Staphylococcus epidermidis. The technique presented here allowed for safe and effective removal of both the thrombus and infected pacing leads, with excellent exposure and minimal post-procedure complications.Superior vena cava (SVC) syndrome is a known but rare complication of pacemaker lead implantation, accounting for approximately less than 0.5% of cases. Its pathophysiology is due to either infection or endothelial mechanical stress, causing inflammation and fibrosis leading to thrombosis, and therefore stenosis of the SVC. Due to the various risks including thrombo-embolic complications and the need to provide symptomatic relief, medical and surgical interventions are sought early. We present the case of a 48-year Caucasian male who presented with localised swelling and pain at the site of pacemaker implantation. Inflammatory markers were normal, but diagnostic imaging revealed three masses along the pacemaker lead passage. A surgical approach using cardiopulmonary bypass and circulatory arrest was used to remove the vegetations. Culture from the vegetations showed  Superior Vena Cava (SVC) syndrome is an extremely rare but serious complication of pacemaker-lead implantation, characterised by symptomatic occlusion of the SVC ,2. MaligThe frequency of pacemaker-induced SVC syndrome is difficult to ascertain; it can either be acute or chronic, with many patients being asymptomatic. The asymptomatic prevalence may be as high as 30% of all patients , with paThe pathophysiology behind this phenomenon is likely endothelial disruption from mechanical stress or infection of the pacemaker leads, leading to inflammation and fibrosis and subsequently, thrombosis ,8. SeverStaphylococcus species account for the majority of infections (Staphylococcus aureus and Staphylococcus epidermidis), while other gram-negative bacilli, Enterococcus faecalis, Pseudomonas aeruginosa, Candida-species have also been implicated [The potential to develop SVC occlusion is a recognised indication for lead extraction. Other indications for device and lead extraction have been set out by the Heart Rhythm Society Expert Consensus . These aplicated .Management of pacemaker lead thrombosis can be either medical or surgical. Medical forms of management include anti-coagulation or thrombolysis, while surgical interventions rely on percutaneous endovascular intervention or lead extraction . Lead exA 48 year-old Caucasian man attended outpatients’ clinic with a six-month history of localised swelling and pain at the site of his pacemaker implantation, particularly upon abduction of his right arm. He had twenty years previously undergone implantation of a VVI  pacemaker due to sick sinus syndrome. Two years prior to his current attendance, the pacemaker was altered due to battery depletion and concomitantly upgraded to a DDD  device.Physical examination revealed venous distension of the neck, upper chest and arms, but was otherwise normal. His electrocardiogram (ECG) was normal and he was not pacemaker dependent. Biochemical laboratory investigations including inflammatory markers were normal, and blood cultures were negative.A trans-esophageal echocardiography (TEE) identified three masses: a 40 × 18 mm mass at the atrial lead during its passage along the superior vena cava (SVC), which it occluded; a second 12 × 11 mm mass at the atrial surface of the ventricular lead; a third 5 × 5 mm mass during passage through the tricuspid valve. An open foramen ovale was further identified. Subsequently, contrast-enhanced chest computed tomography (CT) confirmed the TEE findings  was dissected out. Heparin was administrated 300 μ/kg) and cardiopulmonary bypass (CPB) was established via the ascending aorta, innominate vein Figure  and infe00 μ/kg aStaphylococcus epidermidis. This was treated with daptomycin 500 mg daily for six weeks. Post-operative cultures were negative, and post-operative CT showed a clear SVC  occurring in 2.3%. Importantly, they highlight greater risk with increasing number of leads and lesser experience [et al. described European experiences of laser-assisted extraction whereby there was extraction failure in 5.7%, and a total complication rate of 5.1% of the total 383 lead extractions [Other surgical techniques including transveonous dilators, retrieval baskets and laser-assisted extraction have been previously described . These pperience . Kennergractions . Percutaractions .et al. describe their recent experiences of 6 such procedures, with all surviving the follow-up period and one having a recurrence of infection [et al. demonstrate the well-tolerated use of cardiopulmonary bypass amongst seven patients with pacemaker infections; four with Staphylococcus epidermidis, two with Staphylococcus aureus and one Pseudomonas aeruginosa, with all being successfully managed with a follow-up period greater than two years and new epicardial devices inserted [Our conventional approach of cardiopulmonary bypass and myocardial arrest allows both direct visualisation and complete removal of all pacemaker components (including leads) whilst avoiding dissemination of large thrombus. Wilhelm and colleagues present their experiences of 8 lead removals using extracorporeal circulation, and after a follow-up period of more than 18 months, 6 of 8 patients were alive and infection-free . They alinserted . The useinserted -23 with Our technique is novel in its cannulation of the innominate vein to complete the bypass circuit due to the extent of vegetations within the SVC. Previous practises have utilised the saphenous vein or the superficial femoral vein  whereas In terms of diagnosis, along with clinical suspicion, we used TEE to investigate the underlying cause for the patient’s symptoms. Ultrasonography for detection of severe innominate vein or SVC stenosis using sonography, pulse Doppler and colour flow have been shown to be accurate, and are useful for follow-up . ContrasOur case has shown the safe approach for diagnosis and management of SVC syndrome caused by pacemaker lead thrombosis and infection. Although our approach of cardiopulmonary bypass and cardiac arrest is an invasive and technically challenging surgical procedure, it allows direct visualisation of the vegetations and the extent of disease. Our approach of innominate vein cannulation highlights a strategy for overcoming the problem of extensive disease within the SVC. Due to the heterogeneous nature of thrombus formation, medical or surgical diagnosis should be based upon clinical diagnosis and imaging. There is a lack of large multi-centre data to support one intervention over another. Future studies should therefore compare practices and provide long-term efficacies associated with cardiopulmonary bypass in the context of managing SVC syndrome from pacemaker lead infection and thrombosis.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.SVC: Superior vena cava; ECG: Electrocardiogram; TEE: Trans-esophageal echocardiogram; CT: Computed tomography; IVC: Inferior vena cava; CPB: Cardiopulmonary bypass; ICD: Implantable cardioverter defibrillator.There are no financial or non-financial competing interests.JK, MK, DT, TA carried out the surgical procedure and participated in provision of clinical information and reviewed the manuscript. UC, HA, LH performed the literature review and drafted the manuscript. All authors read and approved the final manuscript.


Since the discovery of antibodies specific to a highly conserved stalk region of the influenza virus hemagglutinin (HA), eliciting such antibodies has been considered the key to developing a universal influenza vaccine that confers broad-spectrum protection against various influenza subtypes. To achieve this goal, a prime/boost immunization strategy has been heralded to redirect host immune responses from the variable globular head domain to the conserved stalk domain of HA. While this approach has been successful in eliciting cross-reactive antibodies against the HA stalk domain, protective efficacy remains relatively poor due to the low immunogenicity of the domain, and the cross-reactivity was only within the same group, rather than among different groups. Additionally, concerns are raised on the possibility of vaccine-associated enhancement of viral infection and whether multiple boost immunization protocols would be considered practical from a clinical standpoint. Live attenuated vaccine hitherto remains unexplored, but is expected to serve as an alternative approach, considering its superior cross-reactivity. This review summarizes recent advancements in the HA stalk-based universal influenza vaccines, discusses the pros and cons of these approaches with respect to the potentially beneficial and harmful effects of neutralizing and non-neutralizing antibodies, and suggests future guidelines towards the design of a truly protective universal influenza vaccine. Influenza viruses belong to the family Orthomyxoviridae and contain a segmented RNA genome. Due to its high propensity for genetic mutations, especially in major surface antigens (hemagglutinin (HA) and neuraminidase (NA)), the virus can easily evade preexisting immunity acquired from previous exposure to the virus, thereby causing seasonal epidemics, with 3–5 million cases of severe illness and 250,000–500,000 deaths each year (antigenic drift) ,2,3. In Vaccination has been considered the most cost-effective measure to prevent and mitigate influenza infections. Currently used seasonal influenza vaccines include the HA and/or NA antigens derived from the virus subtype that is most likely to circulate during the impending season. Such vaccines are considered to elicit neutralizing antibodies directed predominantly to antigenic sites in the variable globular head domain of HA that mediates the receptor binding and virus entry into the cells . Such neImperfections in the surveillance of circulating viruses and the limited breadth of the protection efficacy of HA globular head-based vaccines against heterologous influenza viruses have motivated the development of vaccines with broader and longer-lasting protection, ultimately a universal vaccine that would provide protection against diverse influenza virus strains regardless of their subtypes. Naturally, the regions of viral proteins that are highly conserved across viral strains became the main focus of attention, with the hope that eliciting antibody responses to such conserved regions would present as a promising way of developing universal influenza vaccines. For this purpose, conserved viral proteins or domains, including the M2 extracellular (M2e) domain and HA stalk domain, have been studied and were demonstrated to provide better cross-protection against diverse viruses than HA globular head-based vaccines ,12.While these ideas shed light on the feasibility of conserved domain-based universal influenza vaccines, several challenges remain to be solved: the lower immunogenicity of the conserved regions compared to the variable globular head domain, the incomplete protective efficacy against heterosubtypic strains and the vaccine-induced enhancement of viral diseases . This paHA is a homotrimeric glycoprotein that mediates influenza viral entry via cellular attachment and membrane fusion events ,15. To d21 residue by contacting a larger area using both antibody VH and VK chains, in contrast with the Group 1- or 2-specific bnAbs that use only the VH chain. The results will be conductive to the design of a pan-influenza A universal vaccine by eliciting such antibodies. A highly conserved epitope across all 16 influenza A subtypes and influenza B viruses and its corresponding bnAb CR9114 were also discovered, and its prophylactic efficacy against influenza A and B viruses was evaluated in mice [in vitro assay. However, the passive transfer of the antibody protected the mice from lethal challenges with influenza A and B viruses  or complement-dependent cytotoxicity (CDC), similar to that shown in M2e-based vaccines [in vivo [The first report describing