Three-year tracking of fatty acid composition of plasma phospholipids in healthy children

Objectives: The fatty acid composition of plasma phospholipids reflects the dietary fatty acid intake as well as endogenous turnover. We aimed at investigating the potential tracking of plasma phospholipid fatty acid composition in children that participated in a prospective cohort study. Methods: 26 healthy children participated in a longitudinal study on health risks and had been enrolled after birth. All children were born at term with birth weights appropriate for gestational age. Follow-up took place at ages 24, 36 and 60 months. At each time point a 24-hour dietary recall was obtained, anthropometric parameters were measured and a blood sample for phospholipid fatty acid analysis was taken. Results: Dietary intake of saturated (SFA), monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids at the three time points were not correlated. We found lower values for plasma MUFA and the MUFA/SFA ratio at 60 months compared to 24 months. In contrast, total PUFA, total n-6 and n-6 long-chain polyunsaturated fatty acids (LC-PUFA) were higher at 60 months. Significant averaged correlation coefficients (average of Pearson's R for 24 versus 36 months and 36 versus 60 months) were found for n-6 LC-PUFA (r = 0.67), n-6/n-3 LC-PUFA ratio (r = 0.59) and arachidonic acid/linoleic acid ratio (r = 0.64). Partial tracking was found for the docosahexaenoic acid/alpha-linolenic acid ratio (r = 0.33). Body mass index and sum of skinfolds Z-scores were similar in the three evaluations. Conclusions: A significant tracking of n-6 LC-PUFA, n-6 LC-PUFA/n-3 LC-PUFA ratio, arachidonic acid/ linoleic acid ratio and docosahexaenoic acid/alpha-linolenic acid ratio may reflect an influence of individual endogenous fatty acid metabolism on plasma concentrations of some, but not all, fatty acids. Copyright (c) 2007 S. Karger AG, Basel

Diagnostic stability among chronic patients with functional psychoses: an epidemiological and clinical study

<p>Abstract</p> <p>Background</p> <p>Diagnostic stability and illness course of chronic non-organic psychoses are complex phenomena and only few risk factors or predictors are known that can be used reliably. This study investigates the diagnostic stability during the entire course of illness in patients with non-organic psychoses and attempts to identify non-psychopathological risk factors or predictors.</p> <p>Method</p> <p>100 patients with functional psychosis were initially characterised using the Operational Criteria Checklist for Psychotic Illness and Affective Illness (OPCRIT), medical records and health registers. To study the stability of diagnoses (i.e. shifts per time), we used registry data to define four measures of diagnostic variation that were subsequently examined in relation to four possible measures of time (i.e. observation periods or hospitalisation events). Afterwards, we identified putative co-variables and predictors of the best measures of diagnostic stability.</p> <p>Results</p> <p>All four measures of diagnostic variation are very strongly associated with numbers-of-hospitalisations and less so with duration-of-illness, duration-of-hospitalisation and with year-of-first-admission. The four measures of diagnostic variation corrected for numbers-of-hospitalisations were therefore used to study the diagnostic stability. Conventional predictors of illness course – e.g. age-of-onset and premorbid-functioning – are not significantly associated with stability. Only somatic-comorbidity is significantly associated with two measures of stability, while family-history-of-psychiatric-illness and global-assessment-of-functioning (GAF) scale score show a trend. However, the traditional variables age-of-first-admission, civil-status, first-diagnosis-being-schizophrenia and somatic-comorbidity are able to explain two-fifth of the variation in numbers-of-hospitalisations.</p> <p>Conclusion</p> <p>Diagnostic stability is closely linked with the contact between patient and the healthcare system. This could very likely be due to fluctuation of disease manifestation over time or presence of co-morbid psychiatric illness in combination with rigid diagnostic criteria that are unable to capture the multiple psychopathologies of the functional psychoses that results in differential diagnoses and therefore diagnostic instability. Not surprisingly, somatic-comorbidity was found to be a predictor of diagnostic variation thereby being a non-psychiatric confounder.</p

Significant Role of Collagen XVII And Integrin β4 in Migration and Invasion of The Less Aggressive Squamous Cell Carcinoma Cells

Collagen XVII and integrin alpha 6 beta 4 have well-established roles as epithelial adhesion molecules. Their binding partner laminin 332 as well as integrin alpha 6 beta 4 are largely recognized to promote invasion and metastasis in various cancers, and collagen XVII is essential for the survival of colon and lung cancer stem cells. We have studied the expression of laminin.2, collagen XVII and integrin beta 4 in tissue microarray samples of squamous cell carcinoma (SCC) and its precursors, actinic keratosis and Bowen's disease. The expression of laminin.2 was highest in SCC samples, whereas the expression of collagen XVII and integrin beta 4 varied greatly in SCC and its precursors. Collagen XVII and integrin beta 4 were also expressed in SCC cell lines. Virus-mediated RNAi knockdown of collagen XVII and integrin beta 4 reduced the migration of less aggressive SCC-25 cells in horizontal scratch wound healing assay. Additionally, in a 3D organotypic myoma invasion assay the loss of collagen XVII or integrin beta 4 suppressed equally the migration and invasion of SCC-25 cells whereas there was no effect on the most aggressive HSC-3 cells. Variable expression patterns and results in migration and invasion assays suggest that collagen XVII and integrin beta 4 contribute to SCC tumorigenesis

