Cri du Chat-syndrome mit Chromosomenmosaik 46, XY/46, XY, 5p-

Summary The case of a 2;5 year old boy with the typical features of the Cri du Chatsyndrome is described. The cytogenetical examination of lymphocytes and fibroblasts revealed a mosaicism with an approximated 1:1 relation between normal cells and cells with a deletion of the short arm of a B-chromosome. Autoradiography proved the deleted chromosome to be a chromosome No. 5.     

Leukemia/lymphoma-associated gene fusions in normal individuals

Hematopoietic neoplasias are characterized by recurrent chromosomal aberrations that result in the formation of gene fusions and the subsequent expression of chimeric proteins with unique properties. However, in recent years, different lymphoma/leukemia-associated rearrangements, such as BCR/ABL, IGH/BCL2, ETV6/RUNX1 and MLL duplications, have been detected in healthy individuals. The presence of these rearrangements indicates that such translocations can be generated in normal hematopoietic cells without apparent oncogenic consequences. This article reviews and discusses the data available in the literature.     

Robust Bayesian hierarchical model using normal/independent distributions

The multilevel item response theory (MLIRT) models have been increasingly used in longitudinal clinical studies that collect multiple outcomes. The MLIRT models account for all the information from multiple longitudinal outcomes of mixed types (e.g., continuous, binary, and ordinal) and can provide valid inference for the overall treatment effects. However, the continuous outcomes and the random effects in the MLIRT models are often assumed to be normally distributed. The normality assumption can sometimes be unrealistic and thus may produce misleading results. The normal/independent (NI) distributions have been increasingly used to handle the outlier and heavy tail problems in order to produce robust inference. In this article, we developed a Bayesian approach that implemented the NI distributions on both continuous outcomes and random effects in the MLIRT models and discussed different strategies of implementing the NI distributions. Extensive simulation studies were conducted to demonstrate the advantage of our proposed models, which provided parameter estimates with smaller bias and more reasonable coverage probabilities. Our proposed models were applied to a motivating Parkinson's disease study, the DATATOP study, to investigate the effect of deprenyl in slowing down the disease progression.     

Structure elucidation of arabinoxylan isomers by normal phase HPLC-MALDI-TOF/TOF-MS/MS

Normal phase-high performance liquid chromatography (NP-HPLC) coupled to matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight (MALDI-TOF/TOF) tandem mass spectrometry is evaluated for the detailed structural characterization of various isomers of arabinoxylan (AX) oligosaccharides produced from endo-beta-(1-->4)-xylanase (endoxylanase) digestion of wheat AX. The fragmentation characteristics of these oligosaccharides upon MALDI-TOF/TOF high-energy collision induced dissociation (CID) were investigated using purified AX oligosaccharide standards labeled at the reducing end with 2-aminobenzoic acid (2-AA). A variety of cross-ring cleavages and 'elimination' ions in the fragment ion spectra provided extensive structural information, including Araf substitution patterns along the xylan backbone and comprehensive linkage assignment. The off-line coupling of this MALDI-CID technique to capillary normal phase HPLC enabled the separation and identification of isomeric oligosaccharides (DP 4-8) produced by endoxylanase digestion of AX. Furthermore, this technique was used to characterize structurally different isomeric AX oligosaccharides produced by endoxylanase enzymes with different substrate specificities.     

