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Job coaches are not typically trained to implement systematic instructional strategies to teach vocational skills to students with intellectual and developmental disabilities (IDD). This study replicated and expanded the evaluation of a job coach behavioral skills training program designed by Brock et al. (2016) to teach participants to implement task analysis, simultaneous prompting, and system of least prompts to teach vocational tasks to students with IDD. We used a multiple probe design with probe conditions across strategies, replicated across three participants, to assess acquisition and generalization. Participants demonstrated mastery of the three instructional strategies in simulated assessments with actors and generalized use of the strategies to teach novel vocational tasks to student interns with IDD. Implications for future research and practice are discussed.

Coordinated movements of epithelia tissue are linked with active matter processes. We here consider the influence of curvature on the spatiotemporal arrangements and the shapes of the cells. The cells are represented by a multiphase field model which is defined on the surface of a sphere. Besides the classical solid and liquid phases, which depend on the curvature of the sphere, on mechanical properties of the cells and the strength of activity, we identify a phase of global rotation. This rotation provides a coordinated cellular movement which can be linked to tissue morphogenesis. This investigation on a sphere is a first step to investigate the delicate interplay between topological constraints, geometric properties and collective motion. Besides the rotational state we also analyse positional defects, identify global nematic order and study the associated orientational defects., Comment: 7 pages, 8 figures

Contact inhibition limits migration and proliferation of cells in cell colonies. We consider a multiphase field model to investigate the growth dynamics of a cell colony, composed of proliferating cells. The model takes into account the mechanisms of contact inhibition of locomotion and proliferation by local mechanical interactions. We compare non-migrating and migrating cells, in order to provide a quantitative characterization of the dynamics and analyse the velocity of the colony boundary for both cases. Additionally, we measure single cell velocities, number of neighbour distributions, as well as the influence of stress and age on positions of the cells and with respect to each other. We further compare the findings with experimental data for Madin-Darby canine kidney cells, 5 pages, 5 figures

Human immunodeficiency virus-1 (HIV) infection of the central nervous system damages synapses and promotes axonal injury, ultimately resulting in HIV-associated neurocognitive disorders (HAND). The mechanisms through which HIV causes damage to neurons are still under investigation. The cytoskeleton and associated proteins are fundamental for axonal and dendritic integrity. In this article, we review evidence that HIV proteins, such as the envelope protein gp120 and Transactivator of transcription (Tat), impair the structure and function of the neuronal cytoskeleton. Investigation into the effects of viral proteins on the neuronal cytoskeleton may provide a better understanding of HIV neurotoxicity and suggest new avenues for additional therapies.

OBJECTIVE: Postmortem brains of subjects diagnosed with human immunodeficiency virus-1 (HIV) associated neurocognitive disorders (HAND) exhibit loss of dendrites. However, the mechanisms by which synapses are damaged are not fully understood. DESIGN: Dendrite length and remodeling occurs via microtubules (MTs) the dynamics of which are regulated by microtubule binding proteins, including MT associated protein 2 (MAP2). The HIV protein gp120 is neurotoxic and interferes with neuronal MTs. We measured MAP2 concentrations in human cerebrospinal fluid (CSF) and MAP2 immunoreactivity in rat cortical neurons exposed to HIV and gp120. METHODS: First, we examined whether HIV affects MAP2 levels by analyzing the CSF of 27 persons living with HIV (PLH) whose neurocognitive performance had been characterized. We then used rat cortical neurons to study the mechanisms of HIV-mediated dendritic loss. RESULTS: PLH who had HAND had greater MAP2 concentrations within the CSF than cognitive normal PLH. In cortical neurons, the deleterious effect of HIV on MAP2 positive dendrites occurred through a gp120-mediated mechanism. The neurotoxic effect of HIV was blocked by a CCR5 antagonist and prevented by Helix-A, a peptide that displaces gp120 from binding to MTs, conjugated to a nanolipoprotein particle delivery platform. CONCLUSIONS: Our findings support that HIV at least partially effects its neurotoxicity via neuronal cytoskeleton modifications and provide evidence of a new therapeutic compound that could be used to prevent the HIV-associated neuropathology.

Despite successful antiretroviral drug therapy, a subset of human immunodeficiency virus-1 (HIV)-positive individuals still display synaptodendritic simplifications and functional cognitive impairments referred to as HIV-associated neurocognitive disorders (HANDs). The neurological damage observed in HAND subjects can be experimentally reproduced by the HIV envelope protein gp120. However, the complete mechanism of gp120-mediated neurotoxicity is not entirely understood. Gp120 binds to neuronal microtubules and decreases the level of tubulin acetylation, suggesting that it may impair axonal transport. In this study, we utilized molecular and pharmacological approaches, in addition to microscopy, to examine the relationship between gp120-mediated tubulin deacetylation, axonal transport, and neuronal loss. Using primary rat cortical neurons, we show that gp120 decreases acetylation of tubulin and increases histone deacetylase 6 (HDAC6), a cytoplasmic enzyme that regulates tubulin deacetylation. We also demonstrate that the selective HDAC6 inhibitors tubacin and ACY-1215, which prevented gp120-mediated deacetylation of tubulin, inhibited the ability of gp120 to promote neurite shortening and cell death. We further observed by co-immunoprecipitation and confirmed with mass spectroscopy that exposure of neurons to gp120 decreases the association between tubulin and motor proteins, a well-established consequence of tubulin deacetylation. To assess the physiological consequences of this effect, we examined the axonal transport of brain-derived neurotrophic factor (BDNF). We report that gp120 decreases the velocity of BDNF transport, which was restored to baseline levels when neurons were exposed to HDAC6 inhibitors. Overall, our data suggest that gp120-mediated tubulin deacetylation causes impairment of axonal transport through alterations to the microtubule cytoskeleton.

