Detection of polyomavirus BK and JC in children with kidney diseases and renal transplant recipients

BACKGROUND: Reactivation of polyomavirus is a known reason for severe renal dysfunction in adult renal transplant recipients. Testing for polyomavirus DNA in plasma has been described as a sensitive and specific method to discover viral nephropathy in adult patients. We were now interested in polyomavirus status in a pediatric patient setting. METHODS: Plasma and urine samples were obtained from 80 children including 38 children after renal transplantation (group 1), 7 children with different kidney diseases receiving immunosuppressive treatment (group 2) and 35 children with different kidney diseases not receiving immunosuppressive treatment (group 3). A nested polymerase chain reaction method was used for amplification of polyomavirus DNA fragments. Differentiation between JC and BK virus was done by digestion with restriction endonucleases. RESULTS: Polyomavirus DNA was detected in the urine sample of 19 of 38 (50%) renal transplant recipients (group 1), of 1 of 7 (14%) patients from group 2 and in none of the 35 patients of group 3. Plasma samples from 3 (8%) of group 1 patients and from 1 child each of group 2 (14%) and group 3 (3%) were tested positive for polyomavirus DNA. CONCLUSION: Urinary polyomavirus excretion seems to be more frequent in pediatric patients with kidney diseases receiving immunosuppressive treatment and after renal transplantation than in children with various kidney diseases without immunosuppressive treatment.     

3D structure of Alzheimer's amyloid-beta(1-42) fibrils

Alzheimer's disease is the most fatal neurodegenerative disorder wherein the process of amyloid-beta (Abeta) amyloidogenesis appears causative. Here, we present the 3D structure of the fibrils comprising Abeta(1-42), which was obtained by using hydrogen-bonding constraints from quenched hydrogen/deuterium-exchange NMR, side-chain packing constraints from pairwise mutagenesis studies, and parallel, in-register beta-sheet arrangement from previous solid-state NMR studies. Although residues 1-17 are disordered, residues 18-42 form a beta-strand-turn-beta-strand motif that contains two intermolecular, parallel, in-register beta-sheets that are formed by residues 18-26 (beta1) and 31-42 (beta2). At least two molecules of Abeta(1-42) are required to achieve the repeating structure of a protofilament. Intermolecular side-chain contacts are formed between the odd-numbered residues of strand beta1 of the nth molecule and the even-numbered residues of strand beta2 of the (n - 1)th molecule. This interaction pattern leads to partially unpaired beta-strands at the fibrillar ends, which explains the sequence selectivity, the cooperativity, and the apparent unidirectionality of Abeta fibril growth. It also provides a structural basis for fibrillization inhibitors.     

Morphological abnormalities in nitric-oxide-synthase-positive striatal interneurons of schizophrenic patients

Schizophrenia has been suggested to be a neurodevelopmental disorder, and nitric-oxide-synthase (NOS)-positive neurons were shown to be involved in distorted cortical development in schizophrenia. Here we investigated whether nitrinergic neurons in the striatum of schizophrenic patients also display abnormalities regarding distribution or morphology. To do so, postmortem putaminal sections of schizophrenic subjects were examined by means of nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) staining and NOS immunohistochemistry. NOS-positive neurons were counted and analyzed morphologically. Abnormalities regarding morphology or number of NOS-containing neurons could be found in the putamen of schizophrenics (n = 3), but not controls (n = 5). Neurons were either of abnormal size and branching pattern, or they were markedly reduced (130 +/- 44 vs. 54 +/- 62 NADPHd-positive somata/mm(3) putamen; p < 0.0001). Striatal nitrinergic interneurons might thus be involved in the pathogenesis of at least some forms of schizophrenia. Studies on larger samples are however needed to further corroborate this finding.     

Common mutations of β-catenin in adamantinomatous craniopharyngiomas but not in other tumours originating from the sellar region

Dysregulation of the Wnt signalling pathway contributes to developmental abnormalities and carcinogenesis of solid tumours. Here, we examined -catenin and adenomatous polyposis coli (APC) by mutational analysis in pituitary adenomas (n=60) and a large series of craniopharyngiomas (n=41). Furthermore, the expression pattern of -catenin was immunohistochemically analysed in a cohort of tumours and cysts of the sellar region including pituitary adenomas (n=58), craniopharyngiomas (n=57), arachnoidal cysts (n=8), Rathkes cleft cysts (n=10) and xanthogranulomas (n=6). Whereas APC mutations were not detectable in any tumour entity, -catenin mutations were present in 77% of craniopharyngiomas, exclusively of the adamantinomatous subtype. All mutations affected exon 3, which encodes the degradation targeting box of -catenin compatible with an accumulation of nuclear -catenin protein. In addition, a novel 81-bp deletion of this exonic region was detected in one case. Immunohistochemical analysis confirmed a shift from membrane-bound to nuclear accumulation of -catenin in 94% of the adamantinomatous tumours. Aberrant distribution patterns of -catenin were never observed in the other tumour entities under study. We conclude that -catenin mutations and/or nuclear accumulation serve as diagnostic hallmarks of the adamantinomatous variant, setting it apart from the papillary variant of craniopharyngioma.     

