Intrauterine growth restriction is associated with structural alterations in human umbilical cord and decreased nitric oxide-induced relaxation of umbilical vein.

INTRODUCTION: Intrauterine growth restriction (IUGR) affects ∼8% of all pregnancies and is associated with major perinatal mortality and morbidity, and with an increased risk to develop cardiovascular diseases in adulthood. Despite identification of several risk factors, the mechanisms implicated in the development of IUGR remain poorly understood. In case of placental insufficiency, reduced delivery of oxygen and/or nutrients to the fetus could be associated with alterations in the umbilical circulation, contributing further to the impairment of maternal-fetal exchanges. We compared the structural and functional properties of umbilical cords from growth-restricted and appropriate for gestational age (AGA) term newborns, with particular attention to the umbilical vein (UV). METHODS: Human umbilical cords were collected at delivery. Morphological changes were investigated by histomorphometry, and UV's reactivity by pharmacological studies. RESULTS: Growth-restricted newborns displayed significantly lower growth parameters, placental weight and umbilical cord diameter than AGA controls. Total cross-section and smooth muscle areas were significantly smaller in UV of growth-restricted neonates than in controls. Maximal vasoconstriction achieved in isolated UV was lower in growth-restricted boys than in controls, whereas nitric oxide-induced relaxation was significantly reduced in UV of growth-restricted girls compared to controls. CONCLUSION: IUGR is associated with structural alterations of the UV in both genders, and with a decreased nitric oxide-induced relaxation in UV of newborn girls, whereas boys display impaired vasoconstriction. Further investigations will allow to better understand the regulation of umbilical circulation in growth-restricted neonates, which could contribute to devise potential novel therapeutic strategies to prevent or limit the development of IUGR.

Methylation profile of TP53 regulatory pathway and mtDNA alterations in breast cancer patients lacking TP53 mutations.

The present study investigated promoter hypermethylation of TP53 regulatory pathways providing a potential link between epigenetic changes and mitochondrial DNA (mtDNA) alterations in breast cancer patients lacking a TP53 mutation. The possibility of using the cancer-specific alterations in serum samples as a blood-based test was also explored. Triple-matched samples (cancerous tissues, matched adjacent normal tissues and serum samples) from breast cancer patients were screened for TP53 mutations, and the promoter methylation profile of P14(ARF), MDM2, TP53 and PTEN genes was analyzed as well as mtDNA alterations, including D-loop mutations and mtDNA content. In the studied cohort, no mutation was found in TP53 (DNA-binding domain). Comparison of P14(ARF) and PTEN methylation patterns showed significant hypermethylation levels in tumor tissues (P < 0.05 and <0.01, respectively) whereas the TP53 tumor suppressor gene was not hypermethylated (P < 0.511). The proportion of PTEN methylation was significantly higher in serum than in the normal tissues and it has a significant correlation to tumor tissues (P < 0.05). mtDNA analysis revealed 36.36% somatic and 90.91% germline mutations in the D-loop region and also significant mtDNA depletion in tumor tissues (P < 0.01). In addition, the mtDNA content in matched serum was significantly lower than in the normal tissues (P < 0.05). These data can provide an insight into the management of a therapeutic approach based on the reversal of epigenetic silencing of the crucial genes involved in regulatory pathways of the tumor suppressor TP53. Additionally, release of significant aberrant methylated PTEN in matched serum samples might represent a promising biomarker for breast cancer.

The SPONASTRIME dysplasia: familial short-limb dwarfism with saddle nose, spinal alterations and metaphyseal striation. Report of 4 siblings.

We report clinical, anthropometric and radiological findings in 4 siblings with a new type of skeletal dysplasia. 4 normally intelligent girls exhibit dwarfism between -3.4 and -4.6 standard deviations with accentuated shortening of the lower limbs, moderate deformity of the vertebral bodies, mildly striated metaphyses, saddle nose, frontal bossing, and relatively large head. The family pedigree suggests autosomal recessive inheritance. We propose the designation of SPONASTRIME dysplasia, derived from spondylar and nasal alterations with striation of the metaphyses.

The current molecular phylogeny of Eutherian mammals challenges previous interpretations of placental evolution.

