Autoantibody status, neuroradiological and clinical findings in children with acute cerebellitis.

BACKGROUND: Acute cerebellitis (AC) in children and adolescents is an inflammatory disease of the cerebellum due to viral or bacterial infections but also autoimmune-mediated processes. OBJECTIVE: To investigate the frequency of autoantibodies in serum and CSF as well as the neuroradiological features in children with AC. MATERIAL AND METHODS: Children presenting with symptoms suggestive of AC defined as acute/subacute onset of cerebellar symptoms and MRI evidence of cerebellar inflammation or additional CSF pleocytosis, positive oligoclonal bands (OCBs), and/or presence of autoantibodies in case of negative cerebellar MRI. Children fulfilling the above-mentioned criteria and a complete data set including clinical presentation, CSF studies, testing for neuronal/cerebellar and MOG antibodies as well as MRI scans performed at disease onset were eligible for this retrospective multicenter study. RESULTS: 36 patients fulfilled the inclusion criteria for AC (f:m = 14:22, median age 5.5 years). Ataxia was the most common cerebellar symptom present in 30/36 (83 %) in addition to dysmetria (15/36) or dysarthria (13/36). A substantial number of children (21/36) also had signs of encephalitis such as somnolence or seizures. In 10/36 (28 %) children the following autoantibodies (abs) were found: MOG-abs (n = 5) in serum, GFAPα-abs (n = 1) in CSF, GlyR-abs (n = 1) in CSF, mGluR1-abs (n = 1) in CSF and serum. In two further children, antibodies were detected only in serum (GlyR-abs, n = 1; GFAPα-abs, n = 1). MRI signal alterations in cerebellum were found in 30/36 children (83 %). Additional supra- and/or infratentorial lesions were present in 12/36 children, including all five children with MOG-abs. Outcome after a median follow-up of 3 months (range: 1 a 75) was favorable with an mRS ≤2 in 24/36 (67 %) after therapy. Antibody (ab)-positive children were significantly more likely to have a better outcome than ab-negative children (p = .022). CONCLUSION: In nearly 30 % of children in our study with AC, a range of abs was found, underscoring that autoantibody testing in serum and CSF should be included in the work-up of a child with suspected AC. The detection of MOG-abs in AC does expand the MOGAD spectrum.

N-Methyl-D-Aspartate Receptor Encephalitis with Psychiatric Symptoms and an Ovarian Teratoma Detected by MRI in a 17-Year-Old Girl.

N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare antibody-mediated autoimmune encephalitis often associated with an ovarian teratoma in adolescent females. Here we present a 17-year-old girl with only and unusual psychiatric symptoms as part of her NMDAR encephalitis in combination with a very small ovarian teratoma suspected by magnetic resonance (MR) imaging and finally histologically confirmed. We further review the literature of NMDAR encephalitis in combination with an ovarian teratoma and discuss the recommended radiological workup in children with a suspected ovarian tumor.

Rearrangement of a large novel Pseudomonas aeruginosa gene island in strains isolated from a patient developing ventilator-associated pneumonia.

Bacterial gene islands add to the genetic repertoire of opportunistic pathogens. Here, we perform comparative analyses of three Pseudomonas aeruginosa strains isolated sequentially over a 3-week period from a patient with ventilator-associated pneumonia (VAP) who received clindamycin and piperacillin-tazobactam as part of their treatment regime. While all three strains appeared to be clonal by standard pulsed-field gel electrophoresis, whole-genome sequencing revealed subtle alterations in the chromosomal organization of the last two strains; specifically, an inversion event within a novel 124-kb gene island (PAGI 12) composed of 137 open reading frames [ORFs]. Predicted ORFs in the island included metabolism and virulence genes. Overexpression of a gene island-borne putative ß-lactamase gene was observed following piperacillin-tazobactam exposure and only in those strains that had undergone the inversion event, indicating altered gene regulation following genomic remodeling. Examination of a separate cohort of 76 patients with VAP for integration at this tRNA(lys) recombination site demonstrated that patients exhibiting evidence of integration at this site had significantly higher 28-day mortality. These findings provide evidence that P. aeruginosa can integrate, rapidly remodel, and express exogenous genes, which likely contributes to its fitness in a clinical setting.

Learning chronobiology by improving Wikipedia.

