Calreticulin levels determine onset of early muscle denervation by fast motoneurons of ALS model mice.

Although the precise signaling mechanisms underlying the vulnerability of some sub-populations of motoneurons in ALS remain unclear, critical factors such as metallo-proteinase 9 expression, neuronal activity and endoplasmic reticulum stress have been shown to be involved. In the context of SOD1(G93A) ALS mouse model, we previously showed that a two-fold decrease in calreticulin (CRT) is occurring in the vulnerable fast motoneurons. Here, we asked to which extent the decrease in CRT levels was causative to muscle denervation and/or motoneuron degeneration. Toward this goal, a hemizygous deletion of the crt gene in SOD1(G93A) mice was generated since the complete ablation of crt is embryonic lethal. We observed that SOD1(G93A);crt(+/-) mice display increased and earlier muscle weakness and muscle denervation compared to SOD1(G93A) mice. While CRT reduction in motoneurons leads to a strong upregulation of two factors important in motoneuron dysfunction, ER stress and mTOR activation, it does not aggravate motoneuron death. Our results underline a prevalent role for CRT levels in the early phase of muscle denervation and support CRT regulation as a potential therapeutic approach.

Global transcriptional programs in peripheral nerve endoneurium and DRG are resistant to the onset of type 1 diabetic neuropathy in Ins2 mice.

While the morphological and electrophysiological changes underlying diabetic peripheral neuropathy (DPN) are relatively well described, the involved molecular mechanisms remain poorly understood. In this study, we investigated whether phenotypic changes associated with early DPN are correlated with transcriptional alterations in the neuronal (dorsal root ganglia [DRG]) or the glial (endoneurium) compartments of the peripheral nerve. We used Ins2(Akita/+) mice to study transcriptional changes underlying the onset of DPN in type 1 diabetes mellitus (DM). Weight, blood glucose and motor nerve conduction velocity (MNCV) were measured in Ins2(Akita/+) and control mice during the first three months of life in order to determine the onset of DPN. Based on this phenotypic characterization, we performed gene expression profiling using sciatic nerve endoneurium and DRG isolated from pre-symptomatic and early symptomatic Ins2(Akita/+) mice and sex-matched littermate controls. Our phenotypic analysis of Ins2(Akita/+) mice revealed that DPN, as measured by reduced MNCV, is detectable in affected animals already one week after the onset of hyperglycemia. Surprisingly, the onset of DPN was not associated with any major persistent changes in gene expression profiles in either sciatic nerve endoneurium or DRG. Our data thus demonstrated that the transcriptional programs in both endoneurial and neuronal compartments of the peripheral nerve are relatively resistant to the onset of hyperglycemia and hypoinsulinemia suggesting that either minor transcriptional alterations or changes on the proteomic level are responsible for the functional deficits associated with the onset of DPN in type 1 DM.

Gait disturbances as specific predictive markers of the first fall onset in elderly people: a two-year prospective observational study

Falls are common in the elderly, and potentially result in injury and disability. Thus, preventing falls as soon as possible in older adults is a public health priority, yet there is no specific marker that is predictive of the first fall onset. We hypothesized that gait features should be the most relevant variables for predicting the first fall. Clinical baseline characteristics (e.g., gender, cognitive function) were assessed in 259 home-dwelling people aged 66 to 75 that had never fallen. Likewise, global kinetic behavior of gait was recorded from 22 variables in 1036 walking tests with an accelerometric gait analysis system. Afterward, monthly telephone monitoring reported the date of the first fall over 24 months. A principal components analysis was used to assess the relationship between gait variables and fall status in four groups: non-fallers, fallers from 0 to 6 months, fallers from 6 to 12 months and fallers from 12 to 24 months. The association of significant principal components (PC) with an increased risk of first fall was then evaluated using the area under the Receiver Operator Characteristic Curve (ROC). No effect of clinical confounding variables was shown as a function of groups. An eigenvalue decomposition of the correlation matrix identified a large statistical PC1 (termed "Global kinetics of gait pattern"), which accounted for 36.7% of total variance. Principal component loadings also revealed a PC2 (12.6% of total variance), related to the "Global gait regularity." Subsequent ANOVAs showed that only PC1 discriminated the fall status during the first 6 months, while PC2 discriminated the first fall onset between 6 and 12 months. After one year, any PC was associated with falls. These results were bolstered by the ROC analyses, showing good predictive models of the first fall during the first six months or from 6 to 12 months. Overall, these findings suggest that the performance of a standardized walking test at least once a year is essential for fall prevention.

