (rs-fMRI) has been suggested as an alternative task-independent neuroimaging modality suited to discriminate patients with psychiatric disorders from healthy controls , to predThe aim of our study was to investigate alterations in spontaneous brain activity by psychotropic medication within a sample of healthy subjects, to allow for separating drug effects from disease-related changes. Previous studies demonstrated alterations in resting state and task-induced activity in healthy males under serotonergic and dopaminergic agents compared to placebos . To furtLocal spontaneous low frequency oscillations (LFO) have been related to local neuronal activation . Such loThe selective noradrenalin reuptake inhibitor reboxetine (REB) modulates the noradrenergic pathway  has been shown to act on the dopaminergic pathway . It indusychotic . The dopsychotic . AMS hassychotic . In humasychotic , and chasychotic  and cortsychotic . HoweverThis study aimed to investigate local and interregional resting state alterations under both REB and AMS within a randomized, placebo-controlled crossover design. The investigation of drug effects in healthy subjects aims to provide novel aspects to help with interpreting recent rs-fMRI studies on psychiatric disorders, since it allows for disentangling mere drug effects from disease-related alterations.A total of 20 healthy male right-handed participants were investigated under 7-day administrations of standard clinical dosages of AMS, REB, and placebo (PLA) in a counterbalanced order separated by washout phases of 2 weeks minimum. Prior to enrolment, subjects underwent a full medical evaluation, including a physical examination, a review of their medical history, and a structured clinical interview for DSM-IV Axis I psychiatric disorders. Each participant received standard blood tests and an electrocardiogram to exclude cardial, renal, or hepatic pathologies. Exclusion criteria encompassed any serious general medical condition, use of any illegal drugs, as well as excessive consumption of caffeine, alcohol (>14 units/week), or nicotine (>15 cigarettes/week). Participants with any kind of current or past history of psychiatric or neurological disorder were also excluded from the study. Upon recruitment, depressive symptoms were assessed using the Center for Epidemiologic Studies Depression-Scale CES-D;  in its GThe study was approved by the ethical committee of Ulm University. All volunteers gave written informed consent prior to the study, in accordance with the Declaration of Helsinki. One subject had to be excluded from the study due to glial cerebral pathology (gliotic lesions) revealed by MRI scanning, resulting in a group of 19 participants aged 20–32 .Participants took 200mg amisulpride (100mg twice a day), 4mg reboxetine (2mg twice a day), and placebo  for 7 days each in a randomized double-blind crossover design separated by a wash-out phase of at least 2 weeks . fMRI scResting state fMRI data were acquired as part of the protocol, including a separate functional task–related MRI experiment and resting state perfusion data, which are reported elsewhere .Functional and anatomical images were acquired by a 3.0 Tesla Magnetom ALLEGRA Scanner (Siemens). Scanning included acquisition of T1 anatomical volume images (1 x 1 x 1mm voxels), and a 10-minute eyes-closed resting state scan. Task and resting state data were acquired as 23 transversal slices with an image size of 64 x 64 pixels and a field of view of 192mm. A slice thickness of 3mm with a 0.75mm gap resulted in a voxel size of 3 x 3 x 3.75mm. Images were centered on basal structures of the brain, including subcortical regions of interest . T2*-sensitive gradient echo-planar imaging was used to measure changes in Blood-oxygen-level dependent (BOLD) contrast. For the resting state scan, 320 volumes were obtained at a repetition time (TR) of 1500ms (echo time (TE) 35ms, flip angle 90°).http://www.restfmri.net), which is based on Statistical Parametric Mapping  and the Resting State fMRI Data Analysis Toolkit (http://www.restfmri.net). Preprocessing included slice timing, realignment, and spatial normalization to a standard template  based on Echo Planar Imaging (EPI) templates. Due to partial brain coverage, normalized volumes were masked for those voxels covered in each subject to allow for step performance, especially global mean regression, on equal volumes. Those steps included smoothing with an 8mm full-width at half-maximum Gaussian kernel, removing of linear trends, and filtering