Neurodevelopmental trajectories of letter and speech sound processing from preschool to the end of elementary school.

Learning to read alphabetic languages starts with learning letter-speech-sound associations. How this process changes brain function during development is still largely unknown. We followed 102 children with varying reading skills in a mixed-longitudinal/cross-sectional design from the prereading stage to the end of elementary school over five time points (n = 46 with two and more time points, of which n = 16 fully-longitudinal) to investigate the neural trajectories of letter and speech sound processing using fMRI. Children were presented with letters and speech sounds visually, auditorily, and audiovisually in kindergarten (6.7yo), at the middle (7.3yo) and end of first grade (7.6yo), and in second (8.4yo) and fifth grades (11.5yo). Activation of the ventral occipitotemporal cortex for visual and audiovisual processing followed a complex trajectory, with two peaks in first and fifth grades. The superior temporal gyrus (STG) showed an inverted U-shaped trajectory for audiovisual letter processing, a development that in poor readers was attenuated in middle STG and absent in posterior STG. Finally, the trajectories for letter-speech-sound integration were modulated by reading skills and showed differing directionality in the congruency effect depending on the time point. This unprecedented study captures the development of letter processing across elementary school and its neural trajectories in children with varying reading skills.

Microscopic Understanding of Ultrafast Charge Transfer in van der Waals Heterostructures.

Van der Waals heterostructures show many intriguing phenomena including ultrafast charge separation following strong excitonic absorption in the visible spectral range. However, despite the enormous potential for future applications in the field of optoelectronics, the underlying microscopic mechanism remains controversial. Here we use time- and angle-resolved photoemission spectroscopy combined with microscopic many-particle theory to reveal the relevant microscopic charge transfer channels in epitaxial WS_{2}/graphene heterostructures. We find that the timescale for efficient ultrafast charge separation in the material is determined by direct tunneling at those points in the Brillouin zone where WS_{2} and graphene bands cross, while the lifetime of the charge separated transient state is set by defect-assisted tunneling through localized sulphur vacancies. The subtle interplay of intrinsic and defect-related charge transfer channels revealed in the present work can be exploited for the design of highly efficient light harvesting and detecting devices.

Visual word form processing deficits driven by severity of reading impairments in children with developmental dyslexia.

The visual word form area (VWFA) in the left ventral occipito-temporal (vOT) cortex is key to fluent reading in children and adults. Diminished VWFA activation during print processing tasks is a common finding in subjects with severe reading problems. Here, we report fMRI data from a multicentre study with 140 children in primary school (7.9-12.2 years; 55 children with dyslexia, 73 typical readers, 12 intermediate readers). All performed a semantic task on visually presented words and a matched control task on symbol strings. With this large group of children, including the entire spectrum from severely impaired to highly fluent readers, we aimed to clarify the association of reading fluency and left vOT activation during visual word processing. The results of this study confirm reduced word-sensitive activation within the left vOT in children with dyslexia. Interestingly, the association of reading skills and left vOT activation was especially strong and spatially extended in children with dyslexia. Thus, deficits in basic visual word form processing increase with the severity of reading disability but seem only weakly associated with fluency within the typical reading range suggesting a linear dependence of reading scores with VFWA activation only in the poorest readers.

Ultrafast transition between exciton phases in van der Waals heterostructures.

Heterostructures of atomically thin van der Waals bonded monolayers have opened a unique platform to engineer Coulomb correlations, shaping excitonic1-3, Mott insulating4 or superconducting phases5,6. In transition metal dichalcogenide heterostructures7, electrons and holes residing in different monolayers can bind into spatially indirect excitons1,3,8-11 with a strong potential for optoelectronics11,12, valleytronics1,3,13, Bose condensation14, superfluidity14,15 and moiré-induced nanodot lattices16. Yet these ideas require a microscopic understanding of the formation, dissociation and thermalization dynamics of correlations including ultrafast phase transitions. Here we introduce a direct ultrafast access to Coulomb correlations between monolayers, where phase-locked mid-infrared pulses allow us to measure the binding energy of interlayer excitons in WSe2/WS2 hetero-bilayers by revealing a novel 1s-2p resonance, explained by a fully quantum mechanical model. Furthermore, we trace, with subcycle time resolution, the transformation of an exciton gas photogenerated in the WSe2 layer directly into interlayer excitons. Depending on the stacking angle, intra- and interlayer species coexist on picosecond scales and the 1s-2p resonance becomes renormalized. Our work provides a direct measurement of the binding energy of interlayer excitons and opens the possibility to trace and control correlations in novel artificial materials.