Chiasmatic infiltration secondary to late malignant transformation of retinoma.

PURPOSE: To report the lethal course of malignant transformation of retinoma in an adult. METHODS: Case report. A 40-year-old patient presented with retinoma in his right eye and retinoblastoma in his left eye. Enucleation was recommended but refused and the patient received whole eye radiotherapy elsewhere. Five years later he presented again, with temporal hemianopsia of the left eye secondary to chiasmatic invasion. RESULTS: Diagnosis of retinoblastoma infiltration was confirmed by stereotactic biopsy of the chiasmatic lesion. Treatment with intravenous and intrathecal chemotherapy led to partial remission, and was followed by stereotactic irradiation of the chiasmatic mass and right optic nerve. The left eye was enucleated. Death occurred one year later due to cerebrospinal fluid metastases. CONCLUSION: Extraocular extension of retinoblastoma diagnosed in adulthood has never, to our knowledge, been reported. This case stresses the importance of lifelong retinoma monitoring and the necessity for radical treatment in the event of malignant transformation.

Increased risks of early sexual initiators: time makes a difference

BACKGROUND: Years since onset of sexual intercourse (YSSI) is a rarely used variable when studying adolescents- sexual outcomes. The aim of this study is to evaluate the influence of YSSI on the adverse sexual outcomes of early sexual initiators. METHODS: Data were drawn from the 2002 Swiss Multicenter Adolescent Survey on Health database, a nationally representative cross-sectional survey including 7429 adolescents in post mandatory school aged 16-20 years. Only adolescents reporting sexual intercourse (SI) were included (N=4388; 45% females) and divided by age of onset of SI (early initiators, age<16: N=1469, 44% females; and late initiators, age≥16: N=2919, 46% females). Analyses were done separately by gender. Groups were compared for personal characteristics at the bivariate level. We analyzed three sexual outcomes (≥4 sexual partners, pregnancy and non-use of condom at last SI) controlling for all significant personal variables with two logistic regressions first using age, then YSSI as one of the confounding variables. Results are given as adjusted odds ratios (aOR) using lSI as the reference category. RESULTS: After adjusting for YSSI instead of age, negative sexual outcomes among early initiators were no longer significant, except for multiple sexual partners among females, although at a much lower level. Early initiators were less likely to report non-use of condom at last SI when adjusting for YSSI (females: aOR=0.59 [0.44-0.79]; p<0.001; males aOR=0.71 [0.50-1.00]; p=0.053). CONCLUSION: YSSI is an important explanatory variable when studying adolescents- sexuality and needs to be included in future research on adolescents- sexual health.

Données actualisées sur la physiopathologie, les phénotypes et les traitements de la maladie de Still de l'adulte [Pathophysiology, subtypes, and treatments of adult-onset Still's disease: An update].

Adult-onset Still's disease is a rare and difficult to diagnose multisystemic disorder considered as a multigenic autoinflammatory syndrome. Its immunopathogenesis seems to be at the crossroads between inflammasomopathies and hemophagocytic lymphohistiocytosis, the most severe manifestation of the disease. According to recent insights in the pathophysiology and thanks to cohort studies and therapeutic trials, two phenotypes of adult-onset Still's disease may be distinguished: a systemic pattern, initially highly symptomatic and with a higher risk to exhibit life-threatening complications such as reactive hemophagocytic lymphohistiocytosis, where interleukin-1 blockade seems to be very effective, a chronic articular pattern, more indolent with arthritis in the foreground and less severe systemic manifestations, which would threat functional outcome and where interleukin-6 blockade seems to be more effective. This review focuses on these data.