Further evidence for altered cerebellar neuronal integrity in schizophrenia

OBJECTIVE: The authors' goal was to investigate the distribution of metabolites and voxel composition in the pons and three cerebellar subregions and compare metabolite integral values and differences in voxel composition between patients with schizophrenia and healthy subjects. METHOD: Proton magnetic resonance spectroscopic imaging was used to study the cerebellum and pons of 14 patients with schizophrenia and 14 healthy comparison subjects. RESULTS: The voxel composition was not significantly different between the groups, but the patients with schizophrenia had significantly lower N-acetylaspartate levels in the cerebellar cortex and vermis. CONCLUSIONS: The lower integral value of N-acetylaspartate in the cerebellar cortex and the vermis of patients with schizophrenia supports the theory of a dysfunctional corticocerebellar-thalamic-cortical circuit in schizophrenia.     

On the evolutionary significance of encephalization in some eutherian mammals: effects of adaptive radiation, domestication, and feralization

Allometries of the brain to body size relationship in eutherian mammals are examined in this study as they can be used for comparative analyses concerning encephalization. In contrast with some modern presentations of this issue, an older concept is revived and expanded through this author's current study. Three allometries with clearly different slopes are valid and lead to reliable results: interspecific, intraspecific, and ontogenetic allometries. Interspecific allometries follow lines with slope values of 0.56 or 0.63 for larger and smaller species, respectively, and characterize different average encephalization plateaus with rodents and lagomorphs generally more strongly encephalized compared to basal insectivores. Artiodactyls, perissodactyls and carnivores as a whole are again on a higher but rather similar plateau. Several species of carnivores have reached different encephalization levels with respect to their average plateau indicating diverse radiations. A phylogenetic brain size increase from fossil to recent radiations is also evident. Intraspecific allometries have slope values of about 0.25. These are of help in comparing brain sizes of ancestral species with their domesticated relatives. Domestication has generally led to a brain size decrease, but species on higher encephalization plateaus show this trend more strongly than species on a lower level of encephalization. Several brain parts and the sense organs also decrease in size during the domestication process, but vary arbitrarily and to different degrees. Ontogenetic growth allometries are species-specific, but are especially different between altricial and precocial mammals. A very steep 1st phase slope of highly encephalized species is particularly useful for understanding evolutionary and adaptive phenomena. Domesticated mammals that have become feral do not show an increase in brain size despite living many generations in wild habitats.     

Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing-remitting multiple sclerosis

BACKGROUND: The anti-CD20 monoclonal antibody rituximab effectively depletes B lymphocytes and has been successfully used in the therapy of immune-mediated disorders of the peripheral nervous system. A limited effect of rituximab on B lymphocytes in the cerebrospinal fluid compartment of patients with primary progressive multiple sclerosis (MS) was recently reported. OBJECTIVE: To determine the effect of rituximab on clinical, magnetic resonance imaging, and immunological variables in a patient with relapsing-remitting MS. DESIGN: A patient with relapsing-remitting MS was treated with rituximab. The patient was repeatedly examined clinically and by magnetic resonance imaging. The frequency of peripheral blood and cerebrospinal fluid B lymphocytes was assessed by flow cytometry before, during, and after rituximab therapy. RESULTS: Rituximab monotherapy resulted in significant clinical improvement. Inflammatory surrogate markers on magnetic resonance imaging were also reduced. B lymphocytes were depleted in the cerebrospinal fluid and peripheral blood. CONCLUSIONS: Our data demonstrate beneficial clinical effects of rituximab in relapsing-remitting MS, mediated through modulation of humoral systemic and central nervous system intrinsic immune responses. Clinical trials should determine optimal therapeutic strategies for patients with relapsing-remitting MS.     

Differences in activation of the dorsal raphe nucleus depending on performance of suicide

The serotonergic system has been implicated in the pathogenesis of mood disorders as well as in suicidal behavior. It is unknown, however, whether raphe neurons, which are mostly serotonergic, show altered activity in patients with mood disorders who complete suicide as compared to those without suicidal behavior. In order to measure cellular markers of serotonergic activity in the dorsal raphe nucleus in brains of 12 people with mood disorders and of 12 controls (C), stereological measurements were carried out of nucleolar organizer regions (AgNORs) and of serotonergic neuron numbers. Six patients died from suicide (S) and the other six patients died from natural causes (NS). Results were assessed using ANOVA and post hoc Tukey-HSD tests looking for effects of diagnostic group (S, NS, C). Results show that in the rostral subnuclei of the dorsal raphe there was a significant effect of diagnostic group on the ratios of the nucleolar organizer regions to nuclear area (NOR ratio) and a nearly significant effect on numbers of serotonergic neurons. Post hoc tests revealed larger values for those dependent variables in S compared to NS. Dose equivalents of antidepressants correlated positively with NOR ratios and numbers of serotonergic neurons in the rostral part of the dorsal raphe. In conclusion, the present data suggest that there are functional differences in the dorsal raphe of patients with mood disorders depending on suicidal behavior. Antidepressants appear to contribute to cellular activation in the rostral part of the dorsal raphe.