Based on histology, the placentae of eutherians are currently grouped in epitheliochorial, endotheliochorial and haemochorial placentae. In a haeckelian sense, the epitheliochorial contact with marked histiotrophic feeding by uterine milk is generally considered as primitive, especially since similar contacts exist in Marsupials. In contrast, the more intimate endotheliochorial and haemochorial contact, facilitating haemotrophic nutrition, is interpreted as a derived state. A cladistic analysis based on the phylogenetic relationships established by molecular analyses reveals that the basic clades are all characterized by an endotheliochorial or haemochorial placenta, and that the epitheliochorial placenta evolved at least three times in a convergent manner. This evolution may be explained by the fact that the epitheliochorial placenta in eutherians is more efficient in nutritional transfer (flow rate by exchange surface). Moreover, this arrangement may confer an advantage to the mother who can probably reduce the degree of manipulation by a genetically imprinted embryo.

Bilateral uveal pigmented alterations with remarkable evolution: long term follow-up in a case of possible bilateral diffuse uveal melanocytic proliferation

Purpose: to describe a case of probable bilateral diffuse uveal melanocytic proliferation (BDUMP) with scleral involvement, free from systemic malignancies and cataract. Methods: fifty months of follow up with recurrent complete ophthalmological examinations, including fundus photography, fluorescein/indocyanine green angiography (FA) and optical coherence tomography (OCT). Investigations also included an electroretinography (ERG) and histological examination of scleral biopsy. Extraocular malignancies were repeatedly searched. Results: the patient was a 61 year-old Italian man with chronic hepatitis type C. At first visit his best corrected visual acuity (BCVA) was 20/32 in OS and 20/25 in OD. Funduscopy showed multiple patch-shaped pigmented alterations involving macular region and mid retinal periphery. FA showed corresponding areas of late-phase hyperfluorescent pinpoints (figure 1a, OS) and intemediate-phase hypocyanescence (figure 1b, OS), with subtle serous neurosensory retinal detachment confirmed by OCT. Photopic and scotopic ERG tested normal. Systemic prednisone was administered for one month without any improvement. After ten months round pigmentary lesions appeared also in superior scleral surface of both eyes. Biopsy allowed to disclose slightly pigmented spindle cells. BCVA worsened for further 10 months, with enlargement of FA alteration areas but lenses still clear. After 30 months spontaneous coalescence and atrophy of retinal lesions started, paralleled by progressive visual recovery. At the end of our follow up BCVA was 20/25 in OU while scleral pigmentary lesions remained unchanged. Conclusions: we report the case of a patient with main features of BDUMP and some unusual findings. Although not all classical diagnostic criteria were fulfilled, the presence of scleral pigmented lesions and spontaneous visual recovery may enlarge clinical spectrum of the disease.

Potassium channel alterations mediate peripheral nerve hyperexcitability in a mouse model of type 2 diabetes mellitus

Diabetes mellitus (DM) is a major cause of peripheral neuropathy. More than 220 million people worldwide suffer from type 2 DM, which will, in approximately half of them, lead to the development of diabetic peripheral neuropathy. While of significant medical importance, the pathophysiological changes present in DPN are still poorly understood. To get more insight into DPN associated with type 2 DM, we decided to use the rodent model of this form of diabetes, the db/db mice. During the in-vivo conduction velocity studies on these animals, we observed the presence of multiple spiking followed by a single stimulation. This prompted us to evaluate the excitability properties of db/db peripheral nerves. Ex-vivo electrophysiological evaluation revealed a significant increase in the excitability of db/db sciatic nerves. While the shape and kinetics of the compound action potential of db/db nerves were the same as for control nerves, we observed an increase in the after-hyperpolarization phase (AHP) under diabetic conditions. Using pharmacological inhibitors we demonstrated that both the peripheral nerve hyperexcitability (PNH) and the increased AHP were mostly mediated by the decreased activity of Kv1-channels. Importantly, we corroborated these data at the molecular level. We observed a strong reduction of Kv1.2 channel presence in the juxtaparanodal regions of teased fibers in db/db mice as compared to control mice. Quantification of the amount of both Kv1.2 isoforms in DRG neurons and in the endoneurial compartment of peripheral nerve by Western blotting revealed that less mature Kv1.2 was integrated into the axonal membranes at the juxtaparanodes. Our observation that peripheral nerve hyperexcitability present in db/db mice is at least in part a consequence of changes in potassium channel distribution suggests that the same mechanism also mediates PNH in diabetic patients. ∗Current address: Department of Physiology, UCSF, San Francisco, CA, USA.