with a bandwidth of 0.01–0.08 Hz. The regression of nuisance variables included motion parameters as well as white matter and cerebrospinal fluid signals and global mean regression. Functional connectivity was calculated on the whole brain level for subcortical seed regions within the noradrenergic and dopaminergic pathways. Seed regions were centered on anatomical landmarks based on the T1 template in SPM8. All seed regions were defined as spheres with a radius of 3mm to ascertain spacial specificity to very small anatomical structures. Due to stronger left-lateralized dopaminergic drug effects in previous studies (www.cma.mgh.harvard.edu/fsl_atlas.html) were chosen as additional regions that are mainly modulated by both neurotransmitter systems  was calculated on detrended unsmoothed data of the whole volume, measuring the power within a typical frequency range of 0.01–0.08 Hz divided by the total power in the entire frequency range . To redup < 0.001, adding an additional cluster threshold of more than 10 adjacent voxels for significance , analogous to A flexible factorial design, as implemented in SPM8, was chosen to test for treatment effects on both local (fALFF) and interregional/global (rs-FC) rs-activity. Analyses of variances (ANOVAs) were applied to assess the main drug effects on fALFF or rs-FC at a conservative significance threshold of Further, a simple regression analysis was performed to assess the relationship between alterations in fALFF and drug plasma levels. Here, the region with the strongest main effect from the ANOVA f-test was chosen as the ROI, with individual amisulpride and reboxetine blood levels as the regressor.p < 0.05, uncorrected for the mask. We used MRIcron (http://www.mccauslandcenter.sc.edu/mricro/mricron/index.html) for the creation of displayed figures. Bar plots were created using SPSS Version 15 (IBM Corp.).To be specific to subtle changes in these small regions of interest, correlation analyses were masked with the region of drug-specific main effects at a statistical threshold of Table S1). Post hoc analysis revealed an increase in fALFF within the putamen and pulvinar under AMS compared to PLA, whereas REB led to an increase of fALFF within the locus coeruleus and the hypothalamus compared to PLA. Comparing the two verum drugs, an increase of fALFF was observed in the sgACC and anterior insula under REB compared to AMS .The main effects of the drugs on fALFF were found bilaterally in the locus coeruleus, extending to the tectum and ventral cerebellum, the hypothalamus, and the subgenual anterior cingulate cortex (sgACC) as well as in the right ventral anterior insula, left putamen, and right pulvinar (p < 0.031). Moreover, AMS plasma levels were positively correlated with absolute fALFF in the left putamen .A positive correlation of REB plasma levels with absolute fALFF under REB was observed within the in locus coeruleus .The ANOVA revealed significant treatment effects on rs-FC between the left locus coeruleus and the bilateral medial and dorsal thalamus, the posterior cingulate cortex (PCC), the cerebellum, and the right amygdala and putamen . Decreased locus coeruleus–seeded connectivity under AMS versus PLA was solely found between the locus coeruleus and the cerebellum.Post hoc tests showed mainly increases in rs-FC under AMS compared to PLA on locus coeruleus–seeded connectivity. These increases were found with the putamen, the PCC, and the amygdala . Here, post hoc t-tests revealed an increase in rs-FC between the amygdala and substantia nigra, thalamus, and hippocampus under AMS compared to PLA. Under REB, decreased connectivity of the amygdala with the hippocampus, pgACC, and anterior insula was observed compared to PLA .The main effects of the drugs on the left amygdala-seeded connectivity were observed with the bilateral substantia nigra, tectum, locus coeruleus, thalamus, left hippocampus, left pregenual anterior cingulate cortex (pgACC), and right anterior insula . Under AMS, substantia nigra–seeded connectivity was increased with the bilateral putamen, amygdala, and hippocampus compared to PLA. Indeed, REB decreased rs-FC of the substantia nigra with the left putamen compared to PLA .An ANOVA revealed treatment effects on substantia nigra–seeded connectivity with the bilateral putamen, hippocampus, and right anterior insula .Regarding the left nucleus accumbens seed, the ANOVA analysis revealed treatment effects on rs-FC with the bilateral medial and dorsal thalamus, bilateral sgACC, and left pgACC .Under AMS, a decrease of rs-FC was observed between the nucleus accumbens seed with the bilateral sgACC and left pgACC compared to PLA. Under REB, an increase of rs-FC between the left nucleus accumbens and the bilateral medial and dorsal thalamus was found, whereas a decrease in rs-FC of the nucleus accumbens was observed with the bilateral sgACC as well as the left pgACC compared to PLA  and global (rs-FC) rs-activity in healthy male subjects within a randomized, placebo-controlled crossover design. Significant treatment effects were observed for REB, with increased fALFF compared to placebo in core regions within the NE-pathway, e.g. the locus coeruleus and hypothalamus. In contrast, AMS led to an increase in fALFF in the putamen and the thalamic pulvinar, regions associated with the dopaminergic system, compared to PLA. Moreover, alterations in fALFF within the respective neurotransmitter pathways correlated with blood serum levels of REB and AMS.In terms of connectivity, AMS increased rs-FC between regions of the dopaminergic pathway like the substantia nigra, putamen, thalamus and amygdala compared to PLA .In comparison to PLA, REB led to an increase of rs-FC between major regions of the NE-pathway like the locus coeruleus, hypothalamus, and thalamus, and also the nucleus accumbens .As measured by fALFF, local rs-activity increased under REB compared to PLA foremost in the locus coeruleus, tectum, and hypothalamus. Considering the neuroanatomy of the NE-pathway arising from the locus coeruleus to the tectum and hypothalamus via ascending fibers of the dorsal noradrenergic bundle , the thrAn increase in rs-FC between regions indicates higher temporal synchrony of low frequency fluctuations . TherefoDecreased rs-FC under REB compared to PLA was observed between the amygdala-seed and the pgACC and bilateral insula, as well as for the nucleus accumbens seed with the sgACC. Both sgACC and pgACC are part of the task-negative default-mode network DMN; . In deprCompared to PLA, AMS led to an increase in local rs-activity in the putamen. Neural alterations within the putamen by AMS, compared to PLA, are in line with findings on continuous arterial spin–labelling MRI within the same study sample, which revealed a rise of blood perfusion in the putamen under AMS . MoreoveFigure S2). Anatomically, these regions have been previously associated with the dopaminergic pathway, arising from the substantia nigra to the ventral tegmental area, nucleus accumbens, and hippocampus and terminating in the prefrontal cortex  instead of having larger anatomically-shaped ROIs, e.g. for the substatia nigra and the locus coeruleus, in an attempt to be as precise as possible, especially in the small subcortical structures.By selecting the upper part of the locus coeruleus, we wanted to make sure to catch those parts which can best be normalized, considering deeper structures of the brainstem to be less precise when choosing a standard normalization, as offered by our software, and no specific brainstem normalization, as used by Further, we are aware that the locus coeruleus and intralaminar parts of the thalamus, as part of the ascending arousal system, are influenced by noradrenaline coding for inner arousal and salience , 2013a. Within a double-blind, placebo-controlled, crossover design, we investigated the effects of the noradrenergic antidepressant REB and the dopamine antagonist AMS on resting state activity within a sample of healthy male subjects to examine drug effects independent from disease-related neural alterations. Local resting state behavior was examined by fALFF, whereas interregional characteristics of rs-fMRI were assessed by rs-FC. As measured by fALFF, local rs-activity within regions of the NE-pathway, e.g. the locus coeruleus, was altered by REB and linearly correlated with REB plasma levels. Moreover, REB led to increased rs-FC between regions within the NE-pathway, e.g. the locus coeruleus, tectum, thalamus, amygdala, and hippocampus. AMS increased local rs-activity of regions within the dopaminergic pathway, like the putamen, which is also linearly correlated with AMS plasma levels. Increased rs-FC was also observed between regions of the dopaminergic pathway, comprising the substantia nigra, putamen, thalamus, and amygdala. Thus, our results provide evidence for drug effects on both interregional/global and local neural rs-activity under reboxetine and amisulpride that should be considered in interpreting rs-fMRI data conducted in psychiatric patients.None.


