Quantitative morphometry analysis of the fetal brain using clinical MR imaging

In vivo fetal magnetic resonance imaging provides aunique approach for the study of early human braindevelopment [1]. In utero cerebral morphometry couldpotentially be used as a marker of the cerebralmaturation and help to distinguish between normal andabnormal development in ambiguous situations. However,this quantitative approach is a major challenge becauseof the movement of the fetus inside the amniotic cavity,the poor spatial resolution provided by very fast MRIsequences and the partial volume effect. Extensiveefforts are made to deal with the reconstruction ofhigh-resolution 3D fetal volumes based on severalacquisitions with lower resolution [2,3,4]. Frameworkswere developed for the segmentation of specific regionsof the fetal brain such as posterior fossa, brainstem orgerminal matrix [5,6], or for the entire brain tissue[7,8], applying the Expectation-Maximization MarkovRandom Field (EM-MRF) framework. However, many of theseprevious works focused on the young fetus (i.e. before 24weeks) and use anatomical atlas priors to segment thedifferent tissue or regions. As most of the gyraldevelopment takes place after the 24th week, acomprehensive and clinically meaningful study of thefetal brain should not dismiss the third trimester ofgestation. To cope with the rapidly changing appearanceof the developing brain, some authors proposed a dynamicatlas [8]. To our opinion, this approach however faces arisk of circularity: each brain will be analyzed /deformed using the template of its biological age,potentially biasing the effective developmental delay.Here, we expand our previous work [9] to proposepost-processing pipeline without prior that allow acomprehensive set of morphometric measurement devoted toclinical application. Data set & Methods: Prenatal MRimaging was performed with a 1-T system (GE MedicalSystems, Milwaukee) using single shot fast spin echo(ssFSE) sequences (TR 7000 ms, TE 180 ms, FOV 40 x 40 cm,slice thickness 5.4mm, in plane spatial resolution1.09mm). For each fetus, 6 axial volumes shifted by 1 mmwere acquired under motherâeuro?s sedation (about 1min pervolume). First, each volume is segmentedsemi-automatically using region-growing algorithms toextract fetal brain from surrounding maternal tissues.Inhomogeneity intensity correction [10] and linearintensity normalization are then performed. Brain tissues(CSF, GM and WM) are then segmented based on thelow-resolution volumes as presented in [9]. Ahigh-resolution image with isotropic voxel size of 1.09mm is created as proposed in [2] and using B-splines forthe scattered data interpolation [11]. Basal gangliasegmentation is performed using a levet setimplementation on the high-resolution volume [12]. Theresulting white matter image is then binarized and givenas an input in FreeSurfer software(http://surfer.nmr.mgh.harvard.edu) to providetopologically accurate three-dimensional reconstructionsof the fetal brain according to the local intensitygradient. References: [1] Guibaud, Prenatal Diagnosis29(4) (2009). [2] Rousseau, Acad. Rad. 13(9), 2006. [3]Jiang, IEEE TMI 2007. [4] Warfield IADB, MICCAI 2009. [5]Claude, IEEE Trans. Bio. Eng. 51(4) 2004. [6] Habas,MICCAI 2008. [7] Bertelsen, ISMRM 2009. [8] Habas,Neuroimage 53(2) 2010. [9] Bach Cuadra, IADB, MICCAI2009. [10] Styner, IEEE TMI 19(39 (2000). [11] Lee, IEEETrans. Visual. And Comp. Graph. 3(3), 1997. [12] BachCuadra, ISMRM 2010.

Destruction of lymphoid organ architecture and hepatitis caused by CD4 T cells.