Human immunodeficiency virus 1 and its envelope protein gp120 reduce synaptodendritic complexity. However, the mechanisms contributing to this pathological feature are still not understood. The proneurotrophin brain-derived neurotrophic factor promotes synaptic simplification through the activation of the p75 neurotrophin receptor (p75NTR). Here, we have used gp120 transgenic (gp120tg) mice to investigate whether p75NTR has a role in gp120-mediated neurotoxicity. Old (~10 months) gp120tg mice exhibited an increase in proneurotrophin brain-derived neurotrophic factor levels in the hippocampus as well as a decrease in the number of dendritic spines when compared to age-matched wild type. These effects were not observed in 3- or 6-month-old mice. To test if the reduction in spine density and morphology is caused by the activation of p75NTR, we crossed gp120tg mice with p75NTR null mice. We found that deletion of only 1 copy of the p75NTR gene in gp120tg mice is sufficient to normalize the number of hippocampal spines, strongly suggesting that the neurotoxic effect of gp120 is mediated by p75NTR. These data indicate that p75NTR antagonists could provide an adjunct therapy against synaptic simplification caused by human immunodeficiency virus 1.

The Angiotensin II Receptor Blocker (ARB) Telmisartan reduces inflammation through Angiotensin II AT1 receptor blockade and peroxisome proliferator-activated receptor gamma (PPARγ) activation. However, in a mouse microglia-like BV2 cell line, imitating primary microglia responses with high fidelity and devoid of AT1 receptor gene expression or PPARγ activation, Telmisartan reduced gene expression of pro-injury factors, enhanced that of anti-inflammatory genes, and prevented LPS-induced increase in inflammatory markers. Using global gene expression profiling and pathways analysis, we revealed that Telmisartan normalized the expression of hundreds of genes upregulated by LPS and linked with inflammation, apoptosis and neurodegenerative disorders, while downregulating the expression of genes associated with oncological, neurodegenerative and viral diseases. The PPARγ full agonist Pioglitazone had no neuroprotective effects. Surprisingly, the PPARγ antagonists GW9662 and T0070907 were neuroprotective and enhanced Telmisartan effects. GW9226 alone significantly reduced LPS toxic effects and enhanced Telmisartan neuroprotection, including downregulation of pro-inflammatory TLR2 gene expression. Telmisartan and GW9662 effects on LPS injury negatively correlated with pro-inflammatory factors and upstream regulators, including TLR2, and positively with known neuroprotective factors and upstream regulators. Gene Set Enrichment Analysis (GSEA) of the Telmisartan and GW9662 data revealed negative correlations with sets of genes associated with neurodegenerative and metabolic disorders and toxic treatments in cultured systems, while demonstrating positive correlations with gene sets associated with neuroprotection and kinase inhibition. Our results strongly suggest that novel neuroprotective effects of Telmisartan and GW9662, beyond AT1 receptor blockade or PPARγ activation, include downregulation of the TLR2 signaling pathway, findings that may have translational relevance.

The human immunodeficiency virus (HIV) envelope protein gp120 promotes axonal damage and neurite pruning, similar to that observed in HIV-positive subjects with neurocognitive disorders. Thus, gp120 has been used to examine molecular and cellular pathways underlying HIV-mediated neuronal dysfunction. Gp120 binds to tubulin beta III, a component of neuronal microtubules. Microtubule function, which modulates the homeostasis of neurons, is regulated by polymerization and post-translational modifications. Based on these considerations, we tested the hypothesis that gp120 induces dynamic instability of neuronal microtubules. We first observed that gp120 prevents the normal polymerization of tubulin in vitro. We then tested whether gp120 alters the post-translational modifications in tubulin by examining the ability of gp120 to change the levels of acetylated tubulin in primary rat neuronal cultures. Gp120 elicited a time-dependent decrease in tubulin acetylation that was reversed by Helix-A peptide, a compound that competitively displaces the binding of gp120 to neuronal microtubules. To determine whether post-translational modifications in tubulin also occur in vivo, we measured acetylated tubulin in the cerebral cortex of HIV transgenic rats (HIV-tg). We observed a decrease in tubulin acetylation in 5- and 9-month-old HIV-tg rats when compared to age-matched wild type. Neither changes in microglia morphology nor alterations in mRNA levels for interleukin-1β and tumor necrosis factor α were detected in 5-month-old animals. Our findings propose neuronal microtubule instability as a novel mechanism of HIV neurotoxicity, without evidence of enhanced inflammation.

Neurons that endocytose the human immunodeficiency virus-1 (HIV) protein gp120 exhibit neurite retraction and activation of caspase-3, suggesting that the endocytic process may be crucial for gp120-mediated neuronal injury. The goal of this study is to demonstrate that internalization and accumulation of gp120 play a role in its neurotoxic effects. In mammalian cells, endocytosis is primarily a dynamin-dependent process. To establish whether gp120 is endocytosed in a dynamin-dependent manner, we used fibroblasts in which deletion of dynamins was induced by tamoxifen. We observed a robust reduction of intracellular gp120 immunoreactivity in tamoxifen-treated cells. To examine whether endocytosis of gp120 is crucial for its neurotoxic effect, we blocked gp120 internalization into primary rat cortical neurons by dynasore, an inhibitor of the dynamin GTP-ase activity. We found that dynasore blocks both gp120 internalization and neurotoxicity. We then utilized gp120-loaded mesoporous silica nanoparticles to deliver gp120 intracellularly. We established that once internalized, gp120 is neurotoxic regardless of chemokine receptor activation. Our data suggest that dynamin-dependent endocytosis of gp120 is critical for its neurotoxicity.