Increased fronto-striatal reward prediction errors moderate decision making in obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) has been linked to functional abnormalities in fronto-striatal networks as well as impairments in decision making and learning. Little is known about the neurocognitive mechanisms causing these decision-making and learning deficits in OCD, and how they relate to dysfunction in fronto-striatal networks. METHOD: We investigated neural mechanisms of decision making in OCD patients, including early and late onset of disorder, in terms of reward prediction errors (RPEs) using functional magnetic resonance imaging. RPEs index a mismatch between expected and received outcomes, encoded by the dopaminergic system, and are known to drive learning and decision making in humans and animals. We used reinforcement learning models and RPE signals to infer the learning mechanisms and to compare behavioural parameters and neural RPE responses of the OCD patients with those of healthy matched controls. RESULTS: Patients with OCD showed significantly increased RPE responses in the anterior cingulate cortex (ACC) and the putamen compared with controls. OCD patients also had a significantly lower perseveration parameter than controls. CONCLUSIONS: Enhanced RPE signals in the ACC and putamen extend previous findings of fronto-striatal deficits in OCD. These abnormally strong RPEs suggest a hyper-responsive learning network in patients with OCD, which might explain their indecisiveness and intolerance of uncertainty.

Differentiating Tumor Progression from Pseudoprogression in Patients with Glioblastomas Using Diffusion Tensor Imaging and Dynamic Susceptibility Contrast MRI.

BACKGROUND AND PURPOSE: Early assessment of treatment response is critical in patients with glioblastomas. A combination of DTI and DSC perfusion imaging parameters was evaluated to distinguish glioblastomas with true progression from mixed response and pseudoprogression. MATERIALS AND METHODS: Forty-one patients with glioblastomas exhibiting enhancing lesions within 6 months after completion of chemoradiation therapy were retrospectively studied. All patients underwent surgery after MR imaging and were histologically classified as having true progression (>75% tumor), mixed response (25%-75% tumor), or pseudoprogression (<25% tumor). Mean diffusivity, fractional anisotropy, linear anisotropy coefficient, planar anisotropy coefficient, spheric anisotropy coefficient, and maximum relative cerebral blood volume values were measured from the enhancing tissue. A multivariate logistic regression analysis was used to determine the best model for classification of true progression from mixed response or pseudoprogression. RESULTS: Significantly elevated maximum relative cerebral blood volume, fractional anisotropy, linear anisotropy coefficient, and planar anisotropy coefficient and decreased spheric anisotropy coefficient were observed in true progression compared with pseudoprogression (P < .05). There were also significant differences in maximum relative cerebral blood volume, fractional anisotropy, planar anisotropy coefficient, and spheric anisotropy coefficient measurements between mixed response and true progression groups. The best model to distinguish true progression from non-true progression (pseudoprogression and mixed) consisted of fractional anisotropy, linear anisotropy coefficient, and maximum relative cerebral blood volume, resulting in an area under the curve of 0.905. This model also differentiated true progression from mixed response with an area under the curve of 0.901. A combination of fractional anisotropy and maximum relative cerebral blood volume differentiated pseudoprogression from nonpseudoprogression (true progression and mixed) with an area under the curve of 0.807. CONCLUSIONS: DTI and DSC perfusion imaging can improve accuracy in assessing treatment response and may aid in individualized treatment of patients with glioblastomas.

Migration of polyolefin oligomeric saturated hydrocarbons (POSH) into food.