Although chronobiology is of growing interest to scientists, physicians, and the general public, access to recent discoveries and historical perspectives is limited. Wikipedia is an online, user-written encyclopedia that could enhance public access to current understanding in chronobiology. However, Wikipedia is lacking important information and is not universally trusted. Here, 46 students in a university course edited Wikipedia to enhance public access to important discoveries in chronobiology. Students worked for an average of 9 h each to evaluate the primary literature and available Wikipedia information, nominated sites for editing, and, after voting, edited the 15 Wikipedia pages they determined to be highest priorities. This assignment (http://www.nslc.wustl.edu/courses/Bio4030/wikipedia_project.html) was easy to implement, required relatively short time commitments from the professor and students, and had measurable impacts on Wikipedia and the students. Students created 3 new Wikipedia sites, edited 12 additional sites, and cited 347 peer-reviewed articles. The targeted sites all became top hits in online search engines. Because their writing was and will be read by a worldwide audience, students found the experience rewarding. Students reported significantly increased comfort with reading, critiquing, and summarizing primary literature and benefited from seeing their work edited by other scientists and editors of Wikipedia. We conclude that, in a short project, students can assist in making chronobiology widely accessible and learn from the editorial process.

[Comparative ultrasound visualization of clinically relevant structures for evaluating the infant hip joint utilizing trapezoidal vs. parallel transducers]. / Vergleichende Darstellung beurteilungsrelevanter Strukturen der kindlichen Hüfte mittels paralleler und trapezförmiger Ultraschallabbildung.

PURPOSE: Sonographic evaluation of the infant hip joint according to the method of Graf has proven to be an important pediatric investigative instrument. Our goal was to investigate quantitatively whether (and in what ways) the clinically relevant infant hip joint structures visualize differently when utilizing trapezoidal as opposed to linear transducers. Our approach was both theoretical via a mathematical model and practical with in-vivo measurements in neonates. MATERIALS AND METHODS: In a prospective study: 1. theoretical and computed analyses were performed for both linear and trapezoidal transducers regarding their respective accuracy for demonstrating the anatomic geometry of the infant hip, assuming not only correctly centered transducer positioning but also cases with off-centered displacement in the cranial or caudal direction; 2. both hip joints in 97 infants were examined by experienced investigators with comparison of the results for parallel vs. trapezoidal transducers. RESULTS: Theoretical mathematical error analysis reveals no intrinsic systemic deviations between trapezoidal vs. parallel transducers in US scanning of the infant hip and furthermore no inherent disadvantages in the trapezoidal technique. Even when off-center transducer alignments of 1.5 cm are employed in the mathematical models, there is no significant relative distortion of the required anatomic structures when comparing the characteristics of both transducers. The practical in-vivo data from our 97 neonates confirmed the theoretical considerations. CONCLUSION: No loss of accuracy or other negative factors are evident when trapezoidal transducers are used to visualize the infant hip joint in comparison with the customary parallel technique. There are no significantly measurable differences between the two approaches.

The neuroendocrinological sequelae of stress during brain development: the impact of child abuse and neglect.

Severe stress during the sensitive periods of neurodevelopment, (which include the prenatal period, infancy, childhood and adolescence), has a long-lasting organizing effect on the brain and stress axes. Child abuse and neglect thus exert a cumulative harmful effect on neuroendocrinological development, which persists into adulthood. It is not merely the memory of the trauma which leaves a mark, but rather the effect on neurodevelopment which negatively influences the ability of adult survivors of childhood maltreatment to cope with current stressors. The victims of child abuse and neglect are likely to maltreat their own children and so perpetuate the intergenerational transmission of child maltreatment. In this paper relevant normal brain development is first summarized. Child abuse/neglect is next discussed with detailed reference to the aberrant neuroendocrinological development that is known to occur. We specifically examine effects on the hypothalamo-pituitary-adrenal and central noradrenergic-sympathoadrenomedullary stress axes and other neurotransmitter systems before turning to changes described in the cerebral volumes, corpus callosum and cortical hemispheres, prefrontal cortex and amygdalae, superior temporal gyrus, hippocampus as well as the cerebellar vermis.

The neuroendocrinological sequelae of stress during brain development: the impact of child abuse and neglect

Severe stress during the sensitive periods of neurodevelopment, (which include the prenatal period, infancy, childhood and adolescence), has a long-lasting organizing effect on the brain and stress axes. Child abuse and neglect thus exert a cumulative harmful effect on neuroendocrinological development, which persists into adulthood. It is not merely the memory of the trauma which leaves a mark, but rather the effect on neurodevelopment which negatively influences the ability of adult survivors of childhood maltreatment to cope with current stressors. The victims of child abuse and neglect are likely to maltreat their own children and so perpetuate the intergenerational transmission of child maltreatment. In this paper relevant normal brain development is first summarized. Child abuse / neglect is next discussed with detailed reference to the aberrant neuroendocrinological development that is known to occur. We specifically examine effects on the hypothalamo-pituitary-adrenal and central noradrenergic-sympathoadrenomedullary stress axes and other neurotransmitter systems before turning to changes described in the cerebral volumes, corpus callosum and cortical hemispheres, prefrontal cortex and amygdalae, superior temporal gyrus, hippocampus as well as the cerebellar vermis

The central noradrenergic system: an overview.