Morphine has been shown to increase the expression of brain-derived neurotrophic factor (BDNF) in the brain. However, little is known about the effect of morphine withdrawal on BDNF and its precursor protein, or proBDNF, which induces neuronal apoptosis. In this work, we examined whether BDNF and proBDNF levels change in rats chronically injected with escalating doses of morphine and those who undergo spontaneous withdrawal for 60 h. We observed, in the frontal cortex and striatum, that the ratio of BDNF to proBDNF changed depending upon the experimental paradigm. Morphine treatment and morphine withdrawal increased both BDNF and proBDNF levels. However, the increase in proBDNF immunoreactivity in withdrawal rats was more robust than that observed in morphine-treated rats. proBDNF is processed either intracellularly by furin or extracellularly by the tissue plasminogen activator (tPA)/plasminogen system or matrix metalloproteases (MMPs). To examine the mechanisms whereby chronic morphine treatment and morphine withdrawal differentially affects BDNF/proBDNF, the levels MMP-3 and MMP-7, furin, and tPA were analyzed. We found that morphine increases tPA levels, whereas withdrawal causes a decrease. To confirm the involvement of tPA in the morphine-mediated effect on BDNF/proBDNF, we exposed cortical neurons to morphine in the presence of the tPA inhibitor plasminogen activator inhibitor-1 (PAI-1). This inhibitor reversed the morphine-mediated decrease in proBDNF, supporting the hypothesis that morphine increases the availability of BDNF by promoting the extracellular processing of proBDNF by tPA. Because proBDNF could negatively influence synaptic repair, preventing withdrawal is crucial for reducing neurotoxic mechanisms associated with opioid abuse.

Hypoxia-inducible transcription factor-1 (HIF-1) is critically involved in adaptive endogenous mechanisms to hypoxic brain injury by transcriptional activation of specific target genes that restore oxygen supply. Exogenously, neuroprotective properties of levetiracetam (LEV) have been suggested in experimental cerebral ischemia and epilepsy. We aimed to elucidate 1) effects of acute hypoxic distress on HIF-1 and vasoactive target genes, and 2) effects of LEV on HIF-1-regulated mechanisms in the brain at early developmental stages. To this end, we studied the impact of hypoxia in the presence or absence of LEV on the O2-dependent HIF-1alpha subunit as well as on VEGF and iNOS in the developing brain of normoxic and hypoxic mice. C57BL/6 mice (P0, P7) were treated with saline or LEV (i.p.; 50 mg/kg) 1 h before exposure to either normoxia (21% O2; N) or hypoxia (8% O2 of 6 h; H) without reoxygenation. HIF-1alpha was analyzed by Western blot and immunohistochemistry and mRNA levels were quantified by TaqMan RT-PCR. Hypoxia led to prominent accumulation of cerebral HIF-1alpha protein in cortical neurons and glial cells and significant up-regulation of VEGF mRNA at P0 (N, 0.018+/-0.002, vs. H, 0.031+/-0.003, n=6; p

Intermittent hypoxia seems to be a major pathomechanism of obstructive sleep apnea-associated progression of atherosclerosis. The goal of the present study was to assess the influence of hypoxia on endothelial function depending on the initial stage of vasculopathy. We used 16 ApoE-/- mice were exposed to a 6-week-intermittent hypoxia either immediately (early preatherosclerosis) or after 5 weeks of high-cholesterol diet (advanced preatherosclerosis). Another 16 ApoE-/- mice under normoxia served as corresponding controls. Endothelial function was measured by an organ bath technique. Blood plasma CD31+/annexin V+ endothelial microparticles as well as sca1/flk1+ endothelial progenitor cells in blood and bone marrow were analyzed by flow cytometry. The findings were that intermittent hypoxia impaired endothelial function (56.6±6.2% of maximal phenylephrine-induced vasoconstriction vs. 35.2±4.1% in control) and integrity (increased percentage of endothelial microparticles: 0.28±0.05% vs. 0.15±0.02% in control) in early preatherosclerosis. Peripheral repair capacity expressed as the number of endothelial progenitor cells in blood was attenuated under hypoxia (2.0±0.5% vs. 5.3±1.9% in control), despite the elevated number of these cells in the bone marrow (2.0±0.4% vs. 1.1±0.2% in control). In contrast, endothelial function, as well as microparticle and endothelial progenitor cell levels were similar under hypoxia vs. control in advanced preatherosclerosis. We conclude that hypoxia aggravates endothelial dysfunction and destruction in early preatherosclerosis.

In this paper, a turbo-product-coded, quadrature-vestigial-sideband (QVSB), digital modulation and coding scheme are presented. This scheme is more complex than the VSB modulation and coding format employed for high-definition television; and it achieves spectral-efficiency performance within 4 to 5dB of the Shannon-Bound, with relatively conservative turbo-product-codes. Special QVSB bandlimiting, which is more restrictive than Nyquist filtering, is used to minimize crosstalk between its dual overlapping, quadrature data channels. To unravel the residual cross-channel interference for detection, a quadrature-crosstalk maximum-likelihood-sequence-estimator (QC-MLSE) is needed. The QC-MLSE output is 'hard- to soft-decision converted' to improve subsequent decoding performance. An external interleaver was also used to augment the turbo-product-code's internal helical interleaver, for improved performance

We observed a novel 3.5 Mb 5q subtelomeric deletion in a 3-year-old girl with developmental delay, hypotonia and multiple minor anomalies. Comparison of her phenotype with the few published patients with terminal 5q35 deletions revealed several overlapping features, but also showed remarkable differences such as shortness of stature versus macrosomia. After the report of 5q35.3 microdeletions in Sotos syndrome we integrated the published BACs into the public draft sequence and exactly mapped the deletion size in our patient by FISH analysis with 15 BAC probes. We demonstrated that the deletion in our patient is immediately adjacent to the reported Sotos syndrome deletion site. Subtracting the symptoms of Sotos syndrome from the published patients with larger 5q35.3 deletions allowed us to delineate a distinct phenotype of prenatal lymphedema with increased nuchal translucency, pronounced muscular hypotonia and delay of reaching motor milestones, but speech development within normal limits, wide fontanels, failure to thrive with postnatal short stature, and multiple minor anomalies such as mildly bell-shaped chest, minor congenital heart disease, and a distinct facial gestalt, associated with the novel 3.5 Mb cryptic deletion. We further showed in our patient that the deletion of the LCT(4) synthase gene results in a reduction of cysteinyl leukotriene synthesis to about 65% compared to normal values. The prenatal nuchal lymphedema associated with this deletion syndrome my be related to the deletion of the FLT4 gene causing autosomal dominant primary lymphedema and contributes to the differential diagnosis of increased fetal nuchal translucency.