POSH are polyolefin oligomeric saturated hydrocarbons, such as oligomers from polyethylene or polypropylene. POSH that have migrated into foods are easily mistaken for mineral oil-saturated hydrocarbons (MOSH). In fact, both POSH and MOSH largely consist of highly isomerised branched and possibly cyclic hydrocarbons, both forming humps of unresolved components in gas chromatography. Chromatograms are reported to show typical elution patterns of POSH and help analysts distinguishing POSH from MOSH as far as possible. Since the structures of the POSH are not fundamentally different from those of the MOSH, it would be prudent to apply the evaluation of the MOSH. However, the migration is frequently beyond that for which safety has been demonstrated. This is shown for a few examples, particularly for powdered formula for babies.

Does greater low frequency EEG activity in normal immaturity and in children with epilepsy arise in the same neuronal network?

Greater low frequency power (<8 Hz) in the electroencephalogram (EEG) at rest is normal in the immature developing brain of children when compared to adults. Children with epilepsy also have greater low frequency interictal resting EEG activity. Whether these power elevations reflect brain immaturity due to a developmental lag or the underlying epileptic pathophysiology is unclear. The present study addresses this question by analyzing spectral EEG topographies and sources for normally developing children and children with epilepsy. We first compared the resting EEG of healthy children to that of healthy adults to isolate effects related to normal brain immaturity. Next, we compared the EEG from 10 children with generalized cryptogenic epilepsy to the EEG of 24 healthy children to isolate effects related to epilepsy. Spectral analysis revealed that global low (delta: 1-3 Hz, theta: 4-7 Hz), medium (alpha: 8-12 Hz) and high (beta: 13-25 Hz) frequency EEG activity was greater in children without epilepsy compared to adults, and even further elevated for children with epilepsy. Topographical and tomographic EEG analyses showed that normal immaturity corresponded to greater delta and theta activity at fronto-central scalp and brain regions, respectively. In contrast, the epilepsy-related activity elevations were predominantly in the alpha band at parieto-occipital electrodes and brain regions, respectively. We conclude that lower frequency activity can be a sign of normal brain immaturity or brain pathology depending on the specific topography and frequency of the oscillating neuronal network.

Recurrent uveitis in horses: vitreal examinations with ultrastructural detection of leptospires.

This study documents the examination of 17 horses (both sexes, 3-18 years old) suffering from spontaneous equine recurrent uveitis (ERU). Vitreal samples obtained by pars plana vitrectomy were examined macroscopically and ultrastructurally, and in most cases also by cultural examination, by microscopic agglutination test (MAT) and by polymerase chain reaction. In 24% (4/17) of the animals, ultrastructural examination by electron microscopy revealed intact leptospiral bacteria in the vitreous. The leptospires were detected freely in the vitreous and also incorporated by a phagocyte. They were surrounded by a rim of proteinaceous material which was reduced around a phagocytosed leptospira. Ninety-four per cent (16/17) of the vitreal samples presented significant antibody levels in the MAT, mostly against leptospiral serovar Grippotyphosa. Seventy-five per cent (9/12) of bacterial culture examinations were positive for leptospira. Polymerase chain reaction was positive in all (16/16) examinations performed. Our findings support previous reports suggesting that leptospires play an important role in the pathogenesis of ERU. Interestingly, this study found leptospires after secondary and later acute episodes. A persistent leptospiral infection is therefore suggested as the cause of ERU.

Canine leptospirosis infections - clinical signs and outcome with different suspected Leptospira serogroups (42 cases).