the presence of broadly neutralizing antibodies specific to the HA stalk domain demonstrated that the murine monoclonal antibody C179 recognized the HA stalk domain, thereby inhibiting membrane fusion and neutralizing both H1 and H2 subtypes, even without the HI activity . Subsequ in mice . The CR9 viruses , implyinvaccines ,36,37,38[in vivo . In addi[in vivo ,40,41,42These studies collectively demonstrate that antibodies directed to the conserved regions of HA occur in those who have been exposed to the viruses and that such antibodies confer broadly neutralizing activity against different subtypes of influenza viruses by inhibiting key functions of the HA, such as receptor binding or membrane fusion. The identification and characterization of these bnAbs specific to the HA of influenza A and B viruses not only present therapeutic and prophylactic strategies based on using such monoclonal antibodies, but also provide a basis for the development of a universal influenza vaccine that elicits such antibody responses.Many studies described above have proven the occurrence of bnAbs directed to the conserved HA stalk domain and verified the prophylactic and therapeutic efficacies of such antibodies in passive transfer experiments in animal models ,32,33,34It has been shown that 2009 pdmH1N1 virus infections or vaccinations in humans preferentially induce antibodies with broad specificity to various influenza subtypes, many of which are directed to the HA stalk domain ,47. ConsEscherichia coli expression systems, although their vaccine efficacy remains to be elucidated [E. coli system would be usefully implemented in the production of recombinant universal influenza vaccines, as well as in the evaluation of HA-specific antibody responses induced by the vaccines. Alternatively, viral vector-based delivery of the chimeric HAs using engineered influenza A or B viruses, vesicular stomatitis virus and adenovirus is also able to stimulate the HA stalk-specific antibody responses and provided broad protection against heterologous influenza infections in mice and ferrets [The findings that antibody responses toward the conserved HA stalk domain can be increased through prime/boost vaccinations provide a basis for the development of a universal influenza vaccine based on recombinant chimeric HA proteins that are comprised of the globular head domain and the stalk domain derived from different influenza subtypes . Primingucidated ,56. High ferrets ,52,54, sin vitro assays suggests that shielding immunodominant epitopes in the HA globular head domain by hyperglycosylation could be applied to increase the stalk-reactive antibody responses.There has been convincing evidence that glycosylations in the HA globular head domain modulate the virulence and antigenic properties of influenza viruses. During evolution in humans, influenza A viruses have accumulated genetic mutations at the antigenic sites of HA globular head domain and resulted in changes of the glycosylation pattern, which was shown to be associated with immune evasion or changes in viral antigenicity ,59. MoreAlthough vaccination has been considered the most effective measure against infectious diseases, there have been some reports of rare vaccine-induced enhancement of susceptibility to virus infection or of aberrant viral pathogenesis in humans and animals. Such phenomena were shown to render vaccine-recipients more vulnerable to subsequent viral infection than non-vaccinated subjects, rather than protecting them. Representative examples of the vaccine-induced enhancement of viral infection have been documented in the lentivirus family, including the human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV) and feline immunodeficiency virus (FIV) ,66, and Unfortunately, the VAERD has also been reported in some cases of mismatched influenza vaccine and challenge viruses, especially in swine. Inactivated vaccines of classical swine H1 virus provided protection in pigs against homologous challenges, but failed to protect the animals from challenge with homosubtypic, but heterologous, H1 viruses and enhanced the severity of pneumonia compared to the non-vaccinated control group . In the Although it has been conclusively proven that HA stalk-reactive antibodies are able to neutralize heterologous influenza viruses and can be boosted by repetitive immunizations with a chimeric HA or a hyperglycosylated HA vaccine, their protective efficacy tends to be less potent than conventional globular head-based vaccines. Despite multiple immunizations with those vaccines, immunized animals showed mild clinical symptoms of varying degrees of weight loss and high titers of viruses in their respiratory tracts after lethal challenges with heterologous influenza viruses ,53,54,64The lesser potency of the HA stalk-reactive antibodies could be reasonably attributed to their intrinsic nature. HA stalk-specific antibodies were shown to not only prevent the proteolytic cleavage of the HA0 precursor into HA1 and HA2, but also to stabilize the pre-fusion state of the protein, thereby inhibiting the subsequent fusion process that is essential for the release of viral genome into the cytoplasm for successful infection ,34,83. HAs demonstrated in the swine model, VAERD is closely related with the HA stalk-reactive antibodies as infectivity-enhancing factors that support viral entry into the cells and compromises the neutralizing effect of head-reactive antibodies . AlthougConsidering the relatively weak immunogenicity of the HA stalk domain and, hence, low frequencies of the responsive antibodies, special caution should be given to the potential infectivity-enhancing effect, which could become pronounced against antigenically distant influenza viruses, consequently weakening the protective potency of vaccination. Given that the 2009 pandemic H1N1 infection or vaccination in humans could induce the HA stalk-reactive broadly neutralizing monoclonal antibodies that were as effective as the globular head-reactive antibodies ,91, the Recently, one research group has reported an epitope-focused vaccine design strategy, in which the continuous or discontinuous viral epitopes of RSV or HIV were transplanted into biologically stable scaffold proteins. The resulting epitope-scaffold immunogen complexes, either in monomeric proteins or multivalent virus-like particle (VLP) particles, were able to induce potent neutralizing antibodies in mice and nonhuman primates ,94,95,963 and 104 plaque forming units) of a single immunization with a CAIV or the NS1-truncated virus expressing A/Puerto Rico/8/34 (H1N1) HA did not induce detectable stalk-reactive antibodies in mice, whereas the same infection doses of a wild-type virus could [Despite the recent advances in universal influenza vaccines described above, live attenuated influenza vaccines (LAIVs) remain unexplored. This is possibly due to the relatively low efficiency of the LAIVs in inducing systemic anti-HA antibody responses and a lack of precise immune correlates of protection provided by the LAIVs ,99,100. us could . The resus could ,107. AltGiven that stalk-reactive antibodies can be boosted more efficiently when the HAs expressed by two viruses have different head domains ,48, variIn the last decade, we have witnessed remarkable achievements in controlling influenza virus infections by vaccinations. The highly conserved HA stalk domain of the viruses emerges as a hopeful target for vaccines that would confer broadly protective immunity against various influenza subtypes. Many studies have identified a panel of broadly neutralizing antibodies with specificity to this domain, which provided exciting prospects of a rational design of a universal influenza vaccine that elicits such antibody responses. Along with successful results in broadening protection coverage against diverse influenza viruses, challenging issues still persist, such as incomplete protective efficacy, potentially vaccine-induced enhancement of viral infections and limited protection against different groups of influenza A viruses and influenza B viruses. A better understanding of antigen processing and thepresentation mechanisms of the host immune system, as well as the counteractive evasion strategies of the influenza virus will ultimately guide us toward a truly universal influenza vaccine.


Plasmodium falciparum have become a vital tool to accelerate vaccine and drug development. As CHMI trials are carried out in a controlled environment, they allow unprecedented, detailed evaluation of parasite growth dynamics and immunological responses to infection. Though commonly performed in malaria-naïve populations, CHMI trials have rarely been performed in malaria endemic regions, despite the advantages of early testing of candidate anti-malaria vaccines and drugs in populations where malaria is endemic. To date, modern CHMI studies have not been used to investigate mechanisms of naturally acquired immunity (NAI) to P. falciparum infection.Controlled human malaria infection (CHMI) studies, where healthy volunteers are infected with P. falciparum sporozoites  administered intramuscularly to evaluate safety, infectivity and parasite growth dynamics in healthy Kenyan adults (n = 28). We included adults with varying degrees of prior exposure to malaria in order to allow an evaluation of the effect of NAI on parasite growth dynamics post CHMI.We conducted an open label, randomized CHMI pilot study using aseptic, cryopreserved P = 0.044).All participants developed blood-stage infection, with a similar safety profile to that observed in northern CHMI centres. One volunteer remained asymptomatic and blood-film negative until day 21 post injection of PfSPZ Challenge, despite developing confirmed blood-stage infection by quantitative polymerase chain reaction (qPCR). This volunteer had a notably reduced parasite multiplication rate (1.3) in comparison to the other 27 volunteers (median 11.1). A significant correlation was seen between parasite multiplication rate (PMR) and anti-schizont ELISA OD at screening (P. falciparum malaria.Our study has shown that the PfSPZ Challenge is safe and infectious in malaria endemic populations and could be used to aid early assessment of the efficacy of candidate malaria vaccines and drugs in African populations. Whilst our findings are limited by sample size, our pilot study proves that NAI can impact on PMR post-CHMI in a detectable fashion. Our findings suggest the CHMI sporozoite model could allow identification of a heterogeneous group of participants with varying degrees of NAI for whom the relationship between PMR and candidate assays of blood-stage immunity can be examined to try to gain greater understanding of the mechanisms of NAI to