Immune responses have the important function of host defense and protection against pathogens. However, the immune response also causes inflammation and host tissue injury, termed immunopathology. For example, hepatitis B and C virus infection in humans cause immunopathological sequel with destruction of liver cells by the host's own immune response. Similarly, after infection with lymphocytic choriomeningitis virus (LCMV) in mice, the adaptive immune response causes liver cell damage, choriomeningitis and destruction of lymphoid organ architecture. The immunopathological sequel during LCMV infection has been attributed to cytotoxic CD8(+) T cells. However, we now show that during LCMV infection CD4(+) T cells selectively induced the destruction of splenic marginal zone and caused liver cell damage with elevated serum alanin-transferase (ALT) levels. The destruction of the splenic marginal zone by CD4(+) T cells included the reduction of marginal zone B cells, marginal zone macrophages and marginal zone metallophilic macrophages. Functionally, this resulted in an impaired production of neutralizing antibodies against LCMV. Furthermore, CD4(+) T cells reduced B cells with an IgM(high)IgD(low) phenotype (transitional stage 1 and 2, marginal zone B cells), whereas other B cell subtypes such as follicular type 1 and 2 and germinal center/memory B cells were not affected. Adoptive transfer of CD4(+) T cells lacking different important effector cytokines and cytolytic pathways such as IFNγ, TNFα, perforin and Fas-FasL interaction did reveal that these cytolytic pathways are redundant in the induction of immunopathological sequel in spleen. In conclusion, our results define an important role of CD4(+) T cells in the induction of immunopathology in liver and spleen. This includes the CD4(+) T cell mediated destruction of the splenic marginal zone with consecutively impaired protective neutralizing antibody responses.

Structural changes induced by daily music listening in the recovering brain after middle cerebral artery stroke: a voxel-based morphometry study

Music is a highly complex and versatile stimulus for the brain that engages many temporal, frontal, parietal, cerebellar, and subcortical areas involved in auditory, cognitive, emotional, and motor processing. Regular musical activities have been shown to effectively enhance the structure and function of many brain areas, making music a potential tool also in neurological rehabilitation. In our previous randomized controlled study, we found that listening to music on a daily basis can improve cognitive recovery and improve mood after an acute middle cerebral artery stroke. Extending this study, a voxel-based morphometry (VBM) analysis utilizing cost function masking was performed on the acute and 6-month post-stroke stage structural magnetic resonance imaging data of the patients (n = 49) who either listened to their favorite music [music group (MG), n = 16] or verbal material [audio book group (ABG), n = 18] or did not receive any listening material [control group (CG), n = 15] during the 6-month recovery period. Although all groups showed significant gray matter volume (GMV) increases from the acute to the 6-month stage, there was a specific network of frontal areas [left and right superior frontal gyrus (SFG), right medial SFG] and limbic areas [left ventral/subgenual anterior cingulate cortex (SACC) and right ventral striatum (VS)] in patients with left hemisphere damage in which the GMV increases were larger in the MG than in the ABG and in the CG. Moreover, the GM reorganization in the frontal areas correlated with enhanced recovery of verbal memory, focused attention, and language skills, whereas the GM reorganization in the SACC correlated with reduced negative mood. This study adds on previous results, showing that music listening after stroke not only enhances behavioral recovery, but also induces fine-grained neuroanatomical changes in the recovering brain.

A model for organ donation in switzerland, the latin organ donation programme (lodp); an ongoing successful regional initiative

Background: The 1st Swiss federal Transplant Law was finally enforced in July 2007 with the obligation to promote quality and efficiency in transplant procedures. The LODP was created to develop organ and tissue donation in the Latin area of Switzerland covering seventeen hospitals (29% of the population).Methods: Each of the partner hospitals designated at least one Local Donor Coordinator (LDC), member of the Intensive Care team, trained in the organ donation (OD) process. The principal tasks of the LDC's are the introduction of OD procedures, organisation of educational sessions for hospital staff and execution of the Donor Action programme. The LODP has been operational since July 2009, when training of the LDC's was completed, the web-site and hotline activated and the attendance of Transplant Procurement Coordinators (TPC) during the OD process organised.Results: National and regional guidelines are accessible on the LODP website. The Hospital Attitude Survey obtained a 57% return rate. Many of the staff requested training and sessions are now running in the partner hospitals. The Medical Record Revue revealed an increase in the conversion rate from 3.5% to 4.5%. During the 5 years before creation of LODP the average annual number of utilised donors was 31, an increase of 70%, has since been observed.Conclusion: This clear progression in utilised donors in the past two years can be attributed to the fact that partner hospitals benefit from the various support given (hotline, website and from TPC's). Despite the increase in OD within the LODP the Swiss donation rates remain low, on average 11.9 donors per million population. This successful model should be applied throughout Switzerland, but the crucial point is to obtain financial support.