Fallbericht. Anhand eines Fallberichts werden der typische Verlauf eines Morbus Alexander vom infantilen Typ und die Moglichkeit der nichtinvasiven, molekulargenetischen Diagnosesicherung in vivo dargestellt. Aus den klinischen Befunden mit progressiver Makrozephalie, zerebralen Anfallen und Entwicklungsstillstand ergab sich zusammen mit dem neuroradiologischen Bild einer frontotemporal betonten Leukodystrophie die Verdachtsdiagnose eines Morbus Alexander.Der Nachweis einer heterozygoten De-novo-Mutation im GFAP-Gen (GFAP: glial fibrillary acidic protein) (R239H) des Patienten ermoglichte die Diagnosesicherung. Schlussfolgerung. Durch den Mutationsnachweis im GFAP-Gen sind die fruhe Diagnosesicherung eines Morbus Alexander sowie ggf. eine Pranataldiagnostik moglich.

Die 53-jahrige Patientin war mit einer plotzlich aufgetretenen Verwirrtheit und Orientierungslosigkeit aufgefallen. Die weitere neurologische Untersuchung war unauffallig, die Klinik bildete sich nach einigen Stunden vollstandig zuruck. Im 2 Tage spater durchgefuhrten MRT zeigte sich eine punktformige Diffusionsstorung im rechten lateralen Hippokampus. Diese Veranderung entspricht der typischen Bildmanifestation einer transienten globalen Amnesie (TGA).

AIM: Hormonal deficiencies, visual disturbances, or cerebral symptoms are often the symptoms through which craniopharyngiomas (CP) first become clinically manifest. As these symptoms can exist for a long period of time various specialists are often consulted before the final diagnosis is made. PATIENTS AND METHODS: Between the years 1970 and 1998, 37 children and adolescents with CP were treated in Erlangen. The documents of 35 patients (22 male, 13 female) were evaluated retrospectively. RESULTS: The median age of the children at diagnosis was 9,3 years (1,3 - 15,6 years). The most frequently documented symptoms were: headache 57 % (median duration 7 months; varying from 1 week to 6 years), visual disturbances 45 % (median duration 2 months, range 2 weeks to 10 years), and reduced growth 40 % (median duration 1 year, range 3 months to 5 years). On average the reported symptoms were present for 15 months (median 5 months, time span 1 week to 10 years). CONCLUSION: The clinical symptoms of CP are non-specific and highly varied. Endocrine disturbances are the primary objective finding. Correct interpretation of the symptoms are required for the early diagnosis of CP.

Aim: To increase the diagnostic value of Doppler sonography a uniform lumped parameter model of pulsatile blood flow in human arteries was derived from the serial and/or parallel connection of parallel oscillatory circuits. Methods and patients: In this setting the current (I) in the ohmic resistor (R) represents the volume flow in the vessel, the voltage (V) the blood pressure. The vessel compliance corresponds to the capacitance (C), the inductivity (L) represents the accelerated mass. The flow velocity (v) which is assessible non-invasively is given by v = I/A, where A is the cross-sectional area of the vessel. Mathematically, the model represents a two-dimensional Fourier-series of the input signal by the segments. Thus it seems to be evident that almost all forms of flow and pressure pulses can be generated. The equations of the model were solved numerically. Doppler-sonographically measured flow velocities in the ascending aorta were used as input signal. The parameters for A, R, L and C were optimized to gain the measured flow spectrum in the target vessel as model response. Results: Application in 14 children (aged 3-16 yrs.) with complicated migraine during a symptom-free interval revealed a significantly lowered cross sectional area of the middle cerebral artery on the side of the higher flow velocities. For both middle and posterior cerebral arteries, a decreased vessel compliance (C) (mean - 30 %) was found, whereas values for R and L were within normal limits. Conclusion: These findings suggest an altered vascular compliance even between attacks. This may contribute to the pathogenesis of migraine through increased cerebral impedance resulting in impaired cerebral perfusion. Zielsetzung: Um die diagnostische Aussage der dopplersonographischen Befunde zu erhohen, wurde ein Windkesselmodell durch Einbringen einer Induktivitat in einen Schwingkreis verandert und in mehreren Segmenten kombiniert. Methodik und Patienten: In dieser Anordnung entspricht der Strom (I) im ohmschen Widerstand R dem Volumenfluss im Blutgefas, die Spannung (V) dem arteriellen Blutdruck. Die Kapazitat C des Kondensators ist analog zur Compliance der Gefaswand, die Induktivitat L entspricht der beschleunigten Masse der intravasalen Blutsaule. Die dopplersonographisch ermittelte Flussgeschwindigkeit v entspricht I/A wobei A die Querschnittsflache des Gefases ist. Mathematisch kann das Modell als zweidimensionale Fourierannaherung der Zielflusskurve durch die Modellsegmente angesehen werden. Deswegen scheint es evident zu sein, dass alle real auftretenden Flusskurven bei genugend groser Anzahl von verwendeten Segmenten beliebig genau angenahert werden konnen. Als Eingangssignal wurden dopplersonographische Flussmessungen in der aszendierenden Aorta verwendet. Die Modellparameter (A, R, L, C) werden optimiert, um die Modellantwort an die in den intrakraniellen Zielgefasen gemessenen Flussprofile anzunahern. Ergebnisse: Die Anwendung bei 14 Kindern mit komplizierter Migrane (Alter 3 - 16 Jahre) ergab als Modellergebnis eine deutlich reduzierte relative Querschnittsflache der A. cerebri media mit der hoheren Flussgeschwindingkeit (bei 8 der 14 Patienten entsprechend der Seite der klinischen Symptomatik). Fur beide Aa. cerebri mediae und posteriores fand sich eine deutlich verminderte vaskulare Compliance C (im Mittel - 30 % im Vergleich zu dem Kontrollkollektiv), die Werte fur R und L zeigten keine signifikante Differenz zu der gesunden Kontrollgruppe. Schlussfolgerung: Die Ergebnisse sprechen fur eine beeintrachtigte Compliance der intrakraniellen Arterien bei Kindern mit komplizierter Migrane im symptomfreien Intervall. Diese verminderte Compliance konnte uber eine Erhohung der cerebralen Gesamtimpedanz (und damit Verminderung der Durchblutung) zur Pathogenese der Migrane beitragen.