Environmental barriers increase risk for mobility difficulties in old age. Mobility difficulty is preceded by a phase where people try to postpone a difficulty through mobility modification. We studied whether perceived environmental mobility barriers outdoors correlate with mobility modification and mobility difficulty, predict development of mobility difficulty over a two-year follow-up, and whether mobility modification alleviates the risk for difficulty.At baseline, 848 people aged 75–90 were interviewed face-to-face. Telephone follow-up interviews were conducted one (n = 816) and two years (n = 761) later. Environmental barriers to mobility were self-reported using a15-item structured questionnaire at baseline, summed and divided into tertiles . Mobility difficulty was assessed as self-reported ability to walk 2 km at all assessment points and categorized into ‘no difficulty’, ‘no difficulty but mobility modifications’  and ‘difficulty’.At baseline, 212 participants reported mobility modifications and 356 mobility difficulties. Those reporting one or multiple environmental barriers had twice the odds for mobility modifications and up to five times the odds for mobility difficulty compared to those reporting no environmental barriers. After multiple adjustments for health and functioning, reporting multiple environmental barriers outdoors continued to predict the development of incident mobility difficulty over the two-year follow-up. Mobility modifications attenuated the association.For older people who successfully modify their performance, environmental influence on incident mobility difficulty can be diminished. Older people use mobility modification to alleviate environmental press on mobility. Mobility outside home is a prerequisite for independent living in old age. Mobility modifications are compensatory strategies that enable people to maintain their possibility to move outdoors when experiencing functional decline . These iThe concept of preclinical mobility disability, which is characterised by the use of mobility modifications, was introduced by Fried and colleagues  who founThe environmental docility hypothesis , 10 posiThe aim was to study whether perceived environmental mobility barriers outdoors are associated with mobility modification and manifest mobility difficulty among community-dwelling older people. In addition, we studied whether environmental mobility barriers predict the development of incident mobility difficulty, assessed as difficulty walking 2 km, and whether mobility modification alleviates this risk over a two-year follow-up.We hypothesized that environmental mobility barriers outdoors would correlate with mobility modification and mobility difficulty in walking 2 km and predict incident mobility difficulty over the follow-up , 12, 14.This study was based on cross-sectional analyses of baseline data and prospective annual follow-up data over two-year period gathered in connection with the “Life-space mobility in old age” (LISPE) project. LISPE is a two-year prospective cohort study on the individual and environmental determinants of life-space mobility among community-dwelling older people in central Finland. The study protocol, methods and non-response analyses have been reported in detail previously , 16. BriThe LISPE project was approved by the Ethical Committee of the University of Jyväskylä, Finland. Participants were informed about the project and they signed a written informed consent prior to the baseline interview.Mobility was assessed as perceived difficulty in walking 2 km. The same standardized questionnaire at the baseline face-to-face interview, and telephone interviews at the one-year and two-year follow-ups were used. The participant was asked whether she/he had difficulties in walking 2 km. The response options were: 1) able to manage without difficulty; 2) able to manage with some difficulty; 3) able to manage with great deal of difficulty; 4) able to manage only with the help of another person; and 5) unable to manage even with help. Those who reported being able to manage without difficulty were asked about their use of five different mobility modifications, using a structured questionnaire that has been shown to be a valid instrument for capturing early signs of mobility decline[For the longitudinal analyses, mobility modification was dichotomized (any modification vs. none). Those who did not report difficulties at baseline, but reported manifest mobility difficulty at either the one- or two-year follow-up interview, were categorized as having incident manifest mobility difficulty.Perceived barriers in the outdoor environment were assessed using the “Checklist for perceived environmental barriers to outdoor mobility” (PENBOM), which is a 15-item questionnaire designed to identify environmental barriers (present/absent) that people perceive as hindering their possibilities for outdoor mobility . The perAs covariates, we included variables known to affect mobility difficulty. Age and gender were derived from the national registers. Other information was obtained in the face-to-face interviews at baseline. Years of education was self-reported. Cognitive functioning was assessed with the Mini-Mental State Examination (MMSE) . ParticiPhysical performance was objectively assessed by the Short Physical Performance Battery (SPPB), which cParticipant characteristics are described using means and standard deviations (SD) or percentages in accordance with the baseline mobility categories. Differences between groups were tested with the chi square or one-way analysis of variance (ANOVA). Associations between type of mobility modification and number of environmental barriers were tested with the chi square test.In the cross-sectional setting, multinomial logistic regression analyses were used to study the associations between environmental barriers outdoors and the mobility categories. All the baseline participants (n = 848) were included in these analyses. Nine participants had missing information on physical performance and were excluded from the corresponding analysis. The model was first adjusted for age and gender, after which all the covariates  were included in the second model.In the longitudinal setting, logistic regression analyses were conducted to determine the influence of the environmental mobility barriers on the development of incident mobility difficulty over the follow-up period. In order to study naturally occurring changes in mobility, participants with manifest mobility difficulty at baseline were excluded, leaving 492 participants for the analyses. Of these, 33 had missing information on incident mobility difficulty . Data were not imputed. The logistic regression model was first adjusted for age and gender, after which all the covariates  were included. Finally baseline mobility modifications (dichotomized as any vs. no modifications) were added to the model to study whether it would attenuate the association between environmental barriers and incident mobility difficulty.Analyses were performed using IBM SPSS version 22.0 . When p < .05 or the 95% confidence intervals (CIs) did not include 1, the results were regarded as statistically significant.The mean age of the participants at baseline was 80.6 (SD 4.3), and 62% of them were women. A total of 212 (25%) participants reported mobility modifications and 356 (42%) mobility difficulties at baseline. Those reporting one environmental barrier had 1.7 times, and those reporting multiple environmental barriers had 2.4 times, the odds for mobility modification compared to those reporting no environmental barriers (age- and sex-adjusted). After adjusting for physical performance, several chronic conditions, cognitive functioning, and sociodemographic indicators, the association between mobility modifications and reporting one environmental barrier was at the borderline of statistical significance; however, for multiple environmental barriers the association remained statistically significant. The odds for manifest mobility difficulty were more than five times higher among those reporting multiple environmental barriers .Of those without manifest mobility difficulty at baseline (n = 492), 31% (n = 153) developed manifest mobility difficulty during the 2-year follow-up period. Reporting multiple (≥2) environmental barriers predicted development of mobility difficulty. Adjusting for several covariates did not materially change the result, but adding baseline mobility modifications into the model attenuated the association between the number of perceived environmental barriers and incident mobility difficulty .This study showed that the perception of multiple environmental mobility barriers outdoors increased the risk for incident mobility difficulty and that mobility modification attenuated the association, which is a novel finding. We also found that the perception of environmental mobility barriers outdoors increased the odds for mobility modification among community-dwelling older people, even after taking into account individuals’ health situation.Our findings are in line with those of previous studies showing that environmental barriers precede the development of walking difficulties , 12, 14 As suggested earlier, mobility modification may not always be a response to physical impairment . In the In daily life, environmental characteristics perceived as problematic may hinder the possibility to run daily errands independently , and so The strengths of the study are the large population-based sample of older community-dwelling people and the availability of good quality data. We conducted both cross-sectional and longitudinal analyses on a topic that has not been widely studied and offer novel findings on the relationship between perceived environmental barriers and the compensatory strategies for impaired mobility that older people use in their daily lives. The study also has its limitations. First, it is possible that some people report difficulty already when they have changed their way of doing a task (e.g. do the task more slowly than before), while some understand difficulty as the inability to perform a task . Thus itTo conclude, our findings suggest that for older people who successfully modify their performance, the influence of the environment on incident mobility difficulty can be diminished. Older people use mobility modification to alleviate environmental press on mobility.


The creatine/phosphocreatine pathway plays a conserved and central role in energy metabolism. Compartmentalization of specific creatine kinase enzymes permits buffering of local high energy phosphates in a thermodynamically favorable manner, enabling both rapid energy storage and energy transfer within the cell. Augmentation of this metabolic pathway by nutritional creatine supplementation has been shown to elicit beneficial effects in a number of diverse pathologies, particularly those that incur tissue ischemia, hypoxia or oxidative stress. In these settings, creatine and phosphocreatine prevent depletion of intracellular ATP and internal acidification, enhance post-ischemic recovery of protein synthesis and promote free radical scavenging and stabilization of cellular membranes. The creatine kinase energy system is itself further regulated by hypoxic signaling, highlighting the existence of endogenous mechanisms in mammals that can enhance creatine metabolism during oxygen deprivation to promote tissue resolution and homeostasis. Here, we review recent insights into the creatine kinase pathway, and provide rationale for dietary creatine supplementation in human ischemic and inflammatory pathologies. Creatine (Cr) plays a pivotal role in cellular energy homeostasis, particularly in tissues with highly dynamic energy demands such as the brain, striated muscle and the gut. Within the cell, creatine and its associated enzyme creatine kinase (CK) facilitate the shuttling of high energy phosphates in the form of phosphocreatine (PCr) between sites of ATP generation, i.e. mitochondrial oxidative phosphorylation and glycolysis, and compartmentalized ATP consumption. As such, the Cr/CK system defines an important and highly conserved phosphagen circuit, providing support for mitochondrial respiration and cellular energy turnover by mitigating temporal and spatial imbalances in ATP supply and demand .Vertebrates express four distinct CK isozymes, and patterns of expression vary by tissue and by developmental stage. Cytosolic muscle creatine kinase (CKM) is expressed primarily in sarcomeric skeletal and cardiac muscle cells, while the ubiquitous cytosolic brain isoform (CKB) is found in most non-muscle tissues. Two mitochondrial CK (mtCK) isoforms have also been characterized, namely muscle-specific sarcomeric (smtCK) and ubiquitous mtCK, both of which localize to the mitochondrial intermembrane space . TemporaAll CK isozymes catalyze the reversible transfer of γ-phosphate from ATP to the guanidino group of Cr to generate PCr and ADP, thus mediating efficient cytosolic storage of high-energy phosphates for rapid, focal ATP replenishment. The Cr/CK circuit is tightly linked to mitochondrial structure and energetics, as MitCK is coupled to ATP export via the adenine nucleotide transporter (ANT), and