Interleukin-13 gene polymorphisms in patients with Graves' disease

OBJECTIVE: In patients with Graves' disease (GD), an elevation of serum immunoglobulin E (IgE) has been recently reported to be associated with the severity of hyperthyroidism and ophthalmopathy. Interleukin 13 (IL-13) is a major cytokine involved in IgE synthesis and therefore may be a potential candidate gene contributing to the development of GD or influencing the clinical course of the disease. DESIGN: In a case-control study, we examined IL-13 gene single-nucleotide polymorphisms in the 5' promoter region at position -1112 (C to T change, termed as C-1112T) and in exon 4 at position 2044 (G to A change, G2044A, which results in an amino acid exchange Arg130Gln) in 261 patients with GD. The control groups consisted of healthy young subjects (n=168) and subjects over 100 years old with no history of autoimmune or allergic diseases recruited from the Polish Centenarians Project (n=50). MEASUREMENTS: C-1112T and G2044A polymorphisms were defined by fluorescent single-strand conformational polymorphism and by restriction fragment length polymorphism analysis, respectively. RESULTS: In patients with GD, the distribution of IL-13 alleles (-1112T 31%; 2044A 25%) and genotypes (-1112T/T 10%; 2044A/A 7%) did not differ significantly compared to control groups. Subdividing GD patients according to clinically evident ophthalmopathy (NOSPECS class III or higher, n=93) revealed no significant differences in the frequencies of -1112T allele (33%vs. 29%; P=0.4), -1112T/T genotype (13%vs. 8%; P=0.3), 2044A allele (27%vs. 24%; P=0.5) and 2044A/A genotype (9%vs. 7%; P=0.7) between GD patients with and without eye involvement. In order to analyse the association with the severity of hyperthyroidism, we examined patients with a first onset of GD treated with antithyroid drugs (n=32). IL-13 genotypes were not associated with the laboratory findings at diagnosis (thyroid volume, serum levels of FT4, TRAb, TPOAb, TGAb) and with the outcome of antithyroid drug treatment. CONCLUSIONS: Our results suggest that IL-13 gene polymorphisms at positions -1112 (C-->T) and 2044 (G-->A): (1) do not confer genetic susceptibility to Graves' disease; (2) do not contribute to the development of clinically evident ophthalmopathy; (3) are not associated with severity of hyperthyroidism.     

Adolescent social isolation affects parvalbumin expression in the medial prefrontal cortex in the MAM-E17 model of schizophrenia

Altered parvalbumin (PV) expression is observed in the prefrontal cortex of subjects with schizophrenia. Environmental context, particularly during adolescence, might regulate PV expression. In the present study, we investigated the effect of adolescent social isolation (SI) on PV expression in the medial prefrontal cortex in a neurodevelopmental model (MAM-E17) of schizophrenia. SI exposure occurred from postnatal day 30 to 40, followed by resocialization until late adolescence or early adulthood. PV mRNA and protein levels, as well as the number of PV cells, were analysed at these ages. Moreover, epigenetic regulation of PV expression by histone methylation was examined by measuring the total and PV gene-bound H3K4me3 levels. MAM only decreased levels of the PV mRNA and protein in adulthood. Decreases in total H3K4me3 levels and its level at the PV gene were also observed at this age. In contrast, in late adolescence, SI induced a decrease in the expression of the PV mRNA in the MAM group that was related to the reduction in total and PV gene-bound H3K4me3 levels. However, at this age, SI increased the levels of the PV protein in both the control and MAM groups. In adulthood, SI did not affect PV mRNA or H3K4me3 levels but decreased levels of the PV protein in both groups. Both MAM and SI failed to change the number of PV cells at any age. The results indicate that adolescent SI accelerated epigenetic impairments of PV expression in MAM-E17 rats; however, subsequent resocialization abolished this dysfunction, but failed to prevent alterations in PV protein.