Objective: To assess biochemical characteristics of adrenarche in patients with myelomeningocele (MMC), we examined serum levels of dehydroepiandrosterone sulfate (DHEAS) in prepubertal MMC patients. Patients and Methods: The study included a total of 54 prepubertal patients with MMC and shunted hydrocephalus: 13 patients (2 m, 11 f; aged 4.6–10.1 years, mean 8.1 ± 0.4) with isolated pubarche (Tanner stage PH 2–4, B1 or testes volume ≤3 ml) and 41 prepubertal MMC patients without pubarche (17 m, 24 f; aged 2.0–11.9 years; mean 6.8 ± 2.5). DHEAS levels were measured directly by chemiluminescence immunoassay (Nichols, USA). Auxological data (supine length, body mass index (BMI), arm span) and bone age (BA) were recorded. Results(mean ± SD): Basal DHEAS levels correlated with chronological age (CA) (r = 0.32, p < 0.05), BA (r = 0.65, p < 0.01; n = 23), BMI (r = 0.54, p < 0.01) and pubic hair stage (PH1 vs. PH2–4, r = 0.49, p < 0.01). 10/11 patients aged 2–4 years had DHEAS levels in the normal range, whereas 18/40 (45.0%) of the 5- to 9-year-old patients showed elevated levels (>+2 SDS). Ten patients with isolated pubarche (10/13; 2 m, 8 f; CA 8.3 ± 1.5 years) and 9 patients without pubarche (9/41; 6 m, 3 f; CA 6.9 ± 2.1 years) had elevated DHEAS levels (+6.34 and +4.05 SDS, respectively). The values correlated with BA/CA ratio (p < 0.05, n = 23). There was a trend to higher BMI SDS levels in patients with elevated DHEAS levels. Conclusion: Our data show an early and increased activation of adrenal androgen secretion in MMC patients.

GH deficiency (GHD) in patients with myelomeningocele leads to the question of whether these disabled patients should be treated with human GH. To date, only a few short-term reports of GH therapy are available in the literature, and long-term data for final height are lacking. We report auxological and laboratory data for seven prepubertal myelomeningocele patients with proven GHD (idiopathic GHD or neurosecretory dysfunction) during GH treatment. All patients (five males and two females; median chronological age, 6.6 yr) had shunted hydrocephalus and were treated with GH (0.5 IU/kg x week; 0.15 mg/kg x week; daily sc injections) over a median period of 38 months (range, 35-49 months). GH secretion was analyzed by measurement of spontaneous overnight GH secretion and two standard stimulation tests. Auxological parameters, bone age, serum levels of insulin-like growth factor I and insulin-like growth factor-binding protein-3, and neurological and orthopedic status were documented regularly. Median growth velocity of supine length improved during treatment (at start, 3.7 cm/yr; after 36 months, 5.7 cm/yr; P0.05), with highest levels 6 months after the start of therapy (8.1 cm/yr). The growth velocity of arm span was greater than these values. Supine length SD score for chronological age increased from -4.71 (at start) to -3.35 (after 36 months; P = NS), length SD score for bone age increased from -2.70 to -2.23 (P = NS), and arm span SD score increased from -2.98 to -1.75 (P0.05). The growth velocities of length and arm span remained significantly above the pretreatment values (P0.05). Symptomatic tethered cord associated with progression of scoliosis developed in two of seven children. GH treatment significantly improved the growth velocities of body length and arm span. However, the increase in length SD score was not significant, whereas arm span SD scores significantly improved over the study period.

In this paper, a new digital intermediate frequency modulator for conventional TV signals using digital signal processing is presented. A composite colour video signal and two associated audio signals are converted into a digital composite TV signal with spectrum at intermediate frequency. The modulator is designed for the high quality requirements that exist in professional equipment for CATV head ends. The architecture of the digital modulator shown is optimized for an implementation with ASICs. The signal processing with reduced complexity is described in detail, the structures and the design of the filters are illustrated and the simulated results are presented.

A new all-digital asynchronous sample-rate converter (SRC) for video signals with an effective resolution of 12 bits using digital signal processing is presented. It is designed for the high quality requirements that exist in professional equipment for CATV head ends. The architecture of the digital SRC which is optimized for an implementation with small memory and low processing power is shown in detail. Furthermore, the design of the building blocks is illustrated and the results of a bit level simulation are presented.