to ATP synthesis and respiratory chain activity. This mitochondrial coupling reduces reactive oxygen species (ROS) generation and inhibits mitochondrial permeability transition, an early event in apoptosis. The Cr/CK reaction also modulates intracellular pH to protect cells from damage associated with internal acidification and ATP depletion , 12. FurDietary Cr supplementation increases the intracellular pool of Cr and PCr available for ATP generation, thereby supporting overall cellular energy homeostasis. As a nutritional supplement, Cr retains an excellent safety profile even in aged individuals with chronic disorders, and has been widely used by athletes in recent decades as an ergogenic aid to improve muscle performance. Additional evidence from recent studies supports the use of Cr supplementation as an adjuvant therapy in a diverse spectrum of disorders, whose central pathologies converge on a dysregulation of cellular bioenergetics. This review outlines our current understanding of the Cr/CK system in cellular energy homeostasis, and discusses recent compelling evidence for the beneficial effects of Cr supplementation in inflammatory and ischemic disorders.S-adenosylmethionine (SAM) as a methyl donor [+ and Cl− -dependent creatine transporter (CrT), encoded by the SLC6A8 gene [The daily Cr requirement for an average 70-kg adult male is approximately 2 g, up to half of which may be derived by intestinal absorption from dietary sources such as meat, fish and other animal products . The remyl donor . Cr biosyl donor , 19. As yl donor . Dietary6A8 gene . Approxi6A8 gene .AGAT, GAMT) and Cr transport (SLC6A8) have been identified and are broadly characterized as Cr deficiency syndromes. Mutations in AGAT and GAMT display an autosomal recessive pattern of inheritance, and deficiency in either of these enzymes manifests in developmental delay or regression, mental retardation, seizures and severe disturbance of expressive and cognitive speech [SLC6A8 gene encoding the Cr transporter are a primary cause of X-linked mental retardation with a prevalence of 2 % in affected males, and have also been described in males with idiopathic mental retardation [Heritable defects in Cr biosynthesis , has recently been identified as a potential candidate for intestinal epithelial basolateral Cr transport [Cytosolic CKB is prominently expressed in smooth muscle and epithelial cells of the human intestine , and immmembrane . The modransport . Alternaransport . Recent ransport . While tIntestinal epithelia that line the gut mucosa constitute the primary cellular barrier against the external luminal environment. This highly dynamic barrier is intricately regulated by myriad factors, including local oxygen tension, to both accommodate nutrient and fluid transport and exclude antigenic material . IntestiCKB and CKM genes emerged as high fidelity HIF-2 selective targets. Likewise, both mitochondrial isoforms of CK as well as the major creatine transporter SLC6A8 were significantly enriched in HIF-2 ChIP. These studies also demonstrated that dietary supplementation with 2 % Cr provided marked protection in two mouse models of experimental IBD.Barrier dysregulation is a prominent determinant of susceptibility to inflammatory bowel disease (IBD). IBD encompasses a spectrum of chronic intestinal inflammatory disorders with increasing global prevalence, with Crohn’s disease and ulcerative colitis comprising the predominant entities . The mucImportantly, intestinal expression of mitochondrial and cytosolic CK enzymes was shown to be attenuated in clinical IBD biopsies. Reduced ATP levels have also been observed in inflamed tissue from patients with IBD , and nonGiven the observation of dysregulated CK bioenergetics in IBD and the intimate integration of intestinal epithelia with mucosal immune cells, an interesting correlate is the influence of Cr and CK on immune cell metabolism and effector function in IBD and other inflammatory diseases. The Cr/CK circuit in intestinal immune cell homeostasis remains largely uncharacterized, but several studies support a central role for Cr signaling in phagocytic function and T cell development. PCr and CK isoforms have been identified in mouse resident tissue and inflammation-elicited peritoneal macrophages, as well as in human monocyte-derived macrophage cultures . CKB actBacillus, Clostridia and Escherichia strains, creatinine is degraded solely to 1-methylhydantoin and ammonia via creatinine deaminase, while in some Pseudomonas, Brevibacterium and anaerobic Clostridia species, 1-methylhydantoin can be degraded further to sarcosine and glycine [The mammalian gastrointestinal tract is host to a diverse microbial ecosystem that helps to shape host immunity and metabolism, as well as support epithelial barrier function. Several lines of evidence suggest that degradation of Cr and creatinine by gut microbiota may impact host physiology and pathology. In contrast to the non-enzymatic conversion of PCr and Cr to creatinine that occurs in vertebrates, a growing number of microorganisms have been shown to express specific enzymes such as creatinine deaminase and creatine amidinohydrolase that mediate creatinine and Cr breakdown. In several  glycine . Studies glycine , 55. Int glycine . This fi glycine , and pro glycine . WhetherOxygen deficit or asphyxia at birth is a significant perinatal complication that can result in neurodegeneration, cognitive and behavioral disturbances or neonatal mortality . SecondaCr is thought to be actively transported across the placenta from maternal circulation during pregnancy, with placental Cr transporter expression evident as early as 13 weeks of gestation . ExpressInitial studies of Cr-elicited protection in neonatal hypoxic/reperfusion injury focused on rodent fetal brain slices , 66 and c release and subsequent caspse-3 activation, possibly via primary buffering of ATP levels [In addition to the fetal neuroprotective effects described above, experimental studies have demonstrated that prophylactic Cr treatment is also widely neuroprotective in adult brain tissue against acute anoxic and ischemic cell damage that occurs in ischemic stroke and other cerebrovascular disorders. Early clinical studies in acute stroke patients revealed depletion of Cr and PCr in infarcted cerebral regions, suggesting that abrogated Cr/CK bioenergetics may contribute to the pathogenic features of ischemic cerebral injury such as acidosis, ROS generation and cell death . StudiesP levels . Mice prP levels .A recent clinical study has now extended these observations to human subjects . Oral CrThe Cr/CK reaction is the major energy reserve of cardiac muscle cells, and myofibrillar ATP delivery is absolutely required to fuel normal contractile function. As such, a prevailing theory of heart failure posits that the failing heart is “energy-starved”. Indeed, impairment of the CK shuttle during heart failure has been recognized since 1939  and reduMyocardial ischemia is characterized by restriction of blood and oxygen supply to the myocardium. In its classic manifestation, cardiac ischemia results from occlusion or narrowing of a coronary artery, inducing tissue hypoxia and rapid depletion of PCr and ATP levels . Stress-Evidence exists to indicate that augmentation of CK and its reactants may prove beneficial in ischemic cardiac disease . Hearts Proof-of-principle experimental studies utilizing knockin mice have also demonstrated that transgenic overexpression of the cardiac creatine transporter or the muscle CK isoform CKM can elicit marked protection against stress-induced heart injury. Creatine transporter overexpression was reported to protect against ischemia–reperfusion injury, with improved cardiac energetics and delayed mitochondrial permeability transition pore opening in response to oxidative stress. Importantly, the extent of myocardial damage was found to negatively correlate with tissue Cr levels . TransgeInterestingly, several studies have implicated the HIF pathway in ischemic preconditioning-mediated cardiac protection from ischemic–reperfusion injury –115 and Although the use of creatine in patients during pregnancy and IBD has yet to be fully evaluated, its profile as a safe nutritional supplement in diverse patient populations is well documented. Creatine has been shown not only to increase muscle mass and prevent age- and disease-related muscle atrophy, but also to enhance overall tissue bioenergetics in a range of pathologies. Clinical evidence strongly supports the profoundly neuroprotective properties of creatine and the beneficial effects of phosphocreatine in cardiovascular stress. Although further work is needed to establish causality, both pre-clinical and clinical studies provide correlative evidence that energetic changes and dysregulation of the Cr/CK pathway are closely linked with the etiology of hypoxic and inflammatory disorders. Altered Cr metabolism by the gut microbiota may define an important influence on the human host creatine pathway, particularly in the context of dysbiosis associated with aging, obesity and IBD. Overall, dietary creatine is a promising candidate as an independent prophylactic treatment or as an adjunct to conventional therapies for ischemic disease.


Optic nerve sheath meningiomas account for only 2 % of orbital lesions and 42 % of optic nerve tumors. Diagnosis remains difficult because histologic confirmation carries a high risk of visual loss. Therefore, a less invasive and specific diagnostic method for differentiating optic nerve sheath meningiomas from other optic nerve lesions is needed to overcome the limitations of computed tomography and magnetic resonance imaging, and make the best individualized treatment decision. This case is a good illustration of the clinical and imaging difficulties inherent in this rare tumor, which may be hard to differentiate from other causes.111In-pentetreotide single-photon emission computed tomography, which is able to bind with very high affinity to somatostatin receptor subtype 2 expressed on meningiomas.A 51-year-old Caucasian woman developed a central scotoma, visual loss, and abnormal visual evoked potentials. The first magnetic resonance imaging scan classified the optic nerve damage as retrobulbar optic neuritis. After magnetic resonance imaging follow-up at 3 months, a negative lumbar puncture and biological workup, and clinical worsening, an optic nerve sheath meningioma was suspected. We confirmed this diagnosis with 111In]-pentetreotide single-photon emission computed tomography-fused magnetic resonance imaging is a valuable additional tool, optimizing the diagnosis and obviating the need for a more invasive procedure.In the diagnosis of optic nerve sheath meningiomas, [ Optic nerve sheath meningiomas (ONSMs) account for 2 % of orbital lesions and are the second most common optic nerve tumors, after optic nerve gliomas –4. Clini111In]-pentetreotide single-photon emission computed tomography/computed tomography (SPECT/CT) in a patient initially followed for a diagnosis of optic neuritis.We present a case of ONSM diagnosed using -pentetreotide and showed an intense uptake in the last third of the intraorbital right optic nerve (Fig. SPECT/CT was performed 24 h after injection of 180 MBq -pentetreotide in the last third of the intraorbital right optic nerve (Fig. 111In]-octreotide. There have also been reports on using somatostatin to treat intracranial meningiomas and monitor the efficacy of the treatment -pentetreotide uptake by ONSMs, and shows the importance of making an early and noninvasive diagnosis compared to other orbital lesions, that is, optic nerve gliomas, optic nerve inflammation, non-Hodgkin lymphomas, vascular lesions, and sarcoidosis -pentetreotide SPECT/CT fused on MRI is a valuable additional tool, optimizing the diagnosis and obviating the need for a more invasive procedure.In the diagnosis of ONSMs, somatostatin receptor subtype 2 detected with [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.