Médicaments et grossesse : modifications pharmacocinétiques et place du suivi thérapeutique pharmacologique [Pharmacokinetic Alterations in Pregnancy and Use of Therapeutic Drug Monitoring].

Following the thalidomide tragedy, pharmacological research in pregnant women focused primarily on drug safety for the unborn child and remains only limited regarding the efficacy and safety of treatment for the mother. Significant physiological changes during pregnancy may yet affect the pharmacokinetics of drugs and thus compromise its efficacy and/or safety. Therapeutic drug monitoring (TDM) would maximize the potential effectiveness of treatments, while minimizing the potential risk of toxicity for the mother and the fetus. At present, because of the lack of concentration-response relationship studies in pregnant women, TDM can rely only on individual assessment (based on an effective concentration before pregnancy) and remains reserved only to unexpected situations such as signs of toxicity or unexplained inefficiency.

Alterations of Neuromuscular Function after the World's Most Challenging Mountain Ultra-Marathon.

We investigated the physiological consequences of the most challenging mountain ultra-marathon (MUM) in the world: a 330-km trail run with 24000 m of positive and negative elevation change. Neuromuscular fatigue (NMF) was assessed before (Pre-), during (Mid-) and after (Post-) the MUM in experienced ultra-marathon runners (n = 15; finish time  = 122.43 hours ±17.21 hours) and in Pre- and Post- in a control group with a similar level of sleep deprivation (n = 8). Blood markers of muscle inflammation and damage were analyzed at Pre- and Post-. Mean ± SD maximal voluntary contraction force declined significantly at Mid- (-13±17% and -10±16%, P<0.05 for knee extensor, KE, and plantar flexor muscles, PF, respectively), and further decreased at Post- (-24±13% and -26±19%, P<0.01) with alteration of the central activation ratio (-24±24% and -28±34% between Pre- and Post-, P<0.05) in runners whereas these parameters did not change in the control group. Peripheral NMF markers such as 100 Hz doublet (KE: -18±18% and PF: -20±15%, P<0.01) and peak twitch (KE: -33±12%, P<0.001 and PF: -19±14%, P<0.01) were also altered in runners but not in controls. Post-MUM blood concentrations of creatine kinase (3719±3045 Ul·(1)), lactate dehydrogenase (1145±511 UI·L(-1)), C-Reactive Protein (13.1±7.5 mg·L(-1)) and myoglobin (449.3±338.2 µg·L(-1)) were higher (P<0.001) than at Pre- in runners but not in controls. Our findings revealed less neuromuscular fatigue, muscle damage and inflammation than in shorter MUMs. In conclusion, paradoxically, such extreme exercise seems to induce a relative muscle preservation process due likely to a protective anticipatory pacing strategy during the first half of MUM and sleep deprivation in the second half.

Improvement in coronary circulatory function in morbidly obese individuals after gastric bypass-induced weight loss: relation to alterations in endocannabinoids and adipocytokines.

AIMS: To investigate the effect of surgical gastric bypass-induced weight loss and related alterations in endocannabinoids (ECs) and adipocytokine plasma levels on coronary circulatory dysfunction in morbidly obese (MOB) individuals. METHODS AND RESULTS: Myocardial blood flow (MBF) responses to cold pressor test (CPT) from rest (ΔMBF) and during pharmacologically induced hyperaemia were measured with &supl;³N-ammonia PET/CT in 18 MOB individuals with a body mass index (BMI) > 40 kg/m² at baseline and after a median follow-up period of 22 months. Gastric bypass intervention decreased BMI from a median of 44.8 (inter-quartile range: 43.3, 48.2) to 30.8 (27.3, 34.7) kg/m² (P < 0.0001). This decrease in BMI was accompanied by a marked improvement in endothelium-related ΔMBF to CPT and hyperaemic MBFs, respectively [0.34 (0.18, 0.41) from 0.03 (-0.08, 0.15) mL/g/min, P = 0.002; and 2.51 (2.17, 2.64) from 1.53 (1.39, 2.18) mL/g/min, P < 0.001]. There was an inverse correlation between decreases in plasma concentrations of the EC anandamide and improvement in ΔMBF to CPT (r = -0.59, P = 0.009), while increases in adiponectin plasma levels correlated positively with hyperaemic MBFs (r = 0.60, P = 0.050). Conversely, decreases in leptin plasma concentrations were not observed to correlate with the improvement in coronary circulatory function (r = 0.22, P = 0.400, and r = -0.31, P = 0.250). CONCLUSIONS: Gastric bypass-related reduction of BMI in MOB individuals beneficially affects coronary circulatory dysfunction. The dysbalance between ECs and adipocytokines appears to be an important determinant of coronary circulatory function in obesity.