Autoimmunologische Prozesse werden sowohl fur die Entwicklung eines insulinabhangigen Diabetes mellitus als auch der Multiplen Sklerose verantwortlich gemacht. Wir berichten uber das nahezu zeitgleiche Auftreten beider Erkrankungen bei einer 14jahrigen Jugendlichen. Diskussion: Obwohl die Atiopathogenese beider Erkrankungen bislang nicht geklart ist, wies die zeitliche Korrelation infektiologischer und immunologischer Parameter in unserem Fall auf eine vorangegangene Virusinfektion bei entsprechender genetischer Pradisposition als gemeinsamen atiologischen Faktor hin.

A new low power integrated pressure sensor system with digital output (1 bit PDM signal) for medical applications is presented. The absolute pressure sensor comprising 400 nm thick surface micromachined polysilicon membranes for capacitive pressure detection and a monolithic integrated 2nd order sigma–delta-modulator including voltage reference and timing generator is extremely miniaturized on an area of approximately 3 mm 2 . For protection and biocompatibility reasons the sensor is coated with a silicone elastomer of up to 100 μm thickness, which does not influence the sensor's performance. The sensor system was tested in vitro in physiological NaCl solution, showing excellent results compared to a commercial available reference sensor. The sensor system is working well down to a supply voltage of 2.2 V with a power consumption of 0.5 mW. The resolution is better than 12 bit. Due to the small chip area, low power consumption and cost effective production process, the sensor is ideal for medical applications, e.g., in combination with telemetric power and data transmission [J. Zacheja, B. Clasbrummel, J. Binder, U. Steinau, Implantable Telemetric Endosystem for Minimal Invasive Pressure Measurements, MedTech95, Berlin, Germany, (1995)] as an implantable sensor to reduce the mortality risk of intensive care patients.

Wir berichten uber den Fall eines 14 Jahre alten Madchens mit bekannter Migrane ohne Aura, die wenige Stunden nach einer Commotio cerebri plotzlich heftigste pulsierende rechtstemporale Kopfschmerzen mit Ubelkeit und Erbrechen entwickelte und eine vollstandige Parese des N. oculomotorius rechts zeigte. Die morphologische Evaluation des ZNS mittels Dopplersonographie, Rontgen, CT, NMR und Angio-NMR sowie erganzende neurophysiologische und laborchemische Untersuchungen waren unauffallig. Die Ophthalmoplegie zeigte sich ab dem 6. postkommotionellen Tag rucklaufig, ab dem 10. Tag konnte eine vollstandige Restitutio ad integrum dokumentiert werden. In den folgenden 2 Monaten zeigte die Patientin, neben ihren typischen Migraneattacken, insgesamt 3 weitere ophthalmoplegische Kopfschmerzattacken mit zunehmend prolongiertem Verlauf, die durch die sonst gut wirksame Selbstmedikation mit Domperidon und Azetylsalizylsaure kaum beeinflust und erst durch die parenterale Gabe von Lysinazetylsalizylat, Prednisolon und Sumatriptan zufriedenstellend behandelt werden konnten. Diskussion: Die ophthalmoplegische Migrane ist eine seltene Migranevariante, bei der wiederholte Kopfschmerzattacken in Verbindung mit einer Parese des III., IV. und/oder VI. Hirnnervs beobachtet werden. Die Erstmanifestation eines opthalmoplegischen Verlaufs erfordert durch umfangreiche Untersuchungen den Ausschlus sekundarer Ursachen. Bei unauffalligen Befunden, typischer Klinik und entsprechender Anamnese kann im Verlauf die Diagnose einer ophthalmoplegischen Migrane gestellt und bei Bedarf eine spezifische Behandlung durchgefuhrt werden.

Background: On clinical grounds, arachnoid cysts are usually associated with neurological dysfunction. There is little information concerning their involvement in endocrinological disorders. Patients: The experience in 6 children (birth to 12 years) with hypothalamic-pituitary disturbances secondary to the presence of intracranial arachnoid cysts is reported and the literature is reviewed. Results: Three of our children were diagnosed with isolated hormone abnormalities (2 children with precocious puberty and 1 child with growth hormone, GH deficiency). One child presented the unusual combination of GH deficiency and precocious puberty. The remaining 2 children developed panhypopituitarism associated with diabetes insipidus. Conclusion: Arachnoid cysts may cause a wide spectrum of endocrinological disorders. Periodical and complete follow-up of every patient is recommended.

EB-PVD zirconia thermal barrier coatings have several advantages over coatings deposited with other techniques. Therefore EB-PVD coaters for deposition onto turbine blades are becoming of increasing interest. This applies to pilot coaters as well as to production coaters. Electron beams are not only suited for generating the evaporation process, they are also highly suitable for preheating the turbine blades. By means of an EB-preheating process the different parts of the rotating turbine blades (which are partially covered to prevent coating of this part) can be heated without temperature differences. Moreover, they can be heated faster than by conventional radiation heating. The possibility of unretarded EB-guidance creates the opportunity to generate very fast alternating heating patterns with matched changes of the power distribution on several parts of the turbine blade. The developed EB-heating technology permits for blades having a weight of more than 7 kg a synchronized temperature increase to 1000 °C within less than 15 min. This helps to shorten the vacuum cycle time per charge and increases the capacity of the coating plant. A modern conception of an EB-PVD production coater for zirconia thermal barrier coating on turbine blades containing the new EB-heating process will be introduced.