The phenylalanine hydroxylase (PAH) locus has high linkage disequilibrium. Haplotypes related to this locus may thus be considered sufficiently informative for genetic diagnosis and carrier screening using multi-allelic markers. In this study, we present an efficientmethod for haplotype analysis of PAH locus using multiplexing dyes. In addition, we explainhow to resolve the dye shift challenge in multiplex short tandem repeat (STR) genotyping. One hundred family trios were included in this descriptivestudy. The forward primer of a tetra-nucleotide STR and the reverse primer of a variablenumber tandem repeat (VNTR) were labeled with three different non-overlapping dyes5-carboxyfluorescein (FAM), 6-carboxy-N,N,N’,N’-tetramethylrhodamine (HEX) and 6-carboxy-N,N,N’,N’-tetramethylrhodamine (TAMRA). The polymerase chain reaction (PCR)products from each family trio were multiplexed for capillary electrophoresis and resultswere analyzed using Peak Scanner software. Multiplexing trio products decreased the cost significantly. The TAMRA labeled products had a significant predictable shift (migrated at a slower electrophoretic rate) relative to theHEX and FAM labeled products. Through our methodology we achieve, the less inter-dye shiftthan intra-dye shift variance. Correcting the dye shift in the labeled products, according to thereference allele size, significantly decreased the inter-dye variability (P<0.001).Multiplexing trio products helps to detect and resolve the dye shift accuratelyin each family, which otherwise would result in diagnostic error. The dye system of FAM,HEX and TAMRA is more feasible and cheaper than other dye systems. PAH) gene (MIM:612349) is the well-known responsible gene for classic phenylketonuria (PKU). It is the most common inborn error of amino acid metabolism with a prevalence of approximately 1 in 10,000 births among Caucasians  scattered throughout the genomic region, a variable number tandem repeat (VNTR) at approximately 3 kb downstream of the last exon  technology based on automated laser induction of fluorescence polymerase chain reaction (PCR) products, has revolutionized marker genotyping and precise allele sizing. Nevertheless, the most important factors in haplotype analysis according to CE results are accurate allele calling and the expense of the procedure. Multiplexing systems are among the different approaches to reduce the cost. In the case of trio-based studies in which the affected offspring and both parents are evaluated simultaneously, two approaches can be considered. Here, we named them Individual multiplexing system,  versus Trio-based multiplexing system (which relies on mixing the PCR products of trio members). Both systems are based on multiplex dye sets for labelling the overlapping fragments. There are some compatible sets of dyes which can be selected according to the guidelines of capillary instruments, local availability and the price. Each dye set requires its own instrumental spectral calibration. Additionally, fluorescent dyes influence the mobility of PCR fragments during electrophoresis. This may lead to misinterpretation of allele sizing in different ranges  and possBy considering different approaches, in this study, we report an efficient method for familybased indirect genetic diagnosis of phenylketonuria using haplotype analysis, which is based on a multiplex dye system for STR, VNTR fragment amplification in each trio. Also, we overcome the dye shift challenge confounding accurate genotype calling. DNA samples of one hundred family trios consisting of Iranian PKU patients and healthy controls were included in the study. The study was a descriptive study and approved by the Research Ethics Committee of Tehran University of Medical Sciences. All subjects and their parents provided informed consent. All DNA samples were genotyped for both the intronic STR (TCTA)n and the 30 bp AT rich 3´-flanking VNTR. Three different non-overlapping dyes were selected for labelling the forward and reverse primers of the STR and VNTR fragments respectively as follows: The FAM labeled primers were used for amplification of the offspring genomic DNA and the HEX and TAMRA labeled primers were used to amplify the paternal and maternal markers respectively. The selected size standard for fragment analysis was LIZ labeled. Primer sequences were described previously ,10. Amplification was performed in the ABI thermal cycler with denaturation at 95˚C for 5 minutes, followed by 37 cycles of 95˚C for 30 seconds, 60˚C for 30 seconds and 72˚C for 30 seconds, and a final extension of 72˚C for 7 minutes using Taq DNA Polymerase 2x Master Mix . PCR products were examined by electrophoresis on a 1.5% agarose gel. For each family trio, 5 µl of each PCR product was mixed to run one single fragment analysis reaction using the Applied Biosystems 3137 Genetic Analyzer. Capillary electrophoresis was provided by Pishgam. Biotech Company (www.pishgambc.com). Genescan results were analyzed by Peak Scanner Software v 1.0. Dye shift analysis was based on evaluating two parameters: the inter-dye shift between FAM, HEX and TAMRA within each run, and the intradye shift of each dye among runs. The expected size of each allele, referred to as the "reference allele size", was taken from the human reference genome, GRCh38.p2 assembly. The accuracy of microsatellite allele sizing was confirmed in each family by comparing the results of the parents and the offspring. The validity of the sequences and core repeats was confirmed by Sanger sequencing in some families. The differences between the dye labeled product size  and the reference allele size for each allele was calculated (dye shift) and the mean size differences were then used as the basis of correction. The polynomial regression equations which relate the observed allele size to the correction coefficients were calculated (http:// www.arachnoid.com/polysolve). For correction, the "calculated correction coefficient" related to each observed allele was subtracted from the observed allele size. In order to determine the intra-dye shift variability we calculated the dye shift standard deviation (SD) within each dye per allelic size. Likewise, the inter-dye shift variability was analyzed between dyes for each trio per allelic size. For efficacy analysis the comparator method was genotyping with a single dye and multiplexing the products of each trio member separately. According to normal or abnormal distributions, groups were compared by parametric or nonparametric tests. Friedman test was used to examine the significance of inter-dye variability. To determine the relationship between reference allele size and dye shift, correlation analysis was done. For statistical analysis, SPSS version 16 software was used and P<0.01 was considered significant. Here, to determine the haplotypes of all trio members in one electrophoresis run, labeledprimers with one of three different fluorophore  were selected for DNA amplification of each family member. STR and VNTR amplified fragments, were labeled with the same dye set given their non-overlapping allele size range. There were some variations in allele sizing among the three dyes, but the most significant difference was observed between TAMRA when compared with both FAM and HEX. In order to validate the allele sizing and overcome the dye shift errors, the mean size of differences with respect to each reference allele was assumed as the correction coefficient for that reference allele size. The polynomial regression equations were then used to facilitate calculating the correction coefficients for the observed alleles . AccordiFurthermore, our data represented a significant correlation between the dye shift and the allelic size before correction (P<0.001) which resolved after shift correction (P>0.05). In tetra-nucleotide STR repeats with less than 300 bp length there was a significant negative correlation between reference allele size and the dye shift in all dye labeled products  but in thirty-nucleotide VNTR repeats with size ranging from 300 to 600 bp, there was a positive correlation which was significant only in FAM and HEX labeled products . MoreoveHere we suggest a more cost-effective and feasiblemultiplex dye set for multi-allelic marker genotypingin trios studies based on FAM, HEX and TAMRAfluorophore labelling and fragment analysis. Usingthis dye set in a pedigree-based study, we demonstrated a size-dependent dye shift which evidently can beresolved.In addition to determining the origin of mutationsand allele distributions in different populations, PAHmini-haplotyping is an informative indirect methodfor genetic diagnosis and carrier screening of PKUpatients. It will be applicable particularly in familieswith one affected individual referred for genetic analysis and facilitates pre-implantation genetic diagnosisand prenatal diagnosis.Capillary electrophoresis is the gold standard method in marker genotyping, nevertheless, there are somesources of errors that needs to be minimized, such as,sampling errors, genotyping errors, including allelicdropout and null alleles , 12 alonFurthermore, reducing the overall cost is anotherconsideration. This would be achieved by differentmultiplexing systems based on PCR multiplexing orpost-PCR multiplexing -also named pseudo-multiplexing or poolplexing . FurtherThe trio-based multiplexing system, based on using a distinctive fluorophore primer for each memberof the trio, enables simultaneous haplotype analysis.Such trio multiplexing can effectively increases theaccuracy of analysis while reducing time. We usedpolynomial regression equations based on our data topredict correction coefficients which can be used incombination with other allele sizing softwares. Thisinevitably facilitates allele sizing and increases accuracy .Despite the fact that ordering three different labeledprimers for each locus seems to increase the cost, reducing the cost per run for each family decreases theoverall price dramatically, and subsequently makesit a cost-effective approach, particularly for centerswhich offer PKU genetic testing and prenatal diagnosis (PND) or preimplantation genetic diagnosis(PGD) services.Also, trio multiplexing results in detection and resolving the dye shift error in each family. Correcting the labeled fragments allelic size using correctioncoefficients can significantly decrease the inter-dyeshift. There are limited number of studies which explore the FAM, HEX and TAMRA dye set mobilityshifts , 17, 18.More detailed investigations showed that thestructure of the attached dye influences the effective charge of the fragment and its molecularmigration through the capillary media. Dyes withmore negative charges migrate faster. However,the relative fluorescent dye charge is the predominant factor in determining DNA mobility, eventhough it can be influenced by dye-DNA base interactions .With respect to capillary electrophoresis instruments, different specified dye sets can be selected for primer labelling. Here we showed that the  set can be used appropriately in replace of  usual dye set in combination with the LIZ size standard. Due to the similarity of spectral characteristics of dyes, the more cost-effective TAMRA dye, can be an alternative for NED while also being compatible with the same matrix standard used for spectral calibration of the instrument . Combination of length, sequence and physicochemical properties of the fluorophore label, determine the migration behavior of each fragment in denaturing CE. So in the case of similar length and sequence, in 100 family trios we can determine the TAMRA labeled products discrepancy in comparison with FAM and HEX ones, and overcome this dye shift error, which can disturb allele sizing specifically in di-nucleotide STR genotyping and leads to diagnostic error. It is worth to mention that identification of all genotyping errors and the nature of the errors might not be possible all the times . In this study, we show that trio-based analysis in a single capillary electrophoretic run may decrease the testing costs and significantly facilitate the analysis when using the method in a diagnostic referral laboratory. As well as reducing the cost, we also demonstrate that the trio-based multiplexing system, after correction , leads to more accurate haplotype analysis. Eventually, all individual haplotypes were determined according to the corrected data for further investigations. Furthermore, the suggested correction coefficients for each allelic size could be considered as an adjustment for genotype calls of every repeat length polymorphic marker with capillary electrophoresis.