Effects of genetic alterations in arbuscular mycorrhizal fungi on plant growth and on their response to a change of host

Abstract :The majority of land plants form the symbiosis with arbuscular mycorrhizal fungi (AMF). The AM symbiosis has existed for hundreds of millions of years but little or no specificity seems to have co- evolved between the partners and only about 200 morphospecies of AMF are known. The fungi supply the plants most notably with phosphate in exchange for carbohydrates. The fungi improve plant growth, protect them against pathogens and herbivores and the symbiosis plays a key role in ecosystem productivity and plant diversity. The fungi are coenocytic, grow clonally and no sexual stage in their life cycle is known. For these reasons, they are presumed ancient asexuals. Evidence suggests that AMF contain populations of genetically different nucleotypes coexisting in a common cytoplasm. Consequently, the nucleotype content of new clonal offspring could potentially be altered by segregation of nuclei at spore formation and by genetic exchange between different AMF. Given the importance of AMF, it is surprising that remarkably little is known about the genetics and genomics of the fungi.The main goal of this thesis was to investigate the combined effects of plant species differences and of genetic exchange and segregation in AMF on the symbiosis. This work showed that single spore progeny can receive a different assortment of nucleotypes compared to their parent and compared to other single spore progeny. This is the first direct evidence that segregation occurs in AMF. We then showed that both genetic exchange and segregation can lead to new progeny that differentially alter plant growth compared to their parents. We also found that genetic exchange and segregation can lead to different development of the fungus during the establishment of the symbiosis. Finally, we found that a shift of host species can differentially alter the phenotypes and genotypes of AMF progeny obtained by genetic exchange and segregation compared to their parents.Overall, this study confirms the multigenomic state of the AMF Glomus intraradices because our findings are possible only if the fungus contains genetically different nuclei. We demonstrated the importance of the processes of genetic exchange and segregation to produce, in a very short time span, new progeny with novel symbiotic effects. Moreover, our results suggest that different host species could affect the fate of different nucleotypes following genetic exchange and segregation in AMF, and can potentially contribute to the maintenance of genetic diversity within AMF individuals. This work brings new insights into understanding how plants and fungi have coevolved and how the genetic diversity in AMF can be maintained. We recommend that the intra-ir1dividual AMF diversity and these processes should be considered in future research on this symbiosis.Résumé :La majorité des plantes terrestres forment des symbioses avec les champignons endomycorhiziens arbusculaires (CEA). Cette symbiose existe depuis plusieurs centaines de millions d'années mais peu ou pas de spécificité semble avoir co-évoluée entre les partenaires et seulement 200 morpho-espèces de CEA sont connues. Le champignon fournit surtout aux plantes du phosphate en échange de carbohydrates. Le champignon augmente la croissance des plantes, les protège contre des pathogènes et herbivores et la symbiose joue un rôle clé dans la productivité des écosystèmes et de la diversité des plantes. Les CEA sont coenocytiques, se reproduisent clonalement et aucune étape sexuée n'est connue dans leur cycle de vie. Pour ces raisons, ils sont présumés comme anciens asexués. Des preuves suggèrent que les CEA ont des populations de nucleotypes différents coexistant dans un cytoplasme commun. Par conséquent, le contenu en nucleotype des nouveaux descendants clonaux pourrait être altéré par la ségrégation des noyaux lors de la fonnation des spores et par l'échange génétique entre différents CEA. Etant donné l'importance des CEA, il est surprenant que si peu soit connu sur la génétique et la génomique du champignon.Le principal but de cette thèse a été d'étudier les effets combinés de différentes espèces de plantes et des mécanismes d'échange génétique et de ségrégation chez les CEA sur la symbiose. Ce travail a montré que chaque nouvelle spore produite pouvait recevoir un assortiment différent de noyaux comparé au parent ou comparé à d'autres nouvelles spores. Ceci est la première preuve directe que la ségrégation peut se produire chez les CEA. Nous avons ensuite montré qu'à la fois l'échange génétique et la ségrégation pouvaient mener à de nouveaux descendants qui altèrent différemment la croissance des plantes, comparé à leurs parents. Nous avons également trouvé que l'échange génétique et la ségrégation pouvaient entraîner des développements différents du champignon pendant l'établissement de la symbiose. Pour finir, nous avons trouvé qu'un changement d'espèce de l'hôte pouvait altérer différemment les phénotypes et génotypes des descendants issus d'échange génétique et de ségrégation, comparé à leurs parents.Globalement, cette étude confirme l'état multigénomique du CEA Glumus intraradices car nous résultats sont possibles seulement si le champignon possède des noyaux génétiquement différents. Nous avons démontrés l'importance des mécanismes d'échange génétique et de ségrégation pour produire en très peu de temps de nouveaux descendants ayant des effets symbiotiques nouveaux. De plus, nos résultats suggèrent que différentes espèces de plantes peuvent agir sur le devenir des nucleotypes après l'échange génétique et la ségrégation chez les CEA, et pourraient contribuer à la maintenance de la diversité génétique au sein d'un même CEA. Ce travail apporte des éléments nouveaux pour comprendre comment les plantes et les champignons ont coévolué et comment la diversité génétique chez les CEA peut être maintenue. Nous recommandons de considérer la diversité génétique intra-individuelle des CEA et ces mécanismes lors de futures recherches sur cette symbiose.