Mate-Finding as an Overlooked Critical Determinant of Dispersal Variation in Sexually-Reproducing Animals

Dispersal is a critically important process in ecology, but robust predictive models of animal dispersal remain elusive. We identify a potentially ubiquitous component of variation in animal dispersal that has been largely overlooked until now: the influence of mate encounters on settlement probability. We use an individual-based model to simulate dispersal in sexually-reproducing organisms that follow a simple set of movement rules based on conspecific encounters, within an environment lacking spatial habitat heterogeneity. We show that dispersal distances vary dramatically with fluctuations in population density in such a model, even in the absence of variation in dispersive traits between individuals. In a simple random-walk model with promiscuous mating, dispersal distributions become increasingly ‘fat-tailed’ at low population densities due to the increasing scarcity of mates. Similar variation arises in models incorporating territoriality. In a model with polygynous mating, we show that patterns of sex-biased dispersal can even be reversed across a gradient of population density, despite underlying dispersal mechanisms remaining unchanged. We show that some widespread dispersal patterns found in nature (e.g. fat tailed distributions) can arise as a result of demographic variability in the absence of heterogeneity in dispersive traits across the population. This implies that models in which individual dispersal distances are considered to be fixed traits might be unrealistic, as dispersal distances vary widely under a single dispersal mechanism when settlement is influenced by mate encounters. Mechanistic models offer a promising means of advancing our understanding of dispersal in sexually-reproducing organisms

Treponema denticola chymotrypsin-like proteinase may contribute to orodigestive carcinogenesis through immunomodulation

Background: Periodontal pathogens have been linked to oral and gastrointestinal (orodigestive) carcinogenesis. However, the exact mechanisms remain unknown. Treponema denticola (Td) is associated with severe periodontitis, a chronic inflammatory disease leading to tooth loss. The anaerobic spirochete Td is an invasive bacteria due to its major virulence factor chymotrypsin-like proteinase. Here we aimed to investigate the presence of Td chymotrypsin-like proteinase (Td-CTLP) in major orodigestive tumours and to elucidate potential mechanisms for Td to contribute to carcinogenesis. Methods: The presence of Td-CTLP within orodigestive tumour tissues was examined using immunohistochemistry. Oral, tonsillar, and oesophageal squamous cell carcinomas, alongside gastric, pancreatic, and colon adenocarcinomas were stained with a Td-CTLP-specific antibody. Gingival tissue from periodontitis patients served as positive controls. SDS-PAGE and immunoblot were used to analyse the immumodulatory activity of Td-CTLP in vitro. Results: Td-CTLP was present in majority of orodigestive tumour samples. Td-CTLP was found to convert pro MMP-8 and -9 into their active forms. In addition, Td-CTLP was able to degrade the proteinase inhibitors TIMP-1, TIMP-2, and alpha-1-antichymotrypsin, as well as complement C1q. Conclusions: Because of its presence within tumours and regulatory activity on proteins critical for the regulation of tumour microenvironment and inflammation, the Td-CTLP may contribute to orodigestive carcinogenesis.Peer reviewe

The Polycomb Repressive Complex 2 Is a Potential Target of SUMO Modifications

The Polycomb Repressive Complex 2 (PRC2) functions as a transcriptional repressor through a mechanism that involves methylation of Histone H3 at lysine 27. The PRC2 complex activity is essential for cellular proliferation, development, and cell fate decisions. PRC2 target genes include important regulators of development and proliferation as well as tumor suppressor genes. Consistent with this, the activity of several Polycomb group (PcG) proteins is deregulated in human cancer suggesting an important role for PcGs in tumor development. Whereas the downstream functions of PcGs are well characterized, the mechanisms of their recruitment to target genes and the regulation of their activity are not fully understood.Here we show that the two PRC2 components SUZ12 and EZH2 are sumoylated in vitro and in vivo. Among several putative sumoylation sites we have mapped the major site of SUZ12 sumoylation. Furthermore, we show that SUZ12 interacts with the E2-conjugating enzyme UBC9 both in vitro and in vivo and that mutation of the SUZ12 sumoylation site does not abolish this binding. Finally, we provide evidence that the E3-ligase PIASXbeta interacts and enhances the sumoylation of SUZ12 in vivo suggesting that PIASXbeta could function as an E3-ligase for SUZ12.Taken together, our data identify sumoylation as a novel post-translational modification of components of the PRC2 complex, which could suggest a potential new mechanism to modulate PRC2 repressive activity. Further work aimed to identify the physiological conditions for these modifications will be required to understand the role of SUZ12 and EZH2 sumoylation in PcG-mediated epigenetic regulation of transcription