Survival during starvation depends largely on metabolic energy, which is stored in the form of neutral lipids in specialized organelles known as lipid droplets. The precursors for the synthesis of neutral lipids are also used for membrane biogenesis, which is required for cell growth and proliferation. Therefore cells must possess mechanisms to preferentially channel lipid precursors toward either membrane synthesis or lipid droplet storage, in response to nutrient status. How this partitioning is spatially regulated within the endoplasmic reticulum (ER) where lipid droplets co-localize, remains poorly understood. We have recently shown that at the onset of starvation lipid droplets concentrate at a perinuclear ER subdomain flanking the nucleus-vacuole junction (NVJ) and that this is crucial for maintaining proper nuclear shape and ER membrane organization. Here we show that disruption of the NVJ does not block the translocation and internalization of lipid droplets into the vacuole for their degradation, which takes place at later stages of starvation. We propose that alternative pathways of lipid droplet translocation from the ER to the vacuole may exist to enable stationary phase-induced lipophagy. Eukaryotic cells store fatty acids (FAs) as inert triacylglycerols or steryl esters  in ubiquitous organelles called lipid droplets (LDs).Saccharomyces cerevisiae, lipolysis is mediated by the LD-associated triacylglycerol lipases Tgl3, Tgl4 and Tgl5 and the steryl ester lipases Tgl1, Yeh1 and Yeh2.In de novo biosynthesis of FAs.atg15Δ mutant.The subsequent release of lipid constituents from internalized LDs during nitrogen starvation-induced lipophagy requires the putative lipase Atg15, which also degrades other autophagic and cytoplasm to vacuole targeting (Cvt) bodies. This activity is important for growth under conditions of compromised +-dependent phosphatidate phosphatase that plays a major role in triglyceride synthesis.NEM1.Since LDs must interact with the vacuolar membrane to be internalized, their spatial organization at the onset of lipophagy may define the mechanism of neutral lipid mobilization. We have recently shown that, as cells face starvation during glucose exhaustion, the biogenesis of LDs takes place at the perinuclear ER flanking the nuclear vacuole junctions (NVJ),NVJ1 mRNA levels increase and the contact site enlarges in stationary phase.NVJ1 does not compromise the formation of the vacuolar membrane microdomains. For example, nvj1Δ cells show the distinctive quasi-symmetrical segregation of Vph1-mCherry (nvj1Δ cells). As in wild-type cells, in cells lacking NVJ1 a clear accumulation of BODIPY-stained LDs is observed in the vacuole (ATG15 that, by preventing the degradation of LDs in the vacuole, facilitate the detection of lipid (During stat-phase lipophagy, LDs must migrate from the perinuclear ER to the vacuolar membrane. It is, therefore, reasonable to speculate that, by keeping the nucleus and vacuole in close proximity, NVJ may promote the movement of LDs. In fact,  vacuole . Similarof lipid .Figure nvj1Δ cells, however, does not exclude a role for other ER-vacuole contact sites in the passage of LDs to the vacuole. Recent studies have identified additional protein components of ER-vacuole contact sites, which are not restricted to the perinuclear ER;NVJ1.nvj1Δ cells (Previous work has shown that loss of Nvj1 disrupts the nucleus-vacuole contact.1Δ cells , which cThe spatial organization of FA storage may have also important implications for the regulation of organelle structure. Recruitment of Pah1 in close proximity to LDs ensures that its product, diacylglycerol, is acylated with FAs so that the resulting triacylglycerol is efficiently stored in LDs. Such metabolic channeling is important because diacylglycerol can be also used for phospholipid synthesis. Consistent with this model, in the absence of LDs or triacylglycerol-synthesizing enzymes, Pah1 is still recruited to the nuclear membrane but diacylglycerol is redirected toward phospholipids, resulting in nuclear shape deformation and ER membrane expansion.


Chronic post-hypoxic myoclonus, also known as Lance-Adams syndrome (LAS) is a neurological complication characterized by uncontrolled myoclonic jerks following cardiac arrest. In this article, clinical manifestation and symptomatic treatment options are discussed especially concerning the rationale of use of levatiracetam in patients with Lance-Adams syndrome. Clinical presentation is action myoclonus associated with cerebellar ataxia, postural imbalance, and very mild intellectual deficit. An 18-year-old female patient was admitted to our intensive care unit in a coma. She had a cardiorespiratory arrest after a splenectomy in a local hospital. Then, myoclonic movements were continuously observed over the entire body, including the face.On day 14 of hospitalization, we started levatiracetam 1000 mg daily. The frequency of convulsion movements was reduced. The patient level of consciousness was 15 on the Glasgow coma scale (GCS) on the Mini-Mental State Examination (MMSE) score was 23 out of 30. She was later transferred tothe rehabilitation department. Vigilance is required to ensure early diagnosis and timely intervention for the myoclonic jerks. We would like to emphasize that LAS should be considered in patients with the myoclonic jerks following cardiac arrest and that levatiracetam therapy may be useful as treatment.  Post-hypoxic myoclonus (PHM) is a neurological complication characterized by uncontrolled myoclonic jerks following cardiac arrest. Two types of PHM, acute and chronic, occur in patients with hypoxic injury of the brain. Chronic PHM, also known as Lance-Adams syndrome (LAS), first described in 1963, is a condition characterized by development of chronic post-hypoxic action myoclonus due to a temporary lack of or inadequate brain oxygen supply . ClinicaAn 18-year-old female patient was admitted to our intensive care unit in a coma. The past medical history of the patient was normal without any additional problems. She had a cardiorespiratory arrest after a splenectomy in a local hospital. On day 3 of hospitalization, she developed a generalized seizure in the intensive care unit after discontinuing an intravenous infusion of midazolam (5 mg per hour) and fentanyl (100 μg). Then, myoclonic movements were continuously observed over the entire body, including the face. Cranial computed tomography (CT) scans, T1 and T2 weighted MR imaging, and DW imaging showed no abnormality . Seven dAN electroencephalography (EEG) performed at this time demonstrated frequent myoclonic polyspikes but did not confirm myoclonic status . She conLance-Adams syndrome (LAS) was first described in the 1960s by Lance and Adams. Clinical presentation is action myoclonus associated with cerebellar ataxia, postural imbalance, and very mild intellectual deficit.Myoclonic jerks are specifically triggered by action and tactile stimulation. They usually disappear with relaxation of the body. Diagnostic imaging tests such as CT or MRI of the brain are not helpful to make a diagnosis of LAS. Neuroimaging, such as brain singlephoton emission computed tomography (SPECT) or brain positron emission tomography (PET) has recently shown anatomical and pathophysiological basis of LAS . AlthougThe neurotransmitters related to LAS are known to be serotonin and gamma-aminobutyric acid (GABA). The loss of serotonin within the inferior olive nucleus has been thought to play some role and GABA may interact with the serotonin system to suppress post-hypoxic myoclonus .Vigilance is required to ensure early diagnosis and timely intervention for the myoclonic jerks. In conclusion, we would like to emphasize that LAS should be considered in patients with the myoclonic jerks following cardiac arrest and that levatiracetam therapy may be useful as treatment.