A comprehensive characterization of genome-wide copy number aberrations in colorectal cancer reveals novel oncogenes and patterns of alterations.

To develop a comprehensive overview of copy number aberrations (CNAs) in stage-II/III colorectal cancer (CRC), we characterized 302 tumors from the PETACC-3 clinical trial. Microsatellite-stable (MSS) samples (n = 269) had 66 minimal common CNA regions, with frequent gains on 20 q (72.5%), 7 (41.8%), 8 q (33.1%) and 13 q (51.0%) and losses on 18 (58.6%), 4 q (26%) and 21 q (21.6%). MSS tumors have significantly more CNAs than microsatellite-instable (MSI) tumors: within the MSI tumors a novel deletion of the tumor suppressor WWOX at 16 q23.1 was identified (p<0.01). Focal aberrations identified by the GISTIC method confirmed amplifications of oncogenes including EGFR, ERBB2, CCND1, MET, and MYC, and deletions of tumor suppressors including TP53, APC, and SMAD4, and gene expression was highly concordant with copy number aberration for these genes. Novel amplicons included putative oncogenes such as WNK1 and HNF4A, which also showed high concordance between copy number and expression. Survival analysis associated a specific patient segment featured by chromosome 20 q gains to an improved overall survival, which might be due to higher expression of genes such as EEF1B2 and PTK6. The CNA clustering also grouped tumors characterized by a poor prognosis BRAF-mutant-like signature derived from mRNA data from this cohort. We further revealed non-random correlation between CNAs among unlinked loci, including positive correlation between 20 q gain and 8 q gain, and 20 q gain and chromosome 18 loss, consistent with co-selection of these CNAs. These results reinforce the non-random nature of somatic CNAs in stage-II/III CRC and highlight loci and genes that may play an important role in driving the development and outcome of this disease.

Early white matter alterations in men predisposed to FXTAS revealed by MT imaging.