     

A seed coat bedding assay shows that RGL2-dependent release of abscisic acid by the endosperm controls embryo growth in Arabidopsis dormant seeds

Seed dormancy is an ecologically important adaptive trait in plants whereby germination is repressed even under favorable germination conditions such as imbibition with water. In Arabidopsis and most plant species, dormancy absolutely requires an unidentified seed coat germination-repressive activity and constitutively higher abscisic acid (ABA) levels upon seed imbibition. The mechanisms underlying these processes and their possible relationship are incompletely understood. We developed a "seed coat bedding" assay monitoring the growth of dissected embryos cultured on a layer of seed coats, allowing combinatorial experiments using dormant, nondormant, and various genetically modified seed coat and embryonic materials. This assay, combined with direct ABA measurements, revealed that, upon imbibition, dormant coats, unlike nondormant coats, actively produce and release ABA to repress embryo germination, whatever the embryo origin, i.e., from dormant, nondormant, or never dormant aba seeds, unable to synthesize ABA. The persistent high ABA levels in imbibed dormant seeds requires the permanent expression of the DELLA gene RGL2, where it remains insensitive to gibberellins (GA) unlike in nondormant seeds. These findings present the seed coat as an organ actively controlling germination upon seed imbibition and provide a framework to investigate how environmental factors break seed dormancy.     

Association Between Quality of Cheap and Unrecorded Alcohol Products and Public Health Consequences in Poland

Background: The research aimed to study the quality of cheap alcohol products in Poland. These included unrecorded alcohols (i.e., home‐produced or illegally imported), estimated to constitute more than 25% of total consumption and fruit wines. Methods: A sample of alcohol products (n = 52) was collected from local markets and chemical analyses were conducted. The parameters studied were alcoholic strength, volatiles (methanol, acetaldehyde, and higher alcohols), ethyl carbamate, inorganic elements, and food additives including preservatives, colors, and sweeteners. The compositions of the beverages were then toxicologically evaluated using international standards. Results: With the exception of 1 fortified wine, the unrecorded alcohols were home‐produced fruit‐derived spirits (moonshine) and spirits imported from other countries. We did not detect any nonbeverage surrogate alcohol. The unrecorded spirits contained, on average, 45% vol of alcohol. However, some products with considerably higher alcoholic strengths were found (up to 85% vol) with no labeling of the content on the bottles. These products may cause more pronounced detrimental health effects (e.g., liver cirrhosis, injuries, some forms of malignant neoplasms, alcohol use disorders, and cardiovascular disease) than will commercial beverages, especially as the consumer may be unaware of the alcohol content consumed. Fruit wines containing between 9.5 and 12.2% vol alcohol showed problems in terms of their additive content and their labeling (e.g., sulfites, sorbic acid, saccharin, and artificial colors) and should be subjected to stricter control. Regarding the other components investigated, the suspected human carcinogens, acetaldehyde and ethyl carbamate, were found at levels relevant to public health concerns. While acetaldehyde is a typical constituent of fermented beverages, ethyl carbamate was found only in home‐produced unrecorded alcohols derived from stone fruits with levels significantly above international guidelines. Conclusions: The contamination of unrecorded alcohols with ethyl carbamate should be analyzed in a larger sample that also should include legal alcoholic beverages. Furthermore, the impacts of unrecorded alcohol on the health of people with lower socioeconomic status should be studied in detail. Overall, given the extent of the alcohol‐attributable disease burden in Poland, the highest priority should be given to the problem of ethanol and its very high content in unrecorded alcohol products.     

Effect of ivabradine on cardiac arrhythmias: Antiarrhythmic or proarrhythmic?