Studies of human emotion perception have linked a distributed set of brain regions to the recognition of emotion in facial, vocal, and body expressions. In particular, lesions to somatosensory cortex in the right hemisphere have been shown to impair recognition of facial and vocal expressions of emotion. Although these findings suggest that somatosensory cortex represents body states associated with distinct emotions, such as a furrowed brow or gaping jaw, functional evidence directly linking somatosensory activity and subjective experience during emotion perception is critically lacking. Using functional magnetic resonance imaging and multivariate decoding techniques, we show that perceiving vocal and facial expressions of emotion yields hemodynamic activity in right somatosensory cortex that discriminates among emotion categories, exhibits somatotopic organization, and tracks self-reported sensory experience. The findings both support embodied accounts of emotion and provide mechanistic insight into how emotional expressions are capable of biasing subjective experience in those who perceive them. The perception of emotion in others often results in related sensory experiences in oneself, which is thought to facilitate the social spread of emotions. Using functional neuroimaging, we have discovered a neural mechanism capable of explaining how percepts of emotion bias subjective experience. We show that activity in right somatosensory cortex can be used to classify emotions conveyed in facial and vocal expressions. Importantly, the capacity of this region to predict perceived emotions in others correlates with reports of subjective experience generated by the expressions in oneself. The results reveal a novel, specialized role for the somatosensory cortex in linking emotional perception with subjective sensory experience.During social interactions, humans recognize emotions from facial and vocal cues with seemingly little effort. Often, the perception of emotions in others leads to the spread of emotional behaviors, such as crying and laughter . SimulatDamage to or inactivation of right somatosensory cortex disrupts the recognition of emotion from facial  and vocaTo bridge this conceptual gap, we conducted a functional magnetic resonance imaging (fMRI) experiment in which participants were presented with facial and vocal expressions of discrete emotions and made on-line ratings of their own subjective experience in response to these percepts. This procedure offers insight into how emotional expression perception alters sensory experience as a component of affect, although emotional events occurring in everyday life or those elicited by laboratory mood inductions generally yield more rigorous, full-blown emotional experiences. Given that expressions of emotion lead to the convergence of facial configuration and shared mood , we expeMage = 26 years, age range = 19–39 years, 11 males) completed the study. One additional participant was run in the experiment, but was excluded from analysis due to excessive head-motion during scanning . All participants provided written informed consent to participate in accordance with the Duke University Institutional Review Board and received $20/h as monetary compensation.Twenty-one healthy, right-handed individuals .The stimuli used included standardized images of faces  and audiDuring the self-report phase, the Geneva Emotion Wheel  was preshttp://www.vislab.ucl.ac.uk/cogent.php). Participants viewed stimuli on mirrors aligned with a LCD screen upon which images were projected from a stimulus control computer. Audio stimulation was presented using MR-compatible headphones (Resonance Technology).Presentation of stimuli and acquisition of behavioral responses were controlled using Cogent 2000 software  for coregistration with the functional data. Structural images were aligned in the near-axial plane defined by the anterior and posterior commissures. Whole-brain functional images were acquired using a spiral-in pulse sequence with sensitivity encoding along the axial plane . The first five images of each run were excluded from analyses to ensure the magnet had reached steady state.Scanning was performed on a 3 Tesla General Electric MR 750 system with 50-mT/m gradients and an eight-channel head coil for parallel imaging . Structural images were acquired using a 3D fast SPGR BRAVO pulse sequence: repetition time (TR) = 7.58 ms; echo time (TE) = 2.936 ms; image matrix = 256http://dbm.neuro.uni-jena.de/vbm.html). Functional data were not spatially smoothed.Processing of MR data was performed using Statistical Parametric Mapping software . Functional images were slice-time-corrected, spatially realigned to correct for motion artifacts , coregisx, y, and z dimensions) and session constants, were incorporated into the model.Whole-brain patterns of neural activation were estimated using the general linear model approach implemented in SPM8. For each subject, blood oxygen level-dependent (BOLD) responses were modeled by convolving box-car functions with a canonical hemodynamic response function separately for each trial. One additional regressor modelling the self-report phase was included in each run. To model nuisance effects, six motion parameters , medial orbitofrontal cortex, inferior frontal operculum, fusiform gyrus, amygdala, and insula. For motor control analyses and lateralization tests, masks for left and right precentral and left postcentral gyrus were additionally used.Anatomical masks were created for brain regions implicated in a neural network model of emotion recognition  using thC and γ, and the outer folds were used to provide cross-validated measures of accuracy. Because distributions of classification accuracy typically violate the assumptions of parametric tests, one-tailed Wilcoxon sign-rank tests were performed for group inference. To examine which cursor locations led to the prediction of each expression, one-sample t tests were performed across subjects on SVM decision values for all coordinates in the grid.Cursor locations  were used to predict the emotional content of stimuli. This data-driven approach was employed because it does not assume fixed stimulus–response mappings for all subjects and provides classification weights to assess the consistency of mappings. Because the self-report format was circular in nature, classification was performed using support vector machines (SVMs) with a radial basis function as implemented in LIBSVM . As curshttp://www.libpls.net). This method was selected because it effectively reduces the dimensionality of data, decreasing chances of overfitting.Decoding of neural activity was performed via PLS-DA  using thClassification was performed using trials including both facial and vocal expressions, in order to identify emotion-specific patterns of neural activity that generalize across modalities. This approach is well suited to identifying embodied representations of emotion because it discourages learning low-level features of expressions . Thus, the learning scheme emphasizes information that is independent of stimulus modality and should be more sensitive in detecting somatic states associated with facial and vocal cues. To ensure that the classifier was not biased toward stimuli of one modality, accuracies were compared for facial versus vocal expressions of emotion.Classification of multiple categories was performed using a winner-takes-all approach, wherein one class is classified against all others. Because this approach creates an uneven proportion of classes (1:5), a weighted approach was taken for discriminant analysis to minimize bias due to class imbalance. Input data  were mean-centered before conducting the analysis. The number of latent variables was fixed at 1, to reduce the complexity of the model, simplify interpretation of model coefficients, and maximize the amount of data available for training and testing. Classification was performed separately for each subject, using cross validation . Randomization of single trial estimates in the wavelet domain  was condt distribution (two-tailed), with FDR correction for multiple comparisons. To identify which region best characterized individual differences in self-report ratings, linear regression models predicting the accuracy of self-report from accuracy of neural classification were estimated, and model log-likelihoods were used to compute Bayesian Information Criterion  versus upper  portions of the face  at the gp < 0.05 and extent of 21 voxels, which we determined to control the false-positive rate at α < 0.05 using Monte Carlo simulations on the present data a , compared to chance levels of 16.67% i–o, indicating that learning was not generally biased toward either modality.To examine whether regional patterns of fMRI response discriminated among perceived emotions, we conducted multivoxel pattern classification on data from brain regions implicated in a neural network hypothesized to be critical for the recognition of emotion : postcenpadj > 0.09)p–u. Given evidence specifically implicating the right somatosensory cortices in emotion recognition v.Although the right postcentral gyrus exhibited the highest accuracy level at 19.9 ± 0.75% (mean ± SEM), follow-up comparisons did not reveal significant differences between right somatosensory cortex and any other region-of-interest  = 3.15)w whereas the other was restricted to BA 2  = 3.65)x. The localization of these peaks is consistent with studies localizing oral and facial ; two clusters were never observed (p = 0.00001). These results demonstrate that expressions of happiness and surprise, compared to fear and anger, were predicted by activity in two distinct clusters in the postcentral gyrus.Because prior research has shown that happiness and surprise contain more distinctive information in lower regions of the face, we speculated that expressions of happiness and surprise would have larger classification weights than those of fear and anger, which contain more distinguishing information in upper portions of the face . This exd facial  represenper se , we next tested whether individual differences in the accuracy of neural classification correlated with those of self-report. We found that the degree to which individuals reported distinct sensory experiences was uniquely associated with the information content of patterns spanning the full extent of postcentral gyrus z, which did not significantly differ from classification accuracy based on stimulus categories, aa. To assess the extent to which classification utilized independent information, the correlation between classification weights from objective and subjective models was computed within subjects and averaged across all six emotions. This analysis revealed a moderate correlation bb, suggesting that subjective experience and objective stimulus category are reflected in at least some shared variance in somatosensory response patterns, although the amount of reliable, unique variance attributed to each remains to be determined.To dissociate subjective representations elicited by the stimuli from simple encoding of emotion categories, we constructed classification models to predict emotion categories defined on the basis of self-report. Classifying somatosensory activity using self-report ratings in lieu of stimulus categories produced similar results: mean accuracy was 19.74 ± 0.82% cc, making it unlikely that motor activity in preparation of moving the joystick drove results. Additionally, activity in this region was not associated with self-report dd. Although voxel patterns in right motor cortex were found to predict the emotional content of stimuli with 19.0 ± 0.59% accuracy ee, they did not correlate with experiential ratings ff. Bayesian analysis revealed the association between the accuracy of self-report and neural activation within somatosensory cortex was much more likely than for classification of left or right precentral gyrus activity .Given the strong interconnections between corresponding sensorimotor areas of precentral and postcentral gyrus, and evidence that neurons in both cortical areas respond during motor or sensory behavior , we condOur results demonstrate that patterned activation within somatosensory cortex contains information sufficient for the decoding of perceived emotional categories. Such refined discrimination of nontactile stimulation within somatosensory cortex runs contrary to the classic view that the region is a unimodal sensory area and suggests that visual and auditory signals modulate neural activity at early stages of cortical processing in this region . AdditioIn an exploratory analysis, we found that emotion-predictive patterns within postcentral gyrus exhibited somatotopic organization, suggesting that information related to body states contributed to the decoding of emotional expressions. This result is concordant with evidence that emotions are associated with categorically distinct bodily sensations . FurtherTopographically organized somatosensory activation has been documented during the observation of touch , during Beyond predicting the emotional content of stimuli, we found that somatic representations of perceived emotions uniquely correlated with the extent of experiential mirroring across individuals. The fact that this correlation was selective to somatosensory cortex suggests that factors influencing global levels of neural activity, such as arousal or attentiveness, were not likely the source of individual differences because they would lead to enhanced discriminability in other brain regions. Our observation of experiential mirroring is consonant with behavioral studies showing the perception of emotional expressions leads to facial mimicry and congruent self-reports  and furtGiven that emotions serve action preparation functions and involve motor feedback, it is important to consider the potential role of these functions as an explanation for the somatosensory findings. The observation that emotion-predictive patterning in primary motor cortex was not associated with behavioral self-report suggests that facial mimicry or other forms of motoric engagement, while potentially contributing to emotion recognition, was not likely responsible for the convergence of perception and subjective experience in the right postcentral gyrus. However, future work more precisely monitoring facial muscle activity will be necessary to definitively resolve this issue. Although null results should be interpreted with caution, this finding is in accordance with other studies that failed to identify a correspondence between facial mimicry and emotional feelings . By linkIn addition to primary somatosensory cortex, we found that patterns of BOLD response within a number of regions implicated in emotion recognition predicted the emotional content of stimuli, but were not associated with individual differences in sensory experience. These regions are thought to process distinct kinds information associated with emotional expressions . The orbOur methodological approach serves as a template for subsequent work examining the role of somatic states in socio-emotional behavior. Independent characterization of somatotopy at the single-subject level  using hi