Introduction: The Fragile X - associated Tremor Ataxia Syndrome (FXTAS) is a recently described, and under-diagnosed, late onset (≈ 60y) neurodegenerative disorder affecting male carriers of a premutation in the Fragile X Mental Retardation 1 (FMR1) gene. The premutation is an CGG (Cytosine-Guanine-Guanine) expansion (55 to 200 CGG repeats) in the proximal region of the FMR1 gene. Patients with FXTAS primarily present with cerebellar ataxia and intention tremor. Neuroradiological features of FXTAS include prominent white matter disease in the periventricular, subcortical, middle cerebellar peduncles and deep white matter of the cerebellum on T2-weighted or FLAIR MR imaging (Jacquemmont 2007, Loesch 2007, Brunberg 2002, Cohen 2006). We hypothesize that a significant white matter alteration is present in younger individuals many years prior to clinical symptoms and/or the presence of visible lesions on conventional MR sequences and might be detectable by magnetization transfer (MT) imaging. Methods: Eleven asymptomatic premutation carriers (mean age = 55 years) and seven intra-familial controls participated to the study. A standardized neurological examination was performed on all participants and a neuropsychological evaluation was carried out before MR scanning performed on a 3T Siemens Trio. The protocol included a sagittal T1-weighted 3D gradient-echo sequence (MPRAGE, 160 slices, 1 mm^3 isotropic voxels) and a gradient-echo MTI (FA 30, TE 15, matrix size 256*256, pixel size 1*1 mm, 36 slices (thickness 2mm), MT pulse duration 7.68 ms, FA 500, frequency offset 1.5 kHz). MTI was performed by acquiring consecutively two set of images; first with and then without the MT saturation pulse. MT images were coregistered to the T1 acquisition. The MTR for every intracranial voxel was calculated as follows: MTR = (M0 - MS)/M0*100%, creating a MTR map for each subject. As first analysis, the whole white matter (WM) was used to mask the MTR image in order to create an histogram of the MTR distribution in the whole tissue class over the two groups examined. Then, for each subject, we performed a segmentation and parcellation of the brain by means of Freesurfer software, starting from the high resolution T1-weighted anatomical acquisition. Cortical parcellations was used to assign a label to the underlying white matter by the construction of a Voronoi diagram in the WM voxels of the MR volume based on distance to the nearest cortical parcellation label. This procedure allowed us to subdivide the cerebral WM in 78 ROIs according to the cortical parcellation (see example in Fig 1). The cerebellum, by the same procedure, was subdivided in 5 ROIs (2 per each hemisphere and one corresponding to the brainstem). For each subject, we calculated the mean value of MTR within each ROI and averaged over controls and patients. Significant differences between the two groups were tested using a two sample T-test (p<0.01). Results: Neurological examination showed that no patient met the clinical criteria of Fragile X Tremor and Ataxia Syndrome yet. Nonetheless, premutation carriers showed some subtle neurological signs of the disorder. In fact, premutation carriers showed a significant increase of tremor (CRST, T-test p=0.007) and increase of ataxia (ICARS, p=0.004) when compared to controls. The neuropsychological evaluation was normal in both groups. To obtain general characterizations of myelination for each subject and premutation carriers, we first computed the distribution of MTR values across the total white matter volume and averaged for each group. We tested the equality of the two distributions with the non parametric Kolmogorov-Smirnov test and we rejected the null-hypothesis at a p=0.03 (fig. 2). As expected, when comparing the asymptomatic permutation carriers with control subjects, the peak value and peak position of the MTR values within the whole WM were decreased and the width of the distribution curve was increased (p<0.01). These three changes point to an alteration of the global myelin status of the premutation carriers. Subsequently, to analyze the regional myelination and white matter integrity of the same group, we performed a ROI analysis of MTR data. The ROI-based analysis showed a decrease of mean MTR value in premutation carriers compared to controls in bilateral orbito-frontal and inferior frontal WM, entorhinal and cingulum regions and cerebellum (Fig 3). The detection of these differences in these regions failed with other conventional MR techniques. Conclusions: These preliminary data confirm that in premutation carriers, there are indeed alterations in "normal appearing white matter" (NAWM) and these alterations are visible with the MT technique. These results indicate that MT imaging may be a relevant approach to detect both global and local alterations within NAWM in "asymptomatic" carriers of premutations in the Fragile X Mental Retardation 1 (FMR1) gene. The sensitivity of MT in the detection of these alterations might point towards a specific physiopathological mechanism linked to an underlying myelin disorder. ROI-based analyses show that the frontal, parahippocampal and cerebellar regions are already significantly affected before the onset of symptoms. A larger sample will allow us to determine the minimum CGG expansion and age associated with these subclinical white matter alterations.