Evaluation of the integrity of human corneal epithelium maintained in organ-culture during eye banking using Corneamax®

Purpose: Mediums have been developed to conserve corneal endothelium in organ-culture during eye banking. CorneaMax® is used by 25% of Eye Bank in Europe. Only little is known about conservation of corneal epithelium with this medium during banking. Its preservation could be of interest in clinic to cure corneal disease with stem cells deficiency. Therefore, we wanted to examine the integrity of human corneal epithelium maintained in CorneaMax®. Methods: Human corneas, considered unsuitable for transplantation, were obtained from the Eye Bank in Lausanne. Average post-mortem time was 14 hours. Cornoscleral rings were maintained in organ-culture in Corneamax® at 32°C. Samples were formalin-fixed after period ranging from 0 (D0) to 35 days (D35, N=5 for each time points) and stained with H&E. Proliferation and apoptosis were evaluated by immunostaining with antibody against Ki67 and Caspase3 respectively. Results: Corneas, which were not in organ-cultured (D0), showed different morphology, including intact epithelium with 5 to 7 layers, but also completely denuded basement membrane. In two cases, at D0, the epithelium lost its adherence to the basal lamina of the cornea creating a large epithelial sheet. During the two first days, corneas and limbus area lost totally their epithelium, except for some remaining limbal basal cells. From day 2 to day 10, regeneration of the epithelium took place, starting from the limbal region in direction to the central cornea. From day 10 to day 35, corneal epithelium appeared as an atrophic epithelium, consisting of only two cell layers. Proliferation happened in the whole cornea during the 35 days of organ-culture, as shown by Ki67 positive cells. Apoptosis was rarely detected in the corneal epithelium. Conclusions: Corneas maintained in CorneaMax® showed a complete disappearance of the corneal epithelium during the two first days and a conservation of limbal basal cells in the limbal region. These remaining cells allowed a full regeneration of the tissue, leading to an atrophic epithelium, composed of only two cell layers. This atrophic epithelium could be seen in all the organ-cultured corneas during the 35 days of conservation. This study is a first step to develop medium in organ-culture in order to conserve corneal epithelial cells.

Recommandations suisses pour la prise en charge des cancers cutanés chez les patients transplantés d'organe [Swiss clinical practice guidelines for skin cancer in organ transplant recipients]

Swiss clinical practice guidelines for skin cancer in organ transplant recipients Transplant patients have increased over the last decades. As a consequence of long-term immunosuppression, skin cancer, in particular squamous cell carcinoma (SCC), has become an important problem. Screening and education of potential organ transplant recipients (OTRs) regarding prevention of sun damage and early recognition of skin cancer are important before transplantation. Once transplanted, OTRs should be seen yearly by a dermatologist to ensure compliance with sun avoidance as well as for treatment of precancerosis and SCC. Early removal is the best treatment for SCC. Reduction of immunosuppression, switch to mTOR inhibitors and chemoprevention with acitretin may reduce the incidence of SCC. The dermatological follow-up of OTRs should be integrated into a comprehensive post-transplant management strategy.

Risk Factors for Incisional and Organ Space Surgical Site Infections After Liver Resection are Different.