OBJECTIVES: The aim of the study was to investigate the presence of serum antibodies to different Leptospira serogroups in dogs with a clinical diagnosis of leptospirosis in southern Germany and to compare seroreactivity to different serogroups with history, clinical signs, laboratory findings and survival rate. METHODS: In this study, the data of 42 dogs with the diagnosis of leptospirosis were evaluated retrospectively. Dogs were presented to the Small Animal Medicine Teaching Hospital (Medizinische Kleintierklinik) of the Ludwig Maximilians University Munich, Germany, between 1990 to 2003. RESULTS: Reactivity to the serogroup grippotyphosa (13/42) was most frequently present, followed by reactivity to the serogroup saxkoebing (10/42). There was no difference in the clinical picture and the laboratory changes between dogs whose sera were reactive to different serogroups. CLINICAL SIGNIFICANCE: Most of the dogs with leptospirosis in southern Germany had sera reacting to serogroups other than icterohaemorrhagiae and canicola, which are contained in the vaccine. Thus, currently available vaccines in Europe do not protect against the most common Leptospira organisms associated with clinical disease.

[Detection of leptospira in the vitreous body of horses without ocular diseases and of horses with equine recurrent uveitis (ERU) using transmission-electron microscopy]. / Darstellung von Leptospiren im Glaskörper augengesunder und an ERU erkrankter Pferde mittels Transmissions-Elektronenmikroskopie.

Equine recurrent uveitis (ERU) is caused by persistent intraocular leptospira, which appear to use the vitreous body as a refuge. The detection of leptospira in the vitreous body of horses with spontaneous ERU by histological methods has not yet been described. Thirty eight vitreous body samples from 36 horses with ERU (collected during vitrectomy), and 10 vitreous body samples obtained from 5 horses without ocular disease (control group) were examined by transmission electron microscopy. Prior to sample collection, 2 ml of a leptospira culture suspension were injected into the vitreous body of 2 eyes enucleated from horses of the control group. The detection of leptospira in samples, experimentally inoculated with these bacteria was uncomplicated; in vitreous body samples from horses with spontaneous ERU the detection was successful in only a few cases (3/38). The morphologically varying envelope of leptospira in vitreous body samples of horses which developed ERU spontaneously suggests the existence of a bacterial masquerade in vivo.

Microbiological and serological study of leptospirosis in horses at slaughter: first isolations.

A bacteriological survey of kidneys from 145 abattoir horses was performed, which resulted in the isolation of two Leptospira strains. The isolates were serologically typed as belonging to serogroups Australis and Pomona, and REA identified them as L. interrogans serovar Bratislava and L. kirschneri serovar Tsaratsovo, respectively. These are the first Leptospira isolates obtained from horses in Portugal and the Bratislava strain is the first serogroup Australis strain to be isolated in this country. The 145 horses were also serologically tested for leptospiral antibodies, and 37% had MAT titres #10878;1:10.

Method for determining novolac glycidyl ether (NOGE) and its chlorohydrins in oily canned foods.

In order to be analysed, NOGE components with epoxy groups must be separated from polar food material to prevent losses through uncontrolled reactions. Samples are homogenized minimally and extracted into a phase of minimized polarity. The NOGE components are then separated from the oil by extraction into acetonitrile and analysed by RPLC with fluorescence detection. Hydrolysis of the epoxy, and chlorohydroxy functions to diols may help the analysis. Application and limitations of the method are illustrated by examples. Detection limits vary widely, depending on interfering food components, but legal limits below 1 mg/kg can hardly be reliably enforced.

Clinical, microbiological and pathological observations in laboratory beagle dogs infected with leptospires of the serogroup Sejroe.

In beagle dogs infections with two different serovars of serogroup Sejroe are described. Saxkoebing titres of 27 beagle dogs were controlled for 7 to 9 months. Dogs serologically positive for saxkoebing showed no clinical symptoms. From the urine, an isolation of the microorganisms was possible. At necropsy, there was no evidence of any changes related to the proven infection. Histopathologically, in animals with persistent titres a mild interstitial nephritis was found. No changes were observed in the liver. Another three beagle dogs died after about two days of acute clinical illness with febrile temperature, exsiccosis and hematuria. Histopathologically, incipient inflammation was seen in the liver and kidneys. Besides, hepatic cholestasis, renal hemoglobin casts and degeneration of renal tubular epithelia were observed. In concurrent animals, an infection with another serovar of serogroup Sejroe was proven serologically. This serovar was also isolated. Transmission and spreading of leptospirosis within animals shelters or laboratories from clinically healthy carriers and its prevention as well as the protection of animal caretakers are discussed. Since leptospires are sensitive to physical and chemical methods of disinfection, this is easily feasible. However, the optimal prevention appears to be a stock- or population-specific vaccination.