The central noradrenergic system belongs to a group of brainstem neuromodulatory systems previously referred to as the ascending reticular activating system. In this article a heuristic model is presented of the central noradrenergic system depicting the major projections to other cerebral areas, its interactions with other neuromodulatory systems, mechanisms through which it can influence cerebral function, as well as the major functions and disorders associated with alterations in central noradrenergic activity. It is not the aim of this paper to provide fine detail on the various aspects, but rather to provide a concise overview where structure and function, as well as the interactions with other systems are brought together. The contents of the paper are summarized in a diagram.

Supportive neurodevelopmental evidence for ADHD as a developmental disorder.

A baby is dependent on its primary caregiver (hereafter referred to as 'mother') for its emotional regulation. The development of emotional self-regulation is dependent on the growth and myelinisation of connections between cortical (control) and limbic (emotion) structures in the infant brain. The subcortical sympathetic limbic system is dominant from birth, and it is only at 14-18 months of age that the parasympathetic cortical inhibitory part develops. The maturation of specifically the right orbitofrontal cortex, which dominates both the sympathetic and parasympathetic limbic systems, is essential for the regulation of emotion for the rest of an individual's life. Behavioral hyperactivity, impulsivity and inattention are considered normal for children in the early practising phase (10-14 months). This stage is characterised by sympathetic dominance stimulated by the ventral tegmental limbic circuit. We hypothesise that children with Attention Deficit Hyperactivity Disorder remain stuck in this phase, and accordingly do not enter the next stage of emotional development, i.e., the late practising period, in which the lateral tegmental limbic circuit, which stimulates the parasympathetic system develops. Parental reactions, which may contribute to this block in emotional development, include: largely ignoring their child, until the child does something the parent disapproves of, then scolding the child, without consoling the child again afterwards. This leads susceptible children to develop defensive hyperactivity and inattention in order to avoid a shame state they are unable to cope with. Implications for therapy are that caregivers should be taught firstly to give lots of positive attention to their child, and if necessary to scold, to console the child immediately afterwards. If this can be achieved consistently, the child will have the chance to develop their parasympathetic lateral limbic circuit, and eventually right orbitofrontal dominance over both limbic circuits, which translates into the ability to self-regulate their emotional states.

Gastro intestinal hyperpermeability: a review.

OBJECTIVE: To present a wide overview of the recent developments in the understanding of the aetiopathogenesis of gastrointestinal hyperpermeability. DATA SOURCES: Medline, from 1985, was sourced for relevant articles. Review articles were included in order to minimise the number of references in the reference list. STUDY SELECTION: Results from experiments and observations on humans and other mammalian species were studied. DATA SYNTHESIS: The major mechanisms elucidated in the aetiopathogenesis of the gastrointestinal hyperpermeability were integrated and consolidated into a flow diagram and the major factors responsible for normal permeability presented for comparison. CONCLUSION: The occurrence of increased gastrointestinal hyperpermeability is probably vastly underestimated. In addition to the hyperpermeability commonly associated with chronic gastro intestinal disorders, an increase in gastrointestinal permeability may occur in any condition of metabolic depletion, enterocyte ATP-depletion, stimulation of gastrointestinal pro-inflammatory cytokine production and disturbances of the normal gastrointestinal flora as with prolonged use of antibiotics.

Associations between psychological profiles and diseases: examining hemispheric dominance and autonomic activation as underlying regulators.

Personality profiles are often typical for specific illnesses, e.g., the type A personality and heart disease. We hypothesize that many more such patterns exist, and have developed a scheme in which many diseases can be classified, depending on hemispheric dominance (i.e., integrated, intellectualising or emotional) and type of autonomic control (i.e., dominance of either sympathetic or parasympathetic system, or an increase in both types of autonomic outflow). Our hypothesis is based on recent findings in neurophysiology, involving the early rearing environmental effects on the developing orbitofrontal cortex, and attachment theory. We conclude with implications for therapy, and a discussion of the limitations of our hypothesis.

Identification of a tyrosine kinase-phosphorylated protein in arachidonic acid- and prostaglandin A(2)-treated cells in vitro.

The effects of 20 microg/ml exogenous arachidonic acid (AA) and prostaglandin A(2) (PGA(2)) were evaluated on total tyrosine kinase (TK) activity and tyrosine phosphorylation status in HeLa and MCF-7 cells. AA and PGA(2) increased TK activity in both HeLa and MCF-7 cells. Western blotting employing an anti-phosphotyrosine antibody showed only one protein of approximately 55 kDa (approximately 55 kDa) to be phosphorylated in the MCF-7 cells, while a variety of proteins were phosphorylated in the HeLa cells, including the approximately 55 kDa protein. Amino acid analyses as well as Matrix Assisted Laser Desorption Ionization were conducted on this protein from different cell lines and it was shown to be similar. Comparison to p53 did not show similarities. The identity of this protein needs to be further characterized to help elucidate the signal transduction pathways of AA and PGA(2).