BACKGROUND: Surgical site infection (SSI) is a common cause of major morbidity after liver resection. This study aimed to identify the risk factors for incisional and organ/space SSIs after liver resection. METHODS: Our liver surgery database was retrospectively analyzed for patients treated between January 2009 and November 2012 in a tertiary care Swiss hospital. Univariate and multivariate analyses were conducted on preoperative, intraoperative, and postoperative variables to identify risk factors for incisional and organ/space SSIs. RESULTS: In a total of 226 patients, SSI incidences were 12.8 % (incisional), 4.0 % (organ/space), and 1.8 % (both). Univariate analysis showed that incisional SSIs were associated with high American Society of Anesthesiologists (ASA) scores, preoperative anemia, hypoalbuminemia, low prothrombin time, viral or alcoholic chronic hepatitis, liver cirrhosis, and prolonged operation times. Organ/space SSIs were associated with high rates of red blood cell transfusions, concomitant bowel surgery, and prolonged operation times. Multivariate analysis revealed that risk factors for incisional SSIs were anemia [odds ratio (OR) 2.82], high ASA scores (OR 2.88), presence of hepatitis or cirrhosis (OR 5.07), and prolonged operation times (OR 9.61). The only risk factor for organ/space SSIs was concomitant bowel surgery (OR 5.53). Hospital stays were similar in organ/space and incisional SSI groups, but significantly longer for those with both organ/space and incisional SSIs. CONCLUSIONS: High ASA scores, anemia, chronic hepatitis or liver cirrhosis, and prolonged operations increased the risk of incisional SSIs; concomitant bowel surgery increased the risk of organ/space SSI. Specific precautions to prevent organ/space and incisional SSIs may shorten hospital stays.

IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid-Organ Transplantation.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in immune genes have been associated with susceptibility to invasive mold infection (IMI) among hematopoietic stem cell but not solid-organ transplant (SOT) recipients. METHODS: Twenty-four SNPs from systematically selected genes were genotyped among 1101 SOT recipients (715 kidney transplant recipients, 190 liver transplant recipients, 102 lung transplant recipients, 79 heart transplant recipients, and 15 recipients of other transplants) from the Swiss Transplant Cohort Study. Association between SNPs and the end point were assessed by log-rank test and Cox regression models. Cytokine production upon Aspergillus stimulation was measured by enzyme-linked immunosorbent assay in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and correlated with relevant genotypes. RESULTS: Mold colonization (n = 45) and proven/probable IMI (n = 26) were associated with polymorphisms in the genes encoding interleukin 1β (IL1B; rs16944; recessive mode, P = .001 for colonization and P = .00005 for IMI, by the log-rank test), interleukin 1 receptor antagonist (IL1RN; rs419598; P = .01 and P = .02, respectively), and β-defensin 1 (DEFB1; rs1800972; P = .001 and P = .0002, respectively). The associations with IL1B and DEFB1 remained significant in a multivariate regression model (P = .002 for IL1B rs16944; P = .01 for DEFB1 rs1800972). The presence of 2 copies of the rare allele of rs16944 or rs419598 was associated with reduced Aspergillus-induced interleukin 1β and tumor necrosis factor α secretion by PBMCs. CONCLUSIONS: Functional polymorphisms in IL1B and DEFB1 influence susceptibility to mold infection in SOT recipients. This observation may contribute to individual risk stratification.

Common Variants of TLR1 Associate with Organ Dysfunction and Sustained Pro- Inflammatory Responses during Sepsis