Animal movement patterns in space and time are a central aspect of animal ecology. Remotely-sensed environmental indices can play a key role in understanding movement patterns by providing contiguous, relatively fine-scale data that link animal movements to their environment. Still, implementation of newly available remotely-sensed data is often delayed in studies of animal movement, calling for a better flow of information to researchers less familiar with remotely-sensed data applications. Here, we reviewed the application of remotely-sensed environmental indices to infer movement patterns of animals in terrestrial systems in studies published between 2002 and 2013. Next, we introduced newly available remotely-sensed products, and discussed their opportunities for animal movement studies. Studies of coarse-scale movement mostly relied on satellite data representing plant phenology or climate and weather. Studies of small-scale movement frequently used land cover data based on Landsat imagery or aerial photographs. Greater documentation of the type and resolution of remotely-sensed products in ecological movement studies would enhance their usefulness. Recent advancements in remote sensing technology improve assessments of temporal dynamics of landscapes and the three-dimensional structures of habitats, enabling near real-time environmental assessment. Online movement databases that now integrate remotely-sensed data facilitate access to remotely-sensed products for movement ecologists. We recommend that animal movement studies incorporate remotely-sensed products that provide time series of environmental response variables. This would facilitate wildlife management and conservation efforts, as well as the predictive ability of movement analyses. Closer collaboration between ecologists and remote sensing experts could considerably alleviate the implementation gap. Ecologists should not expect that indices derived from remotely-sensed data will be directly analogous to field-collected data and need to critically consider which remotely-sensed product is best suited for a given analysis. While hAnimals interact with their environment at multiple spatiotemporal scales, resulting in different movement modes ,13. Finefine-but-infrequent  versus coarse-but-frequent  data recorded by different satellite sensors .Figure Our goal here was to provide a review for movement ecologists who are less familiar with the variety of remotely-sensed data available and their application in animal movement studies, reducing the present time lag in application of available remotely-sensed products in animal movement studies . Thus, wThe studies of small-scale movement that we reviewed included data about land cover, infrastructure, and terrain, and less often data on vegetation phenology, climate and weather Table . SurprisLand cover data are typically derived from fine-but-infrequent remotely-sensed products and researchers can use them to infer animal movement patterns on finer spatial scales . Ancy season . Of the scescens , but areDigital elevation models (DEM) provide fine-but-infrequent information on altitude, aspect, and slope, as well as soil wetness and solar radiation, and have been applied in different ways. DEMs are sometimes combined with coarse-but-frequent remotely-sensed atmospheric variables such as wind speed, turbulent kinetic energy, temperature, and cloud height  products, monthly WorldClim data, or 10-day National Oceanic and Atmospheric Administration data ; Table Cathartes aura and Golden Eagles Aquila chrysaetos [Capreolus capreolus, and their opportunistic migration behavior when there are no predictably extreme winter conditions [rysaetos . The ananditions .Human infrastructure influences many wildlife species’ habitats. Infrastructure can create barriers and can modify daily and seasonal movement patterns. For example, gray wolves Canis lupus cross highways less frequently with increasing human presence [Loxodonta africana movement [Syncerus caffer migrations [Ursus arctos and moose Alces alces avoid roads during the day [Bison bison [fine-but-infrequent data, and typically derived from land cover data and aerial photos. The use of high spatial resolution imagery and LiDAR  also provides opportunities to discriminate between different types of human infrastructure and vegetation, such as highways, roads, railroads, pipelines, power-lines, houses, and trees . In . In Humaes .Plant phenology, the annual dynamics of vegetation greenness, can be tracked using NDVI and the Enhanced Vegetation Index (EVI) [coarse-but-frequent satellite imagery, such as 10-day Satellite Pour l’Oservation de la Terre (SPOT) or 16-day MODIS reflectance data, and can be applied to predict individual and population movement and distribution. Yet animal movement ecologists need to consider the different interpretation