[35 leptospira isolated from the vitreous body of 32 horses with recurrent uveitis (ERU)]. / 35 Leptospirenisolationen aus Glaskörpern von 32 Pferden mit rezidivierender Uveitis (ERU).

130 vitreous samples, systematically collected in 1998 from 117 horses during vitrectomy, were cultured for the presence of leptospires. All horses suffered from equine recurrent uveitis (ERU), also known as periodic ophthalmia or moon blindness, and were treated surgically to combat painful attacks, and to preserve vision. In 35 out of 130 vitreous samples (35/130 = 26.9%), leptospires could be isolated. These isolates belong to the grippotyphosa serogroup (n = 31) and to the australis serogroup (n = 4). So, for the first time, leptospires were recovered from eyes in vivo in a large number of horses with ERU. Vitreous samples and one serum sample from each horse were also tested for leptospiral antibodies using the microscopic agglutination test (MAT). In 92 vitreous samples (92/130 = 70.7%) and 96 serum samples (96/117 = 82.0%) leptospiral antibodies were detected at a dilution of > 1:100. The presence of intact leptospires and specific antibodies in eyes affected with ERU demonstrates a local antibody production to leptospiral antigen. These results indicate an important etiological role of leptospires in equine recurrent uveitis.

Angiogenesis and Cancer Control: From Concept to Therapeutic Trial.

BACKGROUND: There is extraordinary interest in developing angiosuppressive agents for cancer treatment. Several new agents appear promising for the treatment of a variety of human cancers. Current concepts and new agents in clinical trials are the focus of this article. In particular, the introduction of a new treatment for human brain tumors is presented in detail, using an antiangiogenic agent, penicillamine, and depletion of an obligatory cofactor of angiogenesis, copper. METHODS: The explosive increase in literature on antiangiogenesis is reviewed using computerized search, findings presented at the recent national cancer and angiogenesis meetings. A specific protocol, NABTT 97-04, "Penicillamine and Copper Reduction for Newly Diagnosed Glioblastoma," is presented as an example of angiotherapeutic drug discovery. RESULTS: A number of promising molecular approaches are being introduced to suppress tumor angiogenesis. Major categories of angiogenesis antagonists include protease inhibitors, direct inhibitors of endothelial cell proliferation and migration, suppression of angiogenic growth factors, inhibition of endothelial-specific integrin/ survival signaling, chelators of copper, and inhibitors with specific other mechanisms. The preliminary results of early trials offer a glimpse into how antiangiogenesis therapy will be integrated into future care of the patient with cancer. CONCLUSIONS: Thirty-five antiangiogenesis therapies are currently being evaluated in clinical trials. As we learn more about the fundamental mechanisms of angiogenesis, eg, the role of copper in growth factor activation, effective methods of cancer control will be implemented.

MRI measurement of brain tumor response: comparison of visual metric and automatic segmentation.