Mast cells and macrophages in normal C57/BL/6 mice

Mast cells and macrophages have an important role in immunity and inflammation. Because mice are used extensively for experimental studies investigating immunological and inflammatory responses, we examined mast cell and macrophage distribution in normal murine tissues. Mast cells were abundant in the murine dermis, tongue, and skeletal muscle but were rarely found in the heart, lung, spleen, kidney, liver, and the bowel mucosa. In contrast, dogs exhibited large numbers of mast cells in the lung parenchyma, liver, and bowel. Some murine dermal mast cells had long cytoplasmic projections filled with granular content. Mouse mast cells demonstrated intense histamine immunoreactivity and were identified with histochemical enzymatic techniques for tryptase and chymase. Macrophages, identified using the monoclonal antibody F4/80, were abundant in the spleen, lung, liver, kidney, and bowel but relatively rare in the heart, tongue, and dermis. Using a nuclease protection assay we investigated mRNA expression of stem cell factor (SCF), a crucial survival factor for mast cells, and the macrophage growth factors macrophage colony stimulating factor (M-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF). Stem cell factor mRNA was highly expressed in the murine lung. Relatively low levels of SCF mRNA expression were found in the tongue and earlobe, which are tissues containing a high number of mast cells. Macrophage CSF and GM-CSF mRNA was highly expressed in the lung and spleen. The murine heart, an organ with a low macrophage content, expressed high levels of M-CSF but negligible levels of GM-CSF mRNA. Constitutive growth factor mRNA expression in murine tissues without significant populations of mast cells and macrophages may suggest an alternative role for these factors in tissue homeostasis.     

Mosaic normal/15q11-q13 duplication associated with developmental delay but normal phenotype.

We report a proximal duplication in the long arm of chromosome 15 (15q11-15q13) in mosaic with a normal cell line in a 4-year-old boy presenting developmental delay and history of seizures, but normal phenotype.     

Mesoscopic neuron population modeling of normal/epileptic brain dynamics

Simulations of EEG data provide the understanding of how the limbic system exhibits normal and abnormal states of the electrical activity of the brain. While brain activity exhibits a type of homeostasis of excitatory and inhibitory mesoscopic neuron behavior, abnormal neural firings found in the seizure state exhibits brain instability due to runaway oscillatory entrained neural behavior. We utilize a model of mesoscopic brain activity, the KIV model, where each network represents the areas of the limbic system, i.e., hippocampus, sensory cortex, and the amygdala. Our model initially demonstrates oscillatory entrained neural behavior as the epileptogenesis, and then by increasing the external weights that join the three networks that represent the areas of the limbic system, seizure activity entrains the entire system. By introducing an external signal into the model, simulating external electrical titration therapy, the modeled seizure behavior can be ‘rebalanced’ back to its normal state.     

Cell selection in vivo in normal/aneuploid chromosome abnormalities

Summary Cytogenetic follow-up examination has been made of the 9 mixoploid children found among 11148 newborn children. In 4 of the 9 children there was a significant increase in the frequency of the cell line with normal chromosome constitution and a significant decrease in the normal cell line was found in 1 child. In 4 there was no significant difference from the first to the last examination.The frequency of the cell line with normal chromosomes increased from 32–68% to between 93–97% in 3 cases and to 86% in 1. The possibility that children with mixoploid chromosome abnormalities at birth will reveal no cell line with chromosome abnormality in lymphocyte cultures as adults in spite of having clinical signs of the chromosome aberration found in one cell line at birth is discussed.     

On a prezygotic origin of normal/balanced translocation mosaics

Based on a theoretical model for the production of some structural mosaicisms, the authors propose a mechanism for the origin of normal/balanced translocation mosaics. Single strand breaks and nonhomologous hemichromatid joining are implicated and, when applied to homologous chromosomes, could explain some instances of nondisjunction independent of centromere function.     

Courtship-stimulating volatile compounds from normal and mutant Drosophila

Volatile compounds from Drosophila melanogaster males and females dramatically affect male courtship behaviour. These substances, which have been extracted from flies of different ages and genotypes, have been analysed by gas chromatography (GC) and in behavioural assays. Extracts from virgin females and males have different gas chromatographic profiles, which may reflect the fact that extract from virgin females stimulates high levels of courtship between males over short distances, while extract from mature wild-type males does not affect sexual behaviour. However, volatile compounds from very young males or males expressing the fruitless (fru) mutation do stimulate courtship between males, and chromatographic profiles of young male and fru male extracts differ from the GC profile of extracts from mature wild-type males.     