Genetic consequences of population expansions and contractions in the common hippopotamus (Hippopotamus amphibius) since the Late Pleistocene.

Over the past two decades, an increasing amount of phylogeographic work has substantially improved our understanding of African biogeography, in particular the role played by Pleistocene pluvial-drought cycles on terrestrial vertebrates. However, still little is known on the evolutionary history of semi-aquatic animals, which faced tremendous challenges imposed by unpredictable availability of water resources. In this study, we investigate the Late Pleistocene history of the common hippopotamus (Hippopotamus amphibius), using mitochondrial and nuclear DNA sequence variation and range-wide sampling. We documented a global demographic and spatial expansion approximately 0.1-0.3 Myr ago, most likely associated with an episode of massive drainage overflow. These events presumably enabled a historical continent-wide gene flow among hippopotamus populations, and hence, no clear continental-scale genetic structuring remains. Nevertheless, present-day hippopotamus populations are genetically disconnected, probably as a result of the mid-Holocene aridification and contemporary anthropogenic pressures. This unique pattern contrasts with the biogeographic paradigms established for savannah-adapted ungulate mammals and should be further investigated in other water-associated taxa. Our study has important consequences for the conservation of the hippo, an emblematic but threatened species that requires specific protection to curtail its long-term decline.

Mood disorders in eating disorder patients: Prevalence and chronology of ONSET.

OBJECTIVES: In a clinical population, we estimated the frequency of mood disorders among 271 patients suffering from Anorexia Nervosa (AN) and Bulimia Nervosa (BN) in comparison to a control group matched for age and gender. METHOD: The frequency of mood disorders was measured using the Mini International Neuropsychiatric Interview (MINI), DSM-IV version. RESULTS: Mood disorders were more frequent among eating disorder (ED) patients than among controls, with a global prevalence of the order of 80% for each ED group. The majority of the mood disorders comorbid with ED were depressive disorders (MDD and dysthymia). The relative chronology of onset of these disorders was equivocal, because mood disorders in some cases preceded and in others followed the onset of the eating disorders. LIMITATIONS: Our sample was characterized by patients with severe ED and high comorbidities, and thus do not represent the entire population of AN or BN. This also may have resulted in an overestimation of prevalence. CONCLUSION: Mood disorders appear significantly more frequently in patients seeking care for ED than in controls. These results have implications for the assessment and treatment of ED patients, and for the aetio-pathogenesis of these disorders.

Late mesozoic to neogene radiolarian biostratigraphy and palaeoceanography in the Caribbean and East pacific region