The effects of chelidonine on tubulin polymerisation, cell cycle progression and selected signal transmission pathways.

Chelidonine is a tertiary benzophenanthridine alkaloid known to cause mitotic arrest and to interact weakly with tubulin. Our interest in chelidonine began when we found it to be a major contaminant of Ukrain, which is a compound reported to be selectively toxic to malignant cells. The effects of chelidonine in two normal (monkey kidney and Hs27), two transformed (Vero and Graham 293) and two malignant (WHCO5 and HeLa) cell lines, were examined. Chelidonine proved to be a weak inhibitor of cell growth, but no evidence for selective cytotoxicity was found in this study. It was confirmed that chelidonine inhibits tubulin polymerisation (IC50 = 24 microM), explaining its ability to disrupt microtubular structure in cells. A G2/M arrest results, which is characterised by abnormal metaphase morphology, increased levels of cyclin B1 and enhanced cdc2 kinase activity. Exposure of all cell lines examined to chelidonine leads to activation of the stress-activated protein kinase/jun kinase pathway (SAPK/JNK).

Ukrain(TM), a semisynthetic Chelidonium majus alkaloid derivative, acts by inhibition of tubulin polymerization in normal and malignant cell lines.

Ukrain(TM) has been described as a semisynthetic Chelidonium majus alkaloid derivative, which exhibits selective toxicity towards malignant cells only. Its mechanism of action has hitherto been uncertain. We found that Ukrain(TM) inhibits tubulin polymerization, leading to impaired microtubule dynamics. This results in activation of the spindle checkpoint and thus a metaphase block. The effects of Ukrain(TM) on the growth, cell cycle progression and morphology of two normal, two transformed and two malignant cell lines did not differ. We could thus find no evidence for the selective cytotoxicity previously reported for Ukrain(TM).

Chemical analyses of Ukrain, a semi-synthetic Chelidonium majus alkaloid derivative, fail to confirm its trimeric structure.

Ukrain has been described as a semi-synthetic Chelidonium majus alkaloid derivative, consisting of three chelidonine alkaloids combined to triaziridide. We found the actions of Ukrain to be similar to the Chelidonium alkaloids it is prepared from, and therefore became concerned about its chemical integrity. Chemical analyses of Ukrain by thin layer chromatography, high-performance liquid chromatography and liquid chromatography-mass spectrometry was inconsistent with the proposed trimeric structure and demonstrated that at least some commercial preparations of Ukrain consist of a mixture of C. majus alkaloids (including chelidonine).

Fumonisin B1 influenced the effects of arachidonic acid, prostaglandins E2 and A2 on cell cycle progression, apoptosis induction, tyrosine- and CDC2-kinase activity in oesophageal cancer cells.

In a previous study, we showed that, of a group of lipids including arachidonic acid (AA), prostaglandins E2 (PGE2) and A2 (PGA2), PGA2 had the most marked effect on the inhibition of cell growth, activation of tyrosine kinase activity, lowering of the number of G1-phase cells, and induction of p53 levels in oesophageal carcinoma (WHCO3) cells. No significant effects by the three lipids were seen in normal monkey kidney cells. In the present study, the effects of the inhibitor of ceramide synthesis, fumonisin B1 (FB1), a metabolite of Fusarium verticillioides (= F. moniliforme) which is implicated in the high incidence of oesophageal cancer, were determined on AA, PGE2 and PGA2 WHCO3 treated cells. In the presence of FB1, the lipid-enhanced tyrosine kinase activity was lowered. Flow cytometric and morphological studies showed that FB1 lowered the marked apoptosis induced by especially PGA2. FB1, however, in combination with AA, PGE2 or PGA2 increased the number of G2/M cells. AA>PGE2>PGA2 alone decreased CDC2-kinase activity, but, in the presence of FB1, CDC2-kinase activity was significantly increased. The PGA2- and AA-induced p53 levels were lowered in the presence of FB1. We concluded that FB1 diminished the cytotoxic effects of the lipids on oesophageal tumour cells.

The antimitotic effects of Ukrain, a Chelidonium majus alkaloid derivative, are reversible in vitro.

Ukrain is alleged to be an effective chemotherapeutic drug which causes minimal side-effects as a result of selective toxicity towards malignant cells only. We previously failed to confirm this claim and found Ukrain to be equally toxic to normal, transformed and malignant cell lines by causing a metaphase arrest. In this study we have found the antimitotic actions of Ukrain to be reversible in low doses in vitro, as shown by flow cytometry and concurrent haematoxylin and eosin stains. We hypothesize that the lack of side-effects found in vivo may be due to the lack of therapeutically effective dosages being administered, therefore enabling cells to overcome the metaphase arrest and survive.