BDNF and DYRK1A Are Variable and Inversely Correlated in Lymphoblastoid Cell Lines from Down Syndrome Patients

Down syndrome or trisomy 21 is the most common genetic disorder leading to mental retardation. One feature is impaired short- and long-term spatial memory, which has been linked to altered brain-derived neurotrophic factor (BDNF) levels. Mouse models of Down syndrome have been used to assess neurotrophin levels, and reduced BDNF has been demonstrated in brains of adult transgenic mice overexpressing Dyrk1a, a candidate gene for Down syndrome phenotypes. Given the link between DYRK1A overexpression and BDNF reduction in mice, we sought to assess a similar association in humans with Down syndrome. To determine the effect of DYRK1A overexpression on BDNF in the genomic context of both complete trisomy 21 and partial trisomy 21, we used lymphoblastoid cell lines from patients with complete aneuploidy of human chromosome 21 (three copies of DYRK1A) and from patients with partial aneuploidy having either two or three copies of DYRK1A. Decreased BDNF levels were found in lymphoblastoid cell lines from individuals with complete aneuploidy as well as those with partial aneuploidies conferring three DYRK1A alleles. In contrast, lymphoblastoid cell lines from individuals with partial trisomy 21 having only two DYRK1A copies displayed increased BDNF levels. A negative correlation was also detected between BDNF and DYRK1A levels in lymphoblastoid cell lines with complete aneuploidy of human chromosome 21. This finding indicates an upward regulatory role of DYRK1A expression on BDNF levels in lymphoblastoid cell lines and emphasizes the role of genetic variants associated with psychiatric disorders.     

Parathyroid involvement in thyroid cancer: an unforeseen event

ABSTRACT: BACKGROUND: Parathyroid metastatic disease from thyroid cancer has not been studied extensively, mainly due to the need for parathyroid preservation during thyroid surgery. METHODS: We reviewed files from 1,770 patients with thyroid cancer followed up in our department and 10 patients with parathyroid metastases (0.5 %) were identified. Patient and tumor characteristics were recorded. RESULTS: Six out of ten patients had metastasis from papillary thyroid cancer, three from follicular thyroid cancer and one from anaplastic thyroid cancer. In nine patients parathyroid infiltration from thyroid cancer was found in direct contact with the thyroid cancer, and in one patient metastatic foci were observed not in continuity with the thyroid cancer. CONCLUSIONS: Parathyroid involvement, although infrequent, may occur in thyroid cancer independently of patient age and tumor size. The clinical significance of such event is not clear. The influence on disease outcome remains to be elucidated.     

Evaluation of a four-drug, three-antibiotic, nonbismuth-containing "concomitant" therapy as first-line Helicobacter pylori eradication regimen in Greece

Background: The eradication rates of Helicobacter pylori (H. pylori) with standard treatments are decreasing worldwide as in Greece. Studies with new antibiotic combinations are needed to find better methods of eradication. Therefore, the aim of this study was to evaluate efficacy and tolerability of a 10‐day, four‐drug, three‐antibiotic, nonbismuth–containing concomitant regimen. Materials and Methods: This is a prospective, open‐label, multicenter study that included 131 patients infected with H. pylori. All patients were diagnosed with peptic ulcer disease or nonulcer dyspepsia by endoscopy. H. pylori infection was established by at least two positive tests among rapid urease test, gastric histology, and ¹³C‐urea breath test. For 10 days, all patients received esomeprazole 40 mg, amoxycillin 1000 mg, clarithromycin 500 mg, and metronidazole 500 mg, all b.d. eradication was assessed with ¹³C urea breath test 8 weeks after the start of treatment. Intention‐to‐treat and per‐protocol eradication rates were determined. Results: One hundred and twenty‐seven of the 131 patients completed the study. At intention‐to‐treat analysis, the eradication rate was 91.6% (95% confidence interval (CI), 85.5–95.7%). For the per‐protocol analysis, the eradication rate was 94.5% (95% CI, 89–97.8%). Adverse events were noted in 42 of 131 (32.1%); drug compliance was excellent with 96.9% of the patients taking more than 90% of the prescribed medication. Conclusion: A 10‐day concomitant regimen appears to be an effective, safe, and well‐tolerated treatment option for first‐line H. pylori eradication in Greece.     