of traditional phenology and satellite-based landscape phenology; while traditional phenology tracks e.g. flowering and budding of single plant species, satellite-based phenology quantifies dates of greening and browning patterns of multiple plant species at the landscape scale [Connochaetes taurinus [Dolichonyx oryzivorus [Equus burchelli antiquorum [http://smap.jpl.nasa.gov/) and the Global Precipitation Measurement  provide exciting opportunities to improve our understanding of the drivers of animal movement.ex (EVI) ,54, althex (EVI) ). Phenolpe scale ,57. The pe scale . Vegetatpe scale . In our taurinus ; Bobolinyzivorus ), and enyzivorus . NDVI isyzivorus ). The ocyzivorus ). MODIS yzivorus . The comtiquorum ). For vetiquorum ). For bitiquorum ). FurtheProductivity, i.e., seasonal plant growth, can be calculated by merging information from ground biomass measurements and MODIS-derived NDVI, and can predict, e.g., movement patterns of elk at different scales, demonstrating the connection between migration and access to higher-quality forage [Ovis aries [Odocoileus hemionus [y forage . With itis aries , but affhemionus ).Climate and weather indices provide information about precipitation  and temperature , and are generally coarse-but-frequent indices. It is important to distinct between climate and weather. Climate describes the average pattern of meteorological variables such as temperature, wind, precipitation over longer time in a given area. In contrast, weather describes the short-term variations of those meteorological variables. In the context of animal movement, climate affects animals at a broader scale and can, for example, cause seasonal migration. Precipitation and temperature are particularly important determinants of animal movement patterns in seasonal ecosystems  and temperature , and are generally coarse-but-frequent indices.tatarica  and roe tatarica ; Table 2ng birds ,69-71, wn helvum , and temght mode . Climatefine-but-infrequent versus coarse-but-frequent), and more importantly, should avoid the expectation that remotely-sensed data are equivalent to field-collected data. On the other hand, field-collected data will never match the spatial continuity of remotely-sensed data collected over large areas. Remotely-sensed and field-collected data have unique strengths, and their integration allows unique insights.In summary, inclusion of remotely-sensed data can greatly improve our understanding of the drivers of animal movement and provide novel insights about movement strategies across species and ecosystems. The main environmental indices are available from a broad range of remotely-sensed products that can vary in precision, and accuracy Table . The sethttp://earth.google.com).High spatial resolution imagery is recorded by sensors such as IKONOS, QuickBird, OrbView-3 and Spot-5, with spatial resolutions from 0.5 - 10 m , as an alternative to traditional classified land cover data or calculated indices such as NDVI, experience increasing interest for predicting animal distribution. They overcome classification errors and can provide better predictive ability – even at fine resolution – than more commonly-used remotely-sensed products (see for example in birds ).Env-DATA system in Movebank ([https://www.movebank.org), as a direct link in Eurodeer ([www.eurodeer.org), or under development in Wireless Remote Animal Monitoring ([WRAM).A computational challenge for many movement ecologists is the integration of these remotely-sensed data sets into animal movement data sets, as remote sensing data often are provided using complex tiling systems in space and time . Furtherovebank .The use of high temporal resolution satellite data offers new possibilities for animal movement studies as it means increased opportunities for matching satellite imagery with concurrent high resolution animal location data, and captures many temporal dynamics of landscapes . In particular, long-term animal monitoring projects can take advantage of analyzing movement patterns in dynamic landscapes to better understand the impact of a given change and its consequence for management and conservation ,89.For studying fine-scale animal movement, an exciting advancement is the automated analysis of dense time series of Landsat images. In the past, studies rarely incorporated more than a few Landsat images due to cost and processing limitations. Since Landsat data became freely available in 2008, new image processing algorithms have been developed that analyze many decades of annual Landsat imagery simultaneously ,91. The http://www.nateko.lu.se/TIMESAT; version 3.0 [https://lpdaac.usgs.gov/products/modis_products_table/). Substantial work has been done to unify data from older and new sensors to establish consistency in time series data [For analysis of coarse-scale animal movement, indices of vegetation