An automatic magnetic resonance imaging (MRI) multispectral segmentation method and a visual metric are compared for their effectiveness to measure tumor response to therapy. Automatic response measurements are important for multicenter clinical trials. A visual metric such as the product of the largest diameter and the largest perpendicular diameter of the tumor is a standard approach, and is currently used in the Radiation Treatment Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (EGOG) clinical trials. In the standard approach, the tumor response is based on the percentage change in the visual metric and is categorized into cure, partial response, stable disease, or progression. Both visual and automatic methods are applied to six brain tumor cases (gliomas) of varying levels of segmentation difficulty. The analyzed data were serial multispectral MR images, collected using MR contrast enhancement. A fully automatic knowledge guided method (KG) was applied to the MRI multispectral data, while the visual metric was taken from the MRI films using the T1 gadolinium enhanced image, with repeat measurements done by two radiologists and two residents. Tumor measurements from both visual and automatic methods are compared to "ground truth," (GT) i.e., manually segmented tumor. The KG method was found to slightly overestimate tumor volume, but in a consistent manner, and the estimated tumor response compared very well to hand-drawn ground truth with a correlation coefficient of 0.96. In contrast, the visually estimated metric had a large variation between observers, particularly for difficult cases, where the tumor margins are not well delineated. The inter-observer variation for the measurement of the visual metric was only 16%, i.e., observers generally agreed on the lengths of the diameters. However, in 30% of the studied cases no consensus was found for the categorical tumor response measurement, indicating that the categories are very sensitive to variations in the diameter measurements. Moreover, the method failed to correctly identify the response in half of the cases. The data demonstrate that automatic 3D methods are clearly necessary for objective and clinically meaningful assessment of tumor volume in single or multicenter clinical trials.

[Intraocular and serum antibody titers to Leptospira in 150 horses with equine recurrent uveitis (ERU) subjected to vitrectomy]. / Intraokulare und Serumantikörpertiter gegen Leptospiren bei 150 wegen equiner rezidivierender Uveitis (ERU) vitrektomierten Pferden.

Between February 1993 and July 1997, 150 horses suffering from recurrent uveitis were subjected to parsplana vitrectomy. In these horses, antibody titers to Leptospira serovars were determined in serum samples and in samples from diluted vitreous collected during vitrectomy. Although the vitreous samples were diluted with 250 ml of balanced salt solution, in 86 of the 150 vitreous samples (= 57%) the antibody titers were higher than in the serum samples. Additionally, serum samples from 77 horses suffering from ERU, but which were not subjected to vitrectomy, and serum samples from 97 horses with clinically normal eyes were analyzed for antibodies to Leptospira serovars. Among the 227 horses with ERU (150 treated surgically, 77 treated conservatively) 50 horses (50 of 227 = 22%) had serum antibody titers to Leptospira serovars of > or = 1:800. Among the 97 horses with clinically normal eyes, 24 horses (24 of 97 = 25%) had serum antibody titers to Leptospira serovars of > or = 1:800. In undiluted vitreous samples from 20 horses with clinically normal eyes, no antibody titers to Leptospira serovars could be detected. Among the 150 horses with ERU, 90 animals (90 of 150 = 60%) had antibody titers of > or = 1:100 in the diluted vitreous samples, the difference being highly significant (p < 0.001). The findings are discussed in relation to the etiology of recurrent uveitis in horses.

Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: an analysis based on Surveillance, Epidemiology, and End Results (SEER) data, 1973-1991.

OBJECT: The authors present population-based survival rate estimates for patients with malignant primary brain tumors based on an analysis of 18 years of data obtained from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. METHODS: Estimates of survival rates at 2 and 5 years after diagnosis for patients with specific histological tumor types were categorized by patient's age at diagnosis (< or = 20 years, 21-64 years, and 65 years or older) and by the time period in which the patients were diagnosed (1973-1980, 1981-1985, 1986-1991). Where appropriate, survival estimates were adjusted for changing patterns in the mean age at diagnosis. CONCLUSIONS: The authors observed a pattern of declining survival rates in patients with increasing age of the patient at diagnosis for most histological groups and overall improvements in survival rates of patients across these time periods adjusting for age at diagnosis. There were improvements in 2- and 5-year survival rates over the three time periods for children and adults with medulloblastoma and for adults with astrocytoma and oligodendroglioma. Improvements in survival rates for pediatric patients with medulloblastoma have leveled off in the most recent time period, and gender differences in survival rates for patients with this tumor, which were present in the 1970s, have disappeared. Clinically significant improvements in survival rates were not apparent in patients aged 65 years and older. Changes in diagnostic and treatment procedures since the mid-1970s have resulted in improved survival rates for patients diagnosed as having medulloblastoma, oligodendroglioma, and astrocytoma, controlling for age at diagnosis. Glioblastoma multiforme continues to be the most intractable brain tumor.