Extensive natural variation for cellular hydrogen peroxide release is genetically controlled

Natural variation in DNA sequence contributes to individual differences in quantitative traits. While multiple studies have shown genetic control over gene expression variation, few additional cellular traits have been investigated. Here, we investigated the natural variation of NADPH oxidase-dependent hydrogen peroxide (H₂O₂ release), which is the joint effect of reactive oxygen species (ROS) production, superoxide metabolism and degradation, and is related to a number of human disorders. We assessed the normal variation of H₂O₂ release in lymphoblastoid cell lines (LCL) in a family-based 3-generation cohort (CEPH-HapMap), and in 3 population-based cohorts (KORA, GenCord, HapMap). Substantial individual variation was observed, 45% of which were associated with heritability in the CEPH-HapMap cohort. We identified 2 genome-wide significant loci of Hsa12 and Hsa15 in genome-wide linkage analysis. Next, we performed genome-wide association study (GWAS) for the combined KORA-GenCord cohorts (n = 279) using enhanced marker resolution by imputation (>1.4 million SNPs). We found 5 significant associations (p<5.00×10−8) and 54 suggestive associations (p<1.00×10−5), one of which confirmed the linked region on Hsa15. To replicate our findings, we performed GWAS using 58 HapMap individuals and ∼2.1 million SNPs. We identified 40 genome-wide significant and 302 suggestive SNPs, and confirmed genome signals on Hsa1, Hsa12, and Hsa15. Genetic loci within 900 kb from the known candidate gene p67phox on Hsa1 were identified in GWAS in both cohorts. We did not find replication of SNPs across all cohorts, but replication within the same genomic region. Finally, a highly significant decrease in H₂O₂ release was observed in Down Syndrome (DS) individuals (p<2.88×10−12). Taken together, our results show strong evidence of genetic control of H₂O₂ in LCL of healthy and DS cohorts and suggest that cellular phenotypes, which themselves are also complex, may be used as proxies for dissection of complex disorders.     

Enhanced Levels of Cold Shock Proteins in Listeria monocytogenes LO28 upon Exposure to Low Temperature and High Hydrostatic Pressure

Listeria monocytogenes is a psychrotrophic food-borne pathogen that is problematic for the food industry because of its ubiquitous distribution in nature and its ability to grow at low temperatures and in the presence of high salt concentrations. Here we demonstrate that the process of adaptation to low temperature after cold shock includes elevated levels of cold shock proteins (CSPs) and that the levels of CSPs are also elevated after treatment with high hydrostatic pressure (HHP). Two-dimensional gel electrophoresis combined with Western blotting performed with anti-CspB of Bacillus subtilis was used to identify four 7-kDa proteins, designated Csp1, Csp2, Csp3, and Csp4. In addition, Southern blotting revealed four chromosomal DNA fragments that reacted with a csp probe, which also indicated that a CSP family is present in L. monocytogenes LO28. After a cold shock in which the temperature was decreased from 37°C to 10°C the levels of Csp1 and Csp3 increased 10- and 3.5-fold, respectively, but the levels of Csp2 and Csp4 were not elevated. Pressurization of L. monocytogenes LO28 cells resulted in 3.5- and 2-fold increases in the levels of Csp1 and Csp2, respectively. Strikingly, the level of survival after pressurization of cold-shocked cells was 100-fold higher than that of cells growing exponentially at 37°C. These findings imply that cold-shocked cells are protected from HHP treatment, which may affect the efficiency of combined preservation techniques.     