The Interplay between Protein L-Isoaspartyl Methyltransferase Activity and Insulin-Like Signaling to Extend Lifespan in Caenorhabditis elegans

The protein L-isoaspartyl-O-methyltransferase functions to initiate the repair of isomerized aspartyl and asparaginyl residues that spontaneously accumulate with age in a variety of organisms. Caenorhabditis elegans nematodes lacking the pcm-1 gene encoding this enzyme display a normal lifespan and phenotype under standard laboratory growth conditions. However, significant defects in development, egg laying, dauer survival, and autophagy have been observed in pcm-1 mutant nematodes when deprived of food and when exposed to oxidative stress. Interestingly, overexpression of this repair enzyme in both Drosophila and C. elegans extends adult lifespan under thermal stress. In this work, we show the involvement of the insulin/insulin-like growth factor-1 signaling (IIS) pathway in PCM-1-dependent lifespan extension in C. elegans. We demonstrate that reducing the levels of the DAF-16 downstream transcriptional effector of the IIS pathway by RNA interference reduces the lifespan extension resulting from PCM-1 overexpression. Using quantitative real-time PCR analysis, we show the up-regulation of DAF-16-dependent stress response genes in the PCM-1 overexpressor animals compared to wild-type and pcm-1 mutant nematodes under mild thermal stress conditions. Additionally, similar to other long-lived C. elegans mutants in the IIS pathway, including daf-2 and age-1 mutants, PCM-1 overexpressor adult animals display increased resistance to severe thermal stress, whereas pcm-1 mutant animals survive less long under these conditions. Although we observe a higher accumulation of damaged proteins in pcm-1 mutant nematodes, the basal level of isoaspartyl residues detected in wild-type animals was not reduced by PCM-1 overexpression. Our results support a signaling role for the protein L-isoaspartyl methyltransferase in lifespan extension that involves the IIS pathway, but that may be independent of its function in overall protein repair

Pregnane X Receptor and Yin Yang 1 Contribute to the Differential Tissue Expression and Induction of CYP3A5 and CYP3A4

The hepato-intestinal induction of the detoxifying enzymes CYP3A4 and CYP3A5 by the xenosensing pregnane X receptor (PXR) constitutes a key adaptive response to oral drugs and dietary xenobiotics. In contrast to CYP3A4, CYP3A5 is additionally expressed in several, mostly steroidogenic organs, which creates potential for induction-driven disturbances of the steroid homeostasis. Using cell lines and mice transgenic for a CYP3A5 promoter we demonstrate that the CYP3A5 expression in these organs is non-inducible and independent from PXR. Instead, it is enabled by the loss of a suppressing yin yang 1 (YY1)-binding site from the CYP3A5 promoter which occurred in haplorrhine primates. This YY1 site is conserved in CYP3A4, but its inhibitory effect can be offset by PXR acting on response elements such as XREM. Taken together, the loss of YY1 binding site from promoters of the CYP3A5 gene lineage during primate evolution may have enabled the utilization of CYP3A5 both in the adaptive hepato-intestinal response to xenobiotics and as a constitutively expressed gene in other organs. Our results thus constitute a first description of uncoupling induction from constitutive expression for a major detoxifying enzyme. They also suggest an explanation for the considerable tissue expression differences between CYP3A5 and CYP3A4

ICAM-2 Expression Mediates a Membrane-Actin Link, Confers a Nonmetastatic Phenotype and Reflects Favorable Tumor Stage or Histology in Neuroblastoma

The actin cytoskeleton is a primary determinant of tumor cell motility and metastatic potential. Motility and metastasis are thought to be regulated, in large part, by the interaction of membrane proteins with cytoplasmic linker proteins and of these linker proteins, in turn, with actin. However, complete membrane-to-actin linkages have been difficult to identify. We used co-immunoprecipitation and competitive peptide assays to show that intercellular adhesion molecule-2 (ICAM-2)/α-actinin/actin may comprise such a linkage in neuroblastoma cells. ICAM-2 expression limited the motility of these cells and redistributed actin fibers in vitro, and suppressed development of disseminated tumors in an in vivo model of metastatic neuroblastoma. Consistent with these observations, immunohistochemical analysis demonstrated ICAM-2 expression in primary neuroblastoma tumors exhibiting features that are associated with limited metastatic disease and more favorable clinical outcome. In neuroblastoma cell lines, ICAM-2 expression did not affect AKT activation, tumorigenic potential or chemosensitivity, as has been reported for some types of transfected cells. The observed ICAM-2-mediated suppression of metastatic phenotype is a novel function for this protein, and the interaction of ICAM-2/α-actinin/actin represents the first complete membrane-linker protein-actin linkage to impact tumor cell motility in vitro and metastatic potential in an in vivo model. Current work focuses on identifying specific protein domains critical to the regulation of neuroblastoma cell motility and metastasis and on determining if these domains represent exploitable therapeutic targets