We report the case of a patient who had a non-functional metastatic pancreatic neuroendocrine tumour (pNET), which changed in functionality during the course of the disease. This case demonstrates the effectiveness of conventional cytotoxic chemotherapy in the management of select group of patients with this rare, challenging condition.Our patient was a 34 year old man under oncology follow up, diagnosed with a non-functional metastatic pancreatic neuroendocrine tumour treated with a Whipple’s procedure two years ago. Despite treatment with somatostatin analogues and sunitinib, a tyrosine kinase inhibitor, he had demonstrated radiological progression of his metastatic disease. He now presented with a short history of Cushing’s syndrome. A presumptive diagnosis of a rapidly progressive, metastatic, functional pNET with ectopic ACTH production was made, confirmed biochemically and with liver biopsy. The proliferative index, Ki-67 of 20% of the liver biopsy prompted us to treat him with conventional cytotoxic chemotherapy using streptozocin, 5-fluorouracil and doxorubicin. Prior to its administration clinical and biochemical control of the hypercortisolemic state was achieved with metyrapone. However the clinical, biochemical and radiological response to chemotherapy was so dramatic obviating the need for metyrapone therapy.Non-functional pNETs may evolve in their clinical and biologic behaviour producing functional hormonal syndromes. Chemotherapy may be an effective therapeutic modality in such circumstances. ACTH secretion in functional pNETS is rare and it is even more rare for non-functional pNETs to evolve into ACTH secreting functional tumours with only very few cases reported in literature. We describe such an interesting and rare case of evolution in functionality of a non-functional pNET. Apart from control of hypercortisolaemic state, preventing disease progression can be a real challenge despite various therapeutic modalities being increasingly used in the last decade. We report the case of a young patient who had a non-functional pNET, which later started secreting ACTH, highlighting the importance of being very vigilant during the follow up of such patients. Despite novel chemotherapeutic options and PRRT (Peptide Receptor Radionuclide Therapy), conventional chemotherapeutic agents still have a very important role and should be tried if the above agents fail to control disease state as demonstrated by our case.We report the case of a 34-year-old man who presented with a one-month history of lethargy, generalised upper and lower limb weakness and significant weight gain. He had been recently diagnosed with type 2 diabetes mellitus and initiated on pre-mixed insulin injections 30 units twice daily (HbA1c 85 mmol/mol).He had been diagnosed with a pancreatic neuroendocrine tumour (pNET) two years previously, having presented with jaundice and abdominal pain. An abdominal CT had demonstrated tumour in the head of the pancreas with loco-regional metastases (peripancreatic lymph nodes and nine hepatic metastatic lesions varying in size from 7–18 mm) for which he underwent a Whipple’s procedure with resection of lymph nodes and an intra-operative liver biopsy. Measurement of a full fasting gut hormone profile showed elevated chromogranin A but was otherwise normal, consistent with a non-functional tumour. Immunohistochemistry of the pancreatic specimen was positive for chromogranin and synaptophysin with a Ki-67 index of 2% confirming the diagnosis of a Grade 2 pNET (ACTH staining not performed); the liver biopsy appearances were similar morphologically. A careful family history of endocrine tumours or endocrine disorders had been unremarkable.On follow up imaging he had developed further liver metastases, so was commenced on a long-acting somatostatin analogue (Lanreotide), for its anti-proliferative potential, and a tyrosine kinase inhibitor (Sunitinib) was thereafter added upon evidence of further radiological progression.111In-labeled octreotide scanning demonstrated somatostatin receptor positive disease in five of his liver metastatic deposits but not in any other sites . Basal pituitary biochemistry and gadolinium enhanced MRI imaging was otherwise unremarkable. MRI scan of the liver revealed solid and cystic metastatic deposits ranging between 7.8-9.2 cm in segments 6, 7 and 8 indicating further progression despite sunitinib.A diagnosis of a rapidly progressive, functional, metastatic pNET with ectopic ACTH production causing Cushing’s syndrome was made, with an assumption that the tumour had evolved in its functionality from its previous non-functional status. Treatment options discussed at the supra-regional multidisciplinary team meeting (ENETS Centre of Excellence) considered metyrapone, bilateral adrenalectomy, peptide receptor radionuclide therapy (PRRT) or cytotoxic chemotherapy. Mutational analysis of the gene for multiple endocrine neoplasia type 1 (MEN 1) was negative.A repeat liver biopsy was performed to provide an accurate histological grade of the liver metastases, on the premise that primary NETs, and their synchronous/metachronous metastases, frequently differ in grade and proliferative index (Ki-67). Immunohistochemistry was strongly positive for chromogranin and synaptophysin with a Ki-67 index of 20% (ACTH staining not performed)  or may stain positively on immunohistochemistry for certain hormones.The most common functional pancreatic NET syndromes relate to insulinoma and gastrinoma. ACTH secretion occurs only rarely, presenting with features of Cushing’s syndrome, but more than 95% are malignant with an average age at diagnosis of 50–55 years and an equal sex distribution. Functioet al., 24 patients demonstrated de novo evidence of secretion of a second hormone during the course of the disease (median delay of 19 months and 92% reflecting liver metastases)[de novo Cushing’s syndrome, highlighting evolution in tumour functionality should be considered during follow up of patients with pNETs.Even more rarely, initially non-functional pNETs have been reported to evolve into functional tumours. In a series of 353 patients described by Wynick Treatment aims are twofold involving biochemical control of hypercortisolaemia and preventing disease progression. Adrenal blocking agents like metyrapone, or bilateral adrenalectomy in patients who fail to respond to metyrapone therapy, may be used to address hypercortisolaemia. Medical treatment of the neuroendocrine tumour may involve long acting somatostatin analogues (SSA) or occasionally alpha interferon may be effective. Surgery is recommended even in the presence of metastatic disease, including localized liver metastases, if potentially resectable, and symptomatic control of the hormone excess state through cytoreductive surgery or radiofrequency ablation. However, our patient had large, multiple liver metastatic deposits and hence surgery was not deemed to be an option.In patients with advanced, surgically non-resectable, progressive pNETs, everolimus and suniThis clinical case offers several important learning points. Firstly, there should be vigilance to the possibility of an evolution or change of functionality of pNETs, during tumour progression, particularly in non-functional pNETs considering their pluripotency with awareness of the various clinical syndromes that may arise. Secondly, repeat histological examination of metastatic deposits may indicate different biological behaviour of the tumour and this may modify the treatment regime. In the case described, we observed the evolution towards Cushing’s syndrome from a non-functional tumour, with repeat histological findings modifying our treatment approach and facilitating effective treatment with chemotherapy. The different proliferative potential may represent inherent heterogeneity within the tumour or across different anatomical sites but may reflect evolution in the histology towards a higher grade.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 of this journal.pNET: Pancreatic neuroendocrine tumour; PRRT: Peptide receptor radionuclide therapy; MEN: Multiple endocrine neoplasia; SSA: Somatostatin analogues; ACTH: Adrenocorticotrophic hormone.The authors declare that they have no competing interest.SPR drafted the initial manuscript, which was revised by DJC and CD. SM was involved in the management of our patient and helped in preparing the manuscript. MT performed the immunohistochemistry. DHP was involved in the oncological management and helped in the revision of the script. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6823/14/70/prepub


Chordoid glioma (CG) is a rare central nervous system neoplasm (WHO grade II) of uncertain origin whose typical localization is in the anterior part of the third ventricle. Its clinical, radiological, and histological features may vary and furthermore mimic other kind of benign lesions usually associated with a better outcome. We report a case of a 43-year-old female who underwent gross total removal of a lesion of the third ventricle causing hydrocephalus. The imaging studies and the intraoperative examination led at first to a hypothesis of meningioma. Early surgical and neurological outcomes were good. The patient underwent multiple complications related to hypothalamic dysfunctions and thrombohemorragic issues and eventually died because of systemic infections. Definitive examination was of chordoid glioma of the third ventricle. Reviewing literature, we evaluated possible pitfalls in radiological and histological diagnosis as well as in surgical and medical treatment of CGs. Despite their benign presentation, a high incidence of multiple possible severe complications is reported. Early alertness and combined treatment strategies could improve overall CGs treatment strategies. Chordoid glioma is a rare glial neoplasm firstly labeled as a new pathologic entity by Brat et al. in 1998 . World HEscherichia Coli urinary infection she became drowsy. A CT scan showed no anomalies. Hormonal routine revealed diminished thyroid-stimulating hormone (TSH) levels . She presented a single partial seizure  after which she reverted to hyponatremia (128 mEq/l). At the end of the first week post intervention, she developed deep vein thrombosis in the right popliteal district. Therapeutic low molecular weight heparin therapy was administered; no indication of inferior vena cava filter placement was posed. The patient remained drowsy and once again presented tendency to hypernatremia. A MRI scan 20 days post-op was performed showing gross total removal of the tumor, heterogeneous density in the surgical field, small subacute ischemic lesions of the right caudate nucleus and of the left thalamus. She suffered from an acute onset of dyspnea and desaturation, so she underwent a chest CT scan showing bilateral pulmonary thickening in absence of frank signs of pulmonary embolism. The respiratory functions further worsened: a bronchoscopy with sampling isolated Candida Albicans and Staphylococcus Aureus, a percutaneous tracheostomy was performed. Respiratory and neurologic functions improved. Owing to a persistent dilatation of the ventricles, she underwent a ventricular-peritoneal shunt intervention. Postoperative course was complicated by intraventricular hemorrhage and subsequent shunt occlusion  was treated with intense antimicrobial therapy. Neurological examination showed order execution with mild right side hemiplegia. She suffered again from dyspnea and progressive desaturation so she underwent a chest CT scan showing massive acute respiratory distress syndrome (ARDS) secondary to P. Aeruginosa and K. Pneumoniae MDR pneumonia which eventually led her to death about 3 months after admission.We present a case of a 43-year-old woman, with a 6-year history of diabetes mellitus. In the last few weeks preceding her hospitalization she suffered from headache, asthenia, and mood depression; since her headache kept worsening, she was eventually admitted to our Hospital. Neurological examination showed no significant deficit, electroencephalogram (EEG) was normal, fundus oculi study showed an embossed, blurred papilla with peripapillary hemorrhage in the right eye, slightly blurred margins of the left eye papilla. She underwent a CT scan which showed a 4 × 3 × 3 cm lesion in the medial mesencephalic region with heterogeneous density with hyperdense peripheral ring and vivid heterogeneous contrast enhancement causing noncommunicating hydrocephalus. Neither edema, nor calcifications nor cysts were noted. A hypothesis of a neoplasm with a III ventricle origin was made. A MRI scan showed a lesion slightly T1-hypointense, T2-heterogeneally hyperintense with vivid heterogeneous contrast enhancement involving little necrosis areas, cranially dislocating the fornix, minimally proceeding into the lateral ventricles through the foramina of Monro, and anteriorly dislocating the lamina terminalis. A millimetric heterogeneous T1-hyperintense and GE-hypointense oval area resembling a calcification of the lesion margin was noted near the right cerebral peduncle  patients. Further studies are needed to assess the correct treatment strategies in terms of complication prevention, surgical approach, and role of adjuvant therapy.Written informed consent was obtained from the patients 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