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Genetically attenuated Plasmodium berghei liver stages induce sterile protracted protection that is mediated by major histocompatibility complex Class I-dependent interferon-gamma-producing CD8+ T cells

At present, radiation-attenuated plasmodia sporozoites ( gamma -spz) is the only vaccine that induces sterile and lasting protection in malaria-naive humans and laboratory rodents. However, gamma -spz are not without risks. For example, the heterogeneity of the gamma -spz could explain occasional breakthrough infections. To avoid this possibility, we constructed a double-knockout P. berghei parasite by removing 2 genes, UIS3 and UIS4, that are up-regulated in infective spz. We evaluated the double-knockout Pbuis3(-)/4(-) parasites for protective efficacy and the contribution of CD8(+) T cells to protection. Pbuis3(-)/4(-) spz induced sterile and protracted protection in C57BL/6 mice. Protection was linked to CD8(+) T cells, given that mice deficient in beta (2)m were not protected. Pbuis3(-)/4(-) spz-immune CD8(+) T cells consisted of effector/memory phenotypes and produced interferon- gamma . On the basis of these observations, we propose that the development of genetically attenuated P. falciparum parasites is warranted for tests in clinical trials as a pre-erythrocytic stage vaccine candidate.     

Assessment of the Effect of Structural Modification of Ibuprofen on the Penetration of Ibuprofen from Pentravan® (Semisolid) Formulation Using Human Skin and a Transdermal Diffusion Test Model

The effect of transdermal vehicle (Pentravan^®) on skin permeability was examined for unmodified ibuprofen (IBU) and ion pairs of ibuprofen with new L-valine alkyl esters [ValOR][IBU]. The percutaneous permeation across the human skin and transdermal diffusion test model (Strat-M^® membranes) of ibuprofen and its structural modification were measured and compared using Franz diffusion cells. For comparison, the penetration of ibuprofen from a commercial product was also investigated. The cumulative amount of drug permeated through human skin at the end of the 24 h study was highest for ibuprofen derivatives containing propyl (C3), isopropyl (C3), ethyl (C2), and butyl (C4) esters. For Strat-M^®, the best results were obtained with the alkyl chain length of the ester from C2 to C5. The permeation profiles and parameters were appointed, such as steady-state flux, lag time, and permeability coefficient. It has been shown that L-valine alkyl ester ibuprofenates, with the propyl, butyl, and amyl chain, exhibit a higher permeation rate than ibuprofen. The diffusion parameters of analyzed drugs through human skin and Strat-M^® were similar and with good correlation. The resulting Pentravan-based creams with ibuprofen in the form of an ionic pair represent a potential alternative to other forms of the drug-containing analgesics administered transdermally. Furthermore, the Strat-M^® membranes can be used to assess the permeation of transdermal preparations containing anti-inflammatory drugs.     

Parasite load stemming from immunization route determines the duration of liver‐stage immunity

Immunization with radiation‐attenuated Plasmodium sporozoites (RAS) induces sterile and long‐lasting protective immunity. Although intravenous (IV) route of RAS immunization is reported to induce superior immunity compared to intradermal (ID) injection, its role in the maintenance of sterile immunity is yet to be understood. We investigated whether the route of homologous sporozoite challenge of Plasmodium berghei (Pb) RAS‐immunized mice would influence the longevity of protection. C57BL/6 mice immunized with Pb‐RAS by IV were 100% protected upon primary IV/ID sporozoite challenge. In contrast, ID immunization resulted in 80% protection, regardless of primary challenge route. Interestingly, the route of primary challenge was found to bring difference in the maintenance of sterile protection. While IV Pb RAS‐immunized mice remained protected at all challenges regardless of the route of primary challenge, ID Pb‐RAS‐immunized mice receiving ID primary challenge became parasitaemic upon secondary IV challenge. Significantly, primary IV challenge of Pb RAS ID‐immunized mice resulted in 80% and 50% survival at secondary and tertiary challenges, respectively. According to phenotypically diverse liver CD8⁺ T cells, the percentages and the numbers of both CD8⁺ T effector memory and resident memory cells were significantly higher in IV than in ID Pb RAS‐immunized mice. IFN‐γ‐producing CD8⁺ T cells specific to Pb TRAP₁₃₀ and MIP‐4‐Kb‐17 were also found significantly higher in IV mice than in ID mice. The enhanced T‐cell generation and the longevity of protection appear to be dependent on the parasite load during challenge when infection is tolerated under suboptimal CD8⁺ T‐cell response.