Connectome alterations in schizophrenia

Introduction : DTI has proven to be an exquisite biomarker of tissue microstructure integrity. This technique has been successfully applied to schizophrenia in showing that fractional anisotropy (FA, a marker of white matter integrity) is diminished in several areas of the brain (Kyriakopoulos M et al (2008)). New ways of representing diffusion data emerged recently and achieved to create structural connectivity maps in healthy brains (Hagmann P et al. (2008)). These maps have the capacity to study alterations over the entire brain at the connection and network level. This is of high interest in complex disconnection diseases like schizophrenia. We report on the specific network alterations of schizophrenic patients. Methods : 13 patients with chronic schizophrenia were recruited from in-patient, day treatment, out-patient clinics. Comparison subjects were recruited and group-matched to patients on age, sex, handedness, and parental social economic-status. This study was approved by the local IRB and subjects had to give informed written consent. They were scanned with a 3T clinical MRI scanner. DTI and high-resolution anatomical T1w imaging were performed during the same session. The path from diffusion MRI to a multi-resolution structural connection matrices of the entire brain is a five steps process that was performed in a similar way as described in Hagmann P et al. (2008). (1) DTI and T1w MRI of the brain, (2) segmentation of white and gray matter, (3) white matter tractography, (4) segmentation of the cortex into 242 ROIs of equal surface area covering the entire cortex (Fig 1), (5) the connection network was constructed by measuring for each ROI to ROI connection the related average FA along the corresponding tract. Results : For every connection between 2 ROIs of the network we tested the hypothesis H0: "average FA along fiber pathway is larger or equal in patients than in controls". H0 was rejected for connections where average FA in a connection was significantly lower in patients than in controls. Threshold p-value was 0.01 corrected for multiple comparisons with false discovery rate. We identified consistently that temporal, occipito-temporal, precuneo-temporal as well as frontal inferior and precuneo-cingulate connections were altered (Fig 2: significant connections in yellow). This is in agreement with the known literature, which showed across several studies that FA is diminished in several areas of the brain. More precisely, abnormalities were reported in the prefrontal and temporal white matter and to some extent also in the parietal and occipital regions. The alterations reported in the literature specifically included the corpus callosum, the arcuate fasciculus and the cingulum bundle, which was the case here as well. In addition small world indexes are significantly reduced in patients (p<0.01) (Fig. 3). Conclusions : Using connectome mapping to characterize differences in structural connectivity between healthy and diseased subjects we were able to show widespread connectional alterations in schizophrenia patients and systematic small worldness decrease, which is a marker of network desorganization. More generally, we described a method that has the capacity to sensitively identify structure alterations in complex disconnection syndromes where lesions are widespread throughout the connectional network.

Plutonium from above-ground nuclear tests in milk teeth: investigation of placental transfer in children born between 1951 and 1995 in Switzerland.

BACKGROUND: Occupational risks, the present nuclear threat, and the potential danger associated with nuclear power have raised concerns regarding the metabolism of plutonium in pregnant women. OBJECTIVE: We measured plutonium levels in the milk teeth of children born between 1951 and 1995 to assess the potential risk that plutonium incorporated by pregnant women might pose to the radiosensitive tissues of the fetus through placenta transfer. METHODS: We used milk teeth, whose enamel is formed during pregnancy, to investigate the transfer of plutonium from the mother's blood plasma to the fetus. We measured plutonium using sensitive sector field inductively coupled plasma mass spectrometry techniques. We compared our results with those of a previous study on strontium-90 ((90)Sr) released into the atmosphere after nuclear bomb tests. RESULTS: Results show that plutonium activity peaks in the milk teeth of children born about 10 years before the highest recorded levels of plutonium fallout. By contrast, (90)Sr, which is known to cross the placenta barrier, manifests differently in milk teeth, in accordance with (90)Sr fallout deposition as a function of time. CONCLUSIONS: These findings demonstrate that plutonium found in milk teeth is caused by fallout that was inhaled around the time the milk teeth were shed and not from any accumulation during pregnancy through placenta transfer. Thus, plutonium may not represent a radiologic risk for the radiosensitive tissues of the fetus.