phenology can be informative . Satellision 3.0 ); MODIS ies data  and impries data .http://blackbridge.com/rapideye/). RapidEye data are at the cutting-edge of geospatial data, because of their ability to describe foliar nitrogen at impressive resolutions [Although NDVI is the most commonly used index in ecological applications of remotely-sensed data, there is also a broad range of spectral indices that can be derived from satellite data  as wolutions , which cThe 3D structural characteristics of vegetation are important determinants of animals’ space use . For exaPanthera leo hunting strategies and for predation risk in roe deer [LiDAR is a relatively new technology that uses a laser to measure the vertical and horizontal structure of ecosystems ; Table 11, makingroe deer ). Most Lhttp://www.fort.usgs.gov/RavenA; e.g. [Finally, scientists and managers are exploring the use of low-cost pre-programmed or remote-controlled drones equipped with video and photo cameras, as alternative ways to survey landscapes, count animal populations, and monitor human activities . This enA; e.g. ,113.In addition to the technologies and products outlined before, there is a growing number of efforts to reanalyze remote sensing and weather data to derive consistent, long-term, global or regional environmental products at low to medium (12–1000 km) spatial resolution, but very high (1–24 h) temporal resolution. Examples include the North American Regional Reanalysis (NARR), the NOAA global weather reanalysis , and the European weather reanalysis (ECMWF) for weather data, or the Oregon University Ocean NPP reanalysis for ocean products. The NASA’s MERRA project, for example, provides consistent information on weather variability from 1979 to the present. Finally, although not a reanalysis product per se, Hansen and co-authors , recentlAs much promise as new remotely-sensed data and methods offer, it is important to recognize inherent limitations of these approaches. One important issue is that of errors, uncertainties, and accuracies in remotely-sensed products ,116. No Movement ecologists that apply remotely-sensed products to animal movement data also need to consider spatial autocorrelation that are inherent in the data. Advances in statistical tools help to discover spatial patterns and to correct for autocorrelated data, e.g., in mixed models with help of correlation structures ,120. Pat2, compared to minimum mapping units of 3,600 m2 for Landsat imagery, and 250,000 m2 for MODIS data. As movement ecology advances, and integrates more remotely-sensed data, it will be important to keep these inherent limitations of satellite data in mind, and to avoid the temptation to try to obtain more information from the imagery than it contains.The spatial resolution of the satellite data is another critical issue that is pertinent when analyzing fine-scale movement data. First, the size of the pixels, which tend to be 250–1,000 m for those satellites that provide daily observations, are far coarser than GPS-collar-based movement data. Secondly, the smallest observable feature that can reliably be mapped  is considerably larger than the pixel size . This means that only Quickbird or Worldview data can detect habitat features of 1–5 mfine-but-infrequent versus coarse-but-frequent or minimum mapping unit) and how its limitations may affect inferences. Closer collaboration between ecologists and remote sensing experts can facilitate the use of newly available products in movement studies, and minimize the time lag of applying these products in ecological research.Animals move in response to environmental changes, and to fulfill their varying needs for environmental resources over days, weeks, and years. New generations of remotely-sensed products with better spatiotemporal resolution provide great opportunities for insights into animal movement, as they characterize environmental patterns such as temporal dynamics of landscapes and three-dimensional structures of habitats. To capture these dynamics and to improve predictive ability, we recommend that researchers analyze time series of remotely-sensed products, as they can capture environmental dynamics that determine movement responses. The integration of landscape dynamism in movement studies becomes particularly important with respect to meeting the conservation and management challenges of future landscape change and corresponding changes in animal movement in space and time. To be able to provide realistic foundations for management and conservation, movement ecologists need to increase their application of dynamic environmental information when analyzing animal movement. With new tools emerging to automate the integration of remotely-sensed data with animal movement data sets, former computational challenges can be overcome, making environmental data more easily accessible for movement ecologists. Yet, the increasing possibilities of integrated analyses of remotely-sensed products and animal movement data presents new challenges to match these types of data logically, bearing in mind the inherent trade-offs posed by the different resolutions. It is important to critically weigh which remotely-sensed product is best suited for a given scale of analyses (e.g.,