^Raduolarians constitute a good tool for contributing to the biostratigraphy of accreted terranes and in deep-sea sediment sequences. The use of radiolarians is also proven to be valuable as a palaeoceanographic indicator. The present study evaluates radiolarians in three different geological settings, in order to better constrain the age of the sites and to try to understand their palaeoenvironmental situation at different periods, particularly in the Caribbean-Central America area. On the Jarabacoa Block, in Central Dominican Republic, a hundred meters of siliceous mudstones (Pedro Brand section in the Tireo Group) was dated as Turonian- Coniancian in age using radiolarians. A 40Ar-39Ar whole rock age of 75.1±1.1 Ma (Campanian), obtained in a basalt dyke crosscutting the radiolarian bearing rocks, a consistent minimum age for the pelagic-hemipelagic Pedro Brand section. The Jarabacoa Block is considered as the most complete outcrop section of Pacific ocean crust overlain by a first Aptian-Albian phase of Caribbean Large Igneous Province-type activity (CLIP), followed by the development of a Cenomanian-Santonian intraoceanic arc, which is in turn overlain by a late Campanian-Maastrichtian CLIP-phase. The Tireo Group records an episode of pelagic to hemi-pelagic and intermediate to acidic arc-derived sedimentation, previous to the youngest magmatic phase of the CLIP. Thus, the section of Pedro Brand has been interpreted in this study as being part of the intraoceanic arc. In northern Venezuela, a greenish radiolarite section from Siquisique Ophiolite (basalts, gabbros and some associated cherts) in Guaparo Creek has been studied. In previous studies, the Ophiolite unit (Petacas Creek section) has been dated as Bajocian-Bathonian, based on ammonites present in interpillow sediments from basalt blocks. New dating of the present study concluded in an Aptian?-Albian-Cenomanian age for the Guaparo creek section (middle Cretaceous), based on radiolarian assemblage associated to basalts-gabbros rocks of the unit. Previous plagioclase 40Ar-39Ar ages from the Siquisuique Ophiolite may be slightly younger (94-90 Ma.) and may, therefore, represent younger dykes that intruded onto a well-developed sheeted dyke complex of the Siquisique. The geochemistry of these rocks and the palaeotectonic reconstruction of the Caribbean area during this period suggest that these rocks were derived from a mid-ocean ridge with an influence of deep mantle plume. The Siquisique Ophiolite most probably represents a fragment of the proto-Caribbean basin. The Integrated Ocean Drilling Program Expedition 344 drilled a transect across the convergent margin off Costa Rica. Two sites of this expedition were chosen for radiolarian biostratigraphy and palaeoceanographic studies. Both sites (U1381C and U1414A) are located in the incoming Cocos plate, in the eastern Equatorial Pacific. The succession of U1381C yields a Middle Miocene to Pleistocene age, and presents an important hiatus of approximately 10 Ma. The core of U1414A exposes a continuous sequence that deposited during Late Miocene to Pleistocene (radiolarian zones RN6-RN16). The ages were assigned based on radiolarians and correlated with nannofossil zonation and tephra 40Ar-39Ar datation. With those results, and considering the northward movement of the Cocos plate motion (about 7 cm/year), deduction is made that the sites U1381C and U1414A were initially deposited during the Miocene, several hundreds of kilometres from the current location, slightly south of the Equator. This suggests that the faunas of these sites have been subjected to different currents, first influenced by the cold tongue of the South Equatorial Current and followed by the warm Equatorial Countercurrent. At last, coastal upwelling influenced faunas of the Pleistocene. -- Les radiolaires sont considérés comme un outil utile à la biostratigraphie des terrains accrétés et des sédiments profonds. Leur utilité est aussi prouvée comme étant remarquable au niveau des reconstructions paléocéanographiques. La présente étude évalue l'importance et la présence des radiolaires de trois localités géologiquement différentes d'Amérique Centrale-Caraïbes, dans le but d'améliorer les model d'âges et de mieux comprendre la situation paléoenvironnementale à travers le temps. Dans le Bloque de Jarabacoa, au centre de la République Dominicaine, une section de cent mètres (section de Pedro Brand, Groupe de Tireo) a été datée comme faisant partie du Turonien-Santonien, en utilisant les radiolaires. Une datation 40Ar-39Ar sur roche totale de 75±1.1 Ma (Campanien) a été obtenu pour vin dyke traversant les sédiments riches en radiolaires, en cohérence avec l'âge minimum accordé à la section de Pedro Brand. Aux Caraïbes, le Bloque de Jarabacoa est considéré comme l'affleurement le plus complet présentant une succession de croûte océanique d'origine Pacifique recouverte d'une première phase d'activité volcanique de type CLIP (Caribbean Large Igneous Province) d'âge Aptien- Albien, de dépôts d'arc volcanique intra-océanique d'âge Cénomanien-Santonien, puis d'une seconde phase de type CLIP d'âge Campanien-Maastrichtien. Le Groupe de Tireo enregistre un épisode de dépôt pélagiques-hémipélagiques et d'arc volcanique, antérieur à la plus jeune phase de type CLIP. Cette étude place donc la formation de la section de Pedro Brand au moment du développement de l'arc intra-océanique. A Guaparo Creek (nord du Vénézuela), une section de radiolarite verdâtre faisant partie des ophiolites de Siquisique (basaltes, gabbros, cherts) a été étudiée. Dans des études précédentes, sur la localité de Petacas Creek, l'unité ophiolitique a été daté d'âge Bajocien- Bathonien (Jurassique) sur la base d'ammonites trouvées dans des sédiments intercalés entre des laves en coussins. Les nouvelles datations de notre étude, basées sur des assemblages à radiolaires de l'unité à basaltes-gabbros, donnent un âge Aptien?-Albien-Cénomanien (Crétacé moyen). Les âges de l'Ophiolite de Siquisique, précédement calculés par la méthode sur plagioclases, pourraient être légèrement plus jeune (94-90 Ma) et donc représenter des intrusions plus récentes de dykes dans le complexe filonien déjà bien dévelopé. La géochimie de ces roches magmatiques, ainsi que les reconstructions paléotectoniques de la zone Caraïbes durant cette période, suggèrent que ces formations sont dérivées d'une ride médio-océanique associée à l'influence d'un panache mantellique. L'ophiolite de Siquisique représente très probablement un fragment du bassin de proto¬Caraïbe. L'expédition 344 du programme IODP (Integrated Ocean Drilling Program) a eu lieu dans l'optique de forer et dresser une coupe de la marge convergente au large du Costa Rica. Deux sites de cette expédition ont été choisis pour les besoins des études de biostratigraphie et de reconstruction paléocéanographique. Ces deux sites (U1381C et U1414A) sont situés sur la plaque subductante de Cocos, dans la zone Pacifique est-équatoriale. La carotte U1381C expose une séquence s'étalant du Miocène moyen au Pléistocène, et présente un important hiatus d'environ 10 Ma. La carotte U1414A expose une séquence continue s'étalant du Miocène tardif au Pléistocène (zone à radiolaires RN6-RN16). Les âges ont été assignés sur la base des radiolaires et corrélés avec les zones à nanofossiles et les datations 40Ar-39Ar sur téphras. Avec ces résultats, et en considérant le mouvement nord de la plaque de Cocos (environ 7 cm/an), déduction est faite que les deux sites étaient initialement situés, au cours du Miocène, à plusieurs centaines de kilomètres de leur location actuelle, au sud de l'équateur. Cela suggère que les faunes de ces sites ont été sujettes à différents courants; premièrement influencées par la langue froide du SEC (South Equatorial Current), puis par les eaux chaudes du ECC (Equatorial Countercurrent). Pour terminer, les remontées d'eau côtières ont influencées les faunes Pléistocène.