Benign epilepsy of childhood with rolandic spikes (BECRS) is an electroclinical syndrome characterized by partial sensorimotor seizures with centrotemporal spikes. We report a detailed localization analysis of spontaneous magnetic brain activities in seven BECRS patients using magnetoencephalography (MEG). All patients had BECRS diagnosis with typical seizures and electroencephalographic findings and five patients had minor psychomotor deficits. MEG was recorded over both parieto-temporal regions using a 2x37-channel biomagnetic system. The collected data were digitally bandpass-filtered (2-6, 14-30, or 1-70 Hz) to analyze slow- and fast-wave magnetic activities and rolandic spikes. Slow-wave activity was increased in four hemispheres of three patients. Increased fast-wave activity was found in all five patients with minor neuropsychological deficits. The presence of increased fast-wave magnetic brain activity appeared to cause functional anomalies in the higher brain function processes. In the spike analysis, the dipoles of rolandic spikes which constantly manifested anterior positivity in direction were concentrated in the superior rolandic region in four cases and the inferior rolandic region in three cases. The localizations of increased slow- and fast-wave activities were identical with those of the spikes. The seizure profiles were frequently characterized by the spike locations. Source localizations of the focal brain activities and rolandic spikes by MEG will contribute to the different diagnosis and pathophysiological elucidation of BECRS.

Monitoring of therapy-related late effects after acute lymphoblastic leukemia (ALL) therapy in childhood has become an increasingly important area in posttherapeutic patient surveillance. The usefulness of conventional electroencephalographic (EEG) investigations as part of these attempts is controversially discussed. However, EEG recordings have become a popular approach for judgement on the functional integrity of the central nervous system in this subject group. The present report focuses on this problem and discusses the question whether and to what extent conventional EEG recordings were correlated with further measures of central nervous system (CNS) integrity and therapeutic differences. EEGs were recorded in 110 subjects, asymptomatic long-term survivors of ALL in childhood, during a large retrospective multicenter study evaluating CNS late sequelae following antileukemic therapy in Germany and Austria. EEG findings were correlated with demographic data, illness- and treatment-related parameters, as well as with data on the morphological, neurological and psychological status of the participating subjects. At the time of follow-up the EEG was abnormal in 47 cases (42.7%). The most frequent EEG abnormalities observed were disturbances of the background activity (n=45, 95.8%), followed by hypersynchrone activities (n=10, 21.3%) and interhemispheric differences/focal slowings (n=6, 12.8%). With exception of age at diagnosis, none of the observed EEG abnormalities showed a correlation with any of the aforementioned illness- or treatment-related parameters. Eighty percent of the observed EEG abnormalities were found in children younger than 5 years at diagnosis. Children less than 2 years of age as well as those above 5 years at onset of disease showed a significantly reduced prevalence of EEG disturbances compared to subjects between 2 and 5 years at diagnosis. Neither the degree of illness nor therapy-specific differences showed any relationship to EEG outcome. There was no specific EEG finding for a specific morphological substrate, neurological or psychological deficiency and vice versa. Overall, there was no beneficial effect of routine EEG testing in children following therapy for ALL. According to our data, the evaluation of conventional EEG recordings of otherwise asymptomatic ALL long-term survivors is not a very helpful measure for predicting the degree of behavioral deficiencies, neurological disturbances, or morphological CNS abnormalities, which may be present or will develop in this special subject group. Med. Pediatr. Oncol. 29:121–131, 1997. © 1997 Wiley-Liss, Inc.

Wir berichten uber eine jugendliche Patientin mit sekundarer Amenorrho als erstes Symptom eines suprasellaren Germinoms. 13 Monate lang ware keine Menstruationsblutungen aufgeteten, aber erst das Auftreten von zusatzlichen Symptomen wie Gewichtsabnahme und Inappetenz fuhrte zur weiteren Diagnostik. Ein Computertomogram des ZNS zeigte eine Raumforderung im Bereich des 3. Ventrikels und erweiterte innere Liquorraume. Endokrinologisch fanden sich ein hypogonadotroper Hypogonadismus, eine Hyperprolaktinamie sowie Hinweise fur eine Nebennierenrindeninsuffizienz und einen Wachstumshormonmangel. Nach Entlastung des Hydrozephalus, stereotaktischer Biopsie und histologischer Diagnosesicherung wurde eine perkutane Strahlentherapie eingeleitet. Diskussion: Jede sekundare Amenorrho, die nach zuvor regelmasigen Zyklen langer als 3–6 Monate dauert, mus bei Adoleszenten abgeklart werden.

Differentialdiagnostische Schwierigkeiten beim Prader-Willi-Syndrom (PWS) im Neugeborenenalter sind darauf zuruckzufuhren, das die Symptome Muskelhypotonie und Trinkschwache als Folge einer peripartalen Asphyxie fehlgedeutet werden konnen. Die typischen kraniofazialen Dysmorphiezeichen wie schmale Stirn bei ausgepragtem Vorderhaupt, mandelformige Augen und dreiecksformiger offener Mund sind bei der Geburt wenig ausgepragt und konnen insbesondere beim beatmeten Kind ubersehen werden. Der Hypogenitalismus v. a. beim Madchen und in leichterer Auspragung beim Jungen (z. B. Kryptorchismus) ist in diesem Alter ein unspezifisches Merkmal. Die Leitsymptome Adipositas permagna bei Hyperphagie, Akromikrie und Minderwuchs bei psychomotorisch retardierten Kindern treten erst nach dem 1. Lebensjahr auf. Anhand der beiden Falle soll das Krankheitsbild PWS im Neugeborenenalter veranschaulicht und der aktuelle Stand der diagnostischen und therapeutischen Moglichkeiten erortert werden. Ein moglicher Zusammenhang zwischen PWS und dem erstmals beschriebenen Hydrops fetalis wird diskutiert.