Nuclear DNA in normal and refed Amoeba proteus

Amoeba proteus synthesizes DNA in G2 phase of the cell cycle upon feeding after starvation. The characteristics of the DNA synthesized in G2 have been studied by microscope photometry of individual Feulgen-stained nuclei and by buoyant density centrifugation of nuclear DNA in CsCl. Amoeba nuclei were found to contain 42.8 pg of DNA. This DNA bands in CsCl at a density of 1.693 g/cm³ with a satellite at 1.714 g/cm³ which makes up 24% of nuclear DNA. DNA from whole cells has an additional non-nuclear satellite at 1.726 g/cm³. When cells are starved and re-fed with food labeled with [³H]thymidine, the DNA synthesized is predominantly the 1.714 satellite. The amount of DNA synthesized in G2 is small since there is no measurable difference in Feulgen dye binding to nuclei of starved vs starved and re-fed cells. The data suggest that refeeding induces a resumption of late S phase DNA synthesis, or the preferential synthesis of specific DNA sequences such as rRNA genes.     

C/EBP homologous protein is necessary for normal osteoblastic function

C/EBP homologous protein (CHOP) suppresses adipogenesis and accelerates osteoblastogenesis in vitro. However, the effects of CHOP in the skeleton in vivo are not known. To investigate the actions of CHOP on bone remodeling, we examined the skeletal phenotype of chop null mice from 1 to 12 months of age. Chop null mice appeared normal and their growth and serum insulin like growth factor (IGF) I and osteocalcin levels were normal. X-ray analysis of the skeleton revealed no abnormalities and bone mineral density was normal. Static and dynamic histomorphometry revealed that chop null mice had decreased bone formation rates, without changes in osteoblast cell number, indicating an osteoblastic functional defect. The number of osteoblasts and osteoclasts and eroded surface were normal. Northern blot analysis revealed decreased type I collagen and osteocalcin mRNA levels in calvariae of chop null mice. In conclusion, chop null mice exhibit decreased bone formation and impaired osteoblastic function, indicating that CHOP is necessary for the normal expression of the osteoblastic phenotype.     

Modulation of normal myelopoiesis invitro by retinoic acid

The effects of retinoic acid (RA) on the proliferation and differentiation of normal myeloid progenitor cells (CFU-C) were studied. In general, RA at 10^?10 to 10^?6 M enhanced primary myeloid colony formation in the presence of colony-stimulating factor(s). However, macrophage colony formation was strongly inhibited by RA. This may be related to the finding that RA is able to differentiate bipotential HL-60 cells into granulocytes but not into macrophages. Moreover, secondary colony formation was always suppressed by the addition of RA to the primary cultures. It means that self-renewal capacity of CFU-C was suppressed by RA. This finding suggests that normal myelopoiesis will be suppressed eventually by RA.     

The epidermal growth factor receptor/Erb-B/HER family in normal and malignant breast biology

The EGFR/Erb-B receptor tyrosine kinases each play distinct and complementary roles in normal breast development. The four receptors form both homodimers and heterodimers in response to binding by ligands which show selectivity for one or more of the receptors (except Erb-B2). Together with the additional flexibility generated by the formation of different dimer pairs, these signalling networks play key roles in directing a variety of both autocrine and paracrine cellular responses. Complex two-way interactions between mammary epithelial cells and the surrounding stroma direct proliferation, duct formation, branching and terminal differentiation during puberty, pregnancy and lactation, with each receptor and ligand fulfilling distinct roles. Caricatures of the normal role of EGFR/Erb-B signalling resulting in aberrant cellular responses are seen in breast cancers, where over-expression and/or (less commonly) mutation of one or more of the receptors results in enhanced cell proliferation, motility, release of proteases and angiogenic factors. Given their importance in tumour progression, compared with most normal adult tissues and their links with resistance to chemotherapy and anti-endocrine therapy, Erb-B receptors (most notably Erb-B2) have been exploited as therapeutic targets. Monoclonal antibodies (e.g. trastuzumab, pertuzumab) and small molecule tyrosine kinase inhibitors (e.g. lapatinib, afatinib) have shown significant clinical responses in some breast cancer subtypes. Additional approaches include targeted toxins or drugs, peptide vaccines, immunRNase and chaperone inhibitors to deplete Erb-B2 protein levels. Greater understanding of the full spectrum of Erb-B-mediated signalling pathways and their misregulation in breast cancer will provide additional strategies to control malignant progression.