Childhood sexual and physical abuse: age at exposure modulates impact on functional outcome in early psychosis patients.

BACKGROUND: Evidence suggests a relationship between exposure to trauma during childhood and functional impairments in psychotic patients. However, the impact of age at the time of exposure has been understudied in early psychosis (EP) patients. METHOD: Two hundred and twenty-five patients aged 18-35 years were assessed at baseline and after 2, 6, 18, 24, 30 and 36 months of treatment. Patients exposed to sexual and/or physical abuse (SPA) were classified according to age at the time of first exposure (Early SPA: before age 11 years; Late SPA: between ages 12 and 15 years) and then compared to patients who were not exposed to such trauma (Non-SPA). The functional level in the premorbid phase was measured with the Premorbid Adjustment Scale (PAS) and with the Global Assessment of Functioning (GAF) scale and the Social and Occupational Functioning Assessment Scale (SOFAS) during follow-up. RESULTS: There were 24.8% of patients with a documented history of SPA. Late SPA patients were more likely to be female (p = 0.010). Comparison with non-SPA patients revealed that: (1) both Early and Late SPA groups showed poorer premorbid social functioning during early adolescence, and (2) while patients with Early SPA had poorer functional level at follow-up with lower GAF (p = 0.025) and lower SOFAS (p = 0.048) scores, Late SPA patients did not. CONCLUSION: Our results suggest a link between exposure to SPA and the later impairment of social functioning before the onset of the disease. EP patients exposed to SPA before age 12 may present long-lasting functional impairment, while patients exposed at a later age may improve in this regard and have a better functional outcome.