Conventional and quantitative aspects of electroencephalographic recordings obtained during a follow-up surveillance study in long-term survivors of acute lymphoblastic leukemia in childhood were investigated with respect to differences in central nervous system prophylaxis given during antileukemic therapy and compared with data derived from healthy controls. Central nervous system prophylaxis consisted either of cranial irradiation (18 Gray, group A, n = 8) or intermediate high-dose methotrexate (2000 mg/m2; group B, n = 5), each combined with intrathecal methotrexate. Conventional electroencephalographic analysis revealed comparable results in all three study groups. However, quantitative electroencephalography showed significantly increased absolute power scores for all frequency bands in both long-term survivor groups. Relative power estimates revealed a significant increase in delta/tau activities in both prophylaxis groups compared to healthy controls, which were countered by decreased percentage power scores in the alpha-range. Quantitative electroencephalographic comparisons between both central nervous system prophylaxis groups revealed only small differences in quantity, not quality, of the observed power disturbances with slightly higher deviations in irradiated long-term survivors than in nonirradiated ones. Topographical distributions of spectral band power were comparable between all three study groups without evidence for therapy-related topographical differences.

BACKGROUND Extracerebral fluid collections in infancy are a common diagnostic problem, because by noninvasive imaging studies (including cranial ultrasonography, CT and NMR), no definite differentiation between two distinct pathological conditions can be found until today: An enlargement of the subarachnoid spaces in children with macrocephaly is a frequent observation of mostly unknown etiology but is known to be associated with a good prognosis. If surgery is necessary in these patients, ventricular shunting is required. On the other hand subdural effusions are often of traumatic origin and require frequently neurosurgical intervention (subdural shunting). Most reports on extracerebral fluid collections in infancy have not differentiated between both pathological conditions and therefore reveal confusing results. Recent studies using magnetic resonance imaging have shown that vascular flow phenomena in the arachnoid space can be used to a reliable diagnosis, whereas previous noninvasive neuroimaging attempts including high resolution computerized tomography (CT) have been useless. PATIENTS AND METHODS We investigated a cohort of 20 patients aged 4 mths to 30 mths (mean 10.5 +/- 6.6 months) 16 with the history of macrocephaly and normal neurological development and 4 patients after head trauma and symptoms of an elevated intracranial pressure. RESULTS In all 16 patients with the clinical diagnosis of benign subarachnoid space enlargement colour coded Doppler sonography detected archnoid vessels within the fluid collection, furthermore high resolution ultrasound demonstrated the dural border of of the arachnoidea as an echogenic membrane, an observation useful as a further sign of the subarachnoid location of the fluid collection. In the 4 patients with subdural hematoma the fluid collection showed an increased echogenity, no vascular structures and no surrounding border. CONCLUSION Out of these observations we conclude that high resolution ultrasound and colour-Doppler sonography are able to reliably differentiate between a subdural and a subarachnoid fluid collection. An NMR investigation with its higher risks (sedation, anesthesia) focused on this target only seems therefore to be not necessary in these patients.

Our retrospective analysis of growth and pubertal development includes 109 children and adults with meningomyelocele (MMC) (52 M, 57 F) aged 3.2-21.0 years (median 8.9 years). Anthropometric data, growth-retarding factors and data on pubertal development were analysed in comparison to the normal population using standards from Prader et al. (1). The results (mean +/- SD) were as follows. Fifty patients (46.8%) had short stature (height SDS for chronological age (SDS CA)-2). The supine length was influenced by the level of the lesion (height SDS CA:or = L2 -3.13 +/- 1.62,or = S2 -0.46 +/- 1.27), ambulatory status, skeletal deformities and pubertal stage. The mean adult height (n = 15, age 16.1-21.0 years) measured 141.3 cm for women (height SDS CA -3.83 +/- 1.79) and 159.2 cm for men (height SDS CA -2.27 +/- 1.81). In 82.6% of the subjects (n = 90), arm spans were within the normal range. Reduced arm spans (SDS-2) as found in 19 patients (17.4%) with short stature (mean height SDS CA -3.29 +/- 1.29) may be caused by factors other than neurological lesions and skeletal deformities, and require further endocrinological studies. Out of 27 pubertal patients, central precocious puberty was diagnosed in five girls. The stages of puberty in MMC girls developed earlier than expected for the age-related group.

Heterotopias are conglomerates of neurons and glial cells in an abnormal location and belong to a group of malformations, which are the result of a disturbed migration of neurons during the embryonic development of the brain. The MRI-appearance and clinical symptoms of 14 patients with nodular or lamellar heterotopias are presented. Seizures were the leading symptom (12 of 14 patients), in children also a developmental deficit (4/10) with or without seizures. Most of the children (9/10) had further brain malformations especially of the corpus callosum or the cerebellar vermis. Nodular heterotopias without further malformations were found in 4 patients, two of them developing grand-mal seizures after childhood. On MRI heterotopias are characterized by a signal isointense to gray matter in all sequences. MRI-scans in at least 2 orientations are necessary to detect these anomalies reliably. MRI is the optimum method for the demonstration of these anomalies and should always be performed if seizures develop during childhood. At least in nodular heterotopias there is no definite correlation between the extent of the anomalies, the EEG-findings and the clinical symptoms. However there is a frequent combination of heterotopias with further cerebral malformations.

The paper introduces a method to separate partial discharges (PDs) from pulse-shaped noise signals using a neural network. After a short introduction to the problems of PD measurements on-site, the structure of neural networks and their ability for pattern recognition is presented. The adaptive resonance theory (ART) architectures, which are suitable for PD measurement, and especially the fast simulating algorithm ART 2-A, are explained. To ensure the suitability of the chosen network for PD measurement, the electrical noises and PD signals measured on a distribution transformer as well as on a high voltage transformer are classified. Furthermore, it is shown that the same algorithm with changed parameters can make a contribution to PD localisation in a transformer. This takes place with the help of calibration pulses, which are injected in different points of a transformer coil. It is shown that the ART 2-A network is able to classify these pulses in accordance with their origin for the distribution transformer. The paper ends with an examination of the signals measured on a power transformer under high voltage on-site.