Distribution and abundance of larval fish in the northern Aegean Sea--eastern Mediterranean--in relation to early summer oceanographic conditions

Two ichthyoplanktonic surveys were conducted during June 1995and 1996 along the northern Aegean Sea coast with the aim ofdescribing species composition, abundance and distribution patternsof the assemblages of fish larvae and their relationships tooceanographic regimes. The upper water column was generallycooler, fresher and richer in zooplankton during June 1996.The mean abundance of larvae of the small-sized pelagic fish(anchovy and most mesopelagics) was higher in 1996. In contrast,larvae of the middle-sized pelagics (Sardinella aurita, Trachurusmediterraneus, Scomber jaconicus and Auxis rochei) were moreabundant in 1995. The eastern part of the surveyed area (NEAegean Sea) was colder and less saline during both years becauseof the influence of Black Sea and riverine waters. In the colderJune 1996, larvae of many ‘summer spawners', e.g., themiddle-sized pelagics, were present infrequently and at verylow numbers in the NE Aegean Sea. Cluster analysis using theBray–Curtis similarity index revealed well-defined groupsof stations and assemblages of larvae. Ordination scores derivedfrom non-metric multidimensional scaling were compared by multipleregression with various parameters and the analysis showed thattaxonomic composition and abundance was primarily explainedby bathymetry. In the cooler June 1996, a significant amountof variation in ordination scores was related to longitudinaldifferences in temperature, salinity and the width of the continentalshelf. The membership of station and species groups definedby the cluster analysis differed between 1995 and 1996 and reflectedinterannual differences in the distribution and abundance ofcomponent species. Spatial and temporal spawning patterns ofadults played the key role in the formation of assemblages ofearly larvae.     

The ex vivo toll-like receptor 7 tolerance induction in donor lymphocytes prevents murine acute graft-versus-host disease

Background aims

Acute graft-versus-host disease (aGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation, mediated by alloreactive donor T cells. Toll-like receptors (TLRs), a family of conserved pattern-recognition receptors (PRRs), represent key players in donors' T-cell activation during aGVHD; however, a regulatory, tolerogenic role for certain TLRs has been recognized in a different context. We investigated whether the ex vivo–induced TLR-2,-4,-7 tolerance in donor cells could prevent alloreactivity in a mismatched transplantation model.

ULTRASTRUCTURE OF CARPOSPOROGENESIS IN THE PARASITIC RED ALGA FAUCHEOCOLAX ATTENUATA SETCH. (RHODYMENIALES,RHODYMENIACEAE)

Carpospore differentiation in Faucheocolax attenuata Setch. can be separated into three developmental stages. Immediately after cleaving from the multinucleate gonimoblast cell, young carpospores are embedded within confluent mucilage produced by gonimoblast cells. These carpospores contain a large nucleus, few starch grains, concentric lamellae, as well as proplastids with a peripheral thylakoid and occasionally some internal (photosynthetic) thylakoids. Proplastids also contain concentric lamellar bodies. Mucilage with a reticulate fibrous substructure is formed within cytoplasmic concentric membranes, thus giving rise to mucilage sacs. Subsequently, these mucilage sacs release their contents, forming an initial reticulate deposition of carpospore wall material. Dictyosome vesicles with large, single dark-staining granules also contribute to wall formation and may create a separating layer between the mucilage and carpospore wall. During the latter stages of young carpospores, starch is polymerized in the perinuclear cytoplasmic area and is in close contact with endoplasmic reticulum. Intermediate-aged carpospores continue their starch polymerization. Dictyosomes deposit more wall material, in addition to forming fibrous vacuoles. Proplastids form thylakoids from concentric lamellar bodies. Mature carpospores are surrounded by a two-layered carpospore wall. Cytoplasmic constituents include large floridean starch granules, peripheral fibrous vacuoles, mature chloroplasts and curved dictyosomes that produce cored vesicles which in turn are transformed into adhesive vesicles. Pit connections remain intact between carpospores but begin to degenerate. This degeneration appears to be mediated by microtubules.