Global measures of cardiac function may not reflect subtle wall motion abnormalities. In such cases, assessment of regional cardiac wall motion is required, which is usually evaluated visually with highly subjective results. Automatic analysis techniques can be classified into intensity-based and contour-based methods with the latter category avoiding the image quality-related limitations in the first one. In this study, we present a contour-based technique for detecting wall motion abnormality based on studying the temporal pattern of normalized wall thickness.Image datasets from 14 volunteers and 13 patients  were used to train and test the proposed classifier. Three short-axis cine images were acquired at basal-, mid-, and apical sites. All images were manually segmented to extract the epi- and endocardium. Each contour was re-sampled at equi-angular spaces to vectors of 60-points in the mid and basal slices and 40-points in the apical slices. Regional temporal changes in wall thickness were extracted based on standard AHA 17-segment model. The extracted thickness pattern was normalized relative to average epicardial radius. The wall thickness values of all points within each segment were averaged to one value  occurred when one principal-component was used, which captures 89% of all data variations. 100% true-negative and 70% true-positive were achieved for basal- and mid-slices and 70% true-positive for apical-slices. Higher specificity relative to sensitivity was recorded, which reflects that the algorithm's tendency for true identification of normal cases over abnormal cases. The overall system accuracy was 88%, 88%, and 85% for basal, mid, and apical slices, respectively. Fig. The proposed method provides automatic assessment of regional myocardial abnormality in a segmental basis for each slice; therefore, it could be a valuable tool for automatic and fast detection of early signs of cardiac dysfunction from conventional untagged cine images.N/A.


In preclinical and clinical studies aging has been associated with a deteriorated response to antidepressant treatment. We hypothesize that such impairment is explained by an age-related decrease in brain serotonin transporter (SERT) expression associated with low testosterone (T) levels. The objectives of this study were to establish (1) if brain SERT expression is reduced by aging and (2) if the SERT expression in middle-aged rats is increased by T-restitution. Intact young rats (3–5 months) and gonad-intact middle-aged rats with or without T-restitution were used. The identification of the brain SERT expression was done by immunofluorescence in prefrontal cortex, lateral septum, hippocampus, and raphe nuclei. An age-dependent reduction of SERT expression was observed in all brain regions examined, while T-restitution recovered the SERT expression only in the dorsal raphe of middle-aged rats. This last action seems relevant since dorsal raphe plays an important role in the antidepressant action of selective serotonin reuptake inhibitors. All data suggest that this mechanism accounts for the T-replacement usefulness to improve the response to antidepressants in the aged population. In  monkeys , 37–39,  monkeys , the redd humans . These dd humans , support monkeys C(+)McN56to SSRIs –10. The to SSRIs  or HIP [to SSRIs , 43, lowto SSRIs , and redto SSRIs , indicatto SSRIs , implyinto SSRIs , 47. Thuto SSRIs , 45 contThe increased SERT expression in the dorsal RN of MA animals after T-restitution agrees with a study done in young rats where the orchidectomy-dependent reduction of SERT mRNA expression in RN was prevented by T-administration . HoweverThe T-dependent SERT expression increase in the RN of MA rats may facilitate SSRIs' actions, since this region controls the firing rate of serotonergic neurons , 49. ThuOne factor that could limit the conclusions derived from this study is the number (4 or 5) of animals used per group; however, the correspondence of our results with previous studies from several laboratories (as discussed above) gives support to our findings.The current study demonstrates a reduced SERT expression in PC, LS, HIP, and RN of MA rats, which may be related with the retarded response of these animals to antidepressants. T-restitution to MA rats increased SERT expression in the dorsal RN, an important site for the therapeutic action of SSRIs, suggesting that this hormone would improve the response to SSRIs in experimental and clinical conditions.