Background: Toll-like receptors (TLRs) are critical components for host pathogen recognition and variants in genes participating in this response influence susceptibility to infections. Recently, TLR1 gene polymorphisms have been found correlated with whole blood hyper-inflammatory responses to pathogen-associated molecules and associated with sepsis-associated multiorgan dysfunction and acute lung injury (ALI). We examined the association of common variants of TLR1 gene with sepsis-derived complications in an independent study and with serum levels for four inflammatory biomarker among septic patients. Methodology/Principal Findings: Seven tagging single nucleotide polymorphisms of the TLR1 gene were genotyped in samples from a prospective multicenter case-only study of patients with severe sepsis admitted into a network of intensive care units followed for disease severity. Interleukin (IL)-1 b, IL-6, IL-10, and C-reactive protein (CRP) serum levels were measured at study entry, at 48 h and at 7th day. Alleles -7202G and 248Ser, and the 248Ser-602Ile haplotype were associated with circulatory dysfunction among severe septic patients (0.001<=p <= 0.022), and with reduced IL-10 (0.012<= p <=0.047) and elevated CRP (0.011<= p <=0.036) serum levels during the first week of sepsis development. Additionally, the -7202GG genotype was found to be associated with hospital mortality (p =0.017) and ALI (p =0.050) in a combined analysis with European Americans, suggesting common risk effects among studies Conclusions/Significance: These results partially replicate and extend previous findings, supporting that variants of TLR1 gene are determinants of severe complications during sepsis.

PTX3 Polymorphisms and Invasive Mold Infections After Solid Organ Transplant.

Donor PTX3 polymorphisms were shown to influence the risk of invasive aspergillosis among hematopoietic stem cell transplant recipients. Here, we show that PTX3 polymorphisms are independent risk factors for invasive mold infections among 1101 solid organ transplant recipients, thereby strengthening their role in mold infection pathogenesis and patients' risk stratification.

CCL8 and the Immune Control of Cytomegalovirus in Organ Transplant Recipients.

Monitoring of cytomegalovirus cell-mediated immunity is a promising tool for the refinement of preventative and therapeutic strategies posttransplantation. Typically, the interferon-γ response to T cell stimulation is measured. We evaluated a broad range of cytokine and chemokines to better characterize the ex vivo host-response to CMV peptide stimulation. In a cohort of CMV viremic organ transplant recipients, chemokine expression-specifically CCL8 (AUC 0.849 95% CI 0.721-0.978; p = 0.003) and CXCL10 (AUC 0.841, 95% CI 0.707-0.974; p = 0.004)-was associated with control of viral replication. In a second cohort of transplant recipients at high-risk for CMV, the presence of a polymorphism in the CCL8 promoter conferred an increased risk of viral replication after discontinuation of antiviral prophylaxis (logrank hazard ratio 3.6; 95% CI 2.077-51.88). Using cell-sorting experiments, we determined that the primary cell type producing CCL8 in response to CMV peptide stimulation was the monocyte fraction. Finally, in vitro experiments using standard immunosuppressive agents demonstrated a dose-dependent reduction in CCL8 production. Chemokines appear to be important elements of the cell-mediated response to CMV infection posttransplant, as here suggested for CCL8, and translation of this knowledge may allow for the tailoring and improvement of preventative strategies.

Risk Behavior and Reciprocity of Organ Donation Attitudes in Young Men.

BACKGROUND: Lack of donor organs remains a major obstacle in organ transplantation. Our aim was to evaluate (1) the association between engaging in high-risk recreational activities and attitudes toward organ donation and (2) the degree of reciprocity between organ acceptance and donation willingness in young men. METHODS: A 17-item, close-ended survey was offered to male conscripts ages 18 to 26 years in all Swiss military conscription centers. Predictors of organ donation attitudes were assessed in bivariate analyses and multiple logistic regression. Reciprocity of the intentions to accept and to donate organs was assessed by means of donor card status. RESULTS: In 1559 responses analyzed, neither motorcycling nor practicing extreme sports reached significant association with donor card holder status. Family communication about organ donation, student, or academic profession and living in a Latin linguistic region were predictors of positive organ donation attitudes, whereas residence in a German-speaking region and practicing any religion predicted reluctance. Significantly more respondents were willing to accept than to donate organs, especially among those without family communication concerning organ donation. CONCLUSIONS: For the first time, it was shown that high-risk recreational activities do not influence organ donation attitudes. Second, a considerable discrepancy in organ donation reciprocity was identified. We propose that increasing this reciprocity could eventually increase organ donation rates.