GWAS links variants in neuronal development and actin remodeling related loci with pseudoexfoliation syndrome without glaucoma

Pseudoexfoliation syndrome (PEXS) is an age-related elastosis, strongly associated with the development of secondary glaucoma. It is clearly suggested that PEXS has a genetic component, but this has not been extensively studied. Here, a genome-wide association study (GWAS) using a DNA-pooling approach was conducted to explore the potential association of genetic variants with PEXS in a Polish population, including 103 PEXS patients without glaucoma and 106 perfectly (age- and gender-) matched controls. Individual sample TaqMan genotyping was used to validate GWAS-selected single-nucleotide polymorphism (SNP) associations. Multivariate binary logistic regression analysis was applied to develop a prediction model for PEXS. In total, 15 SNPs representing independent PEXS susceptibility loci were selected for further validation in individual samples. For 14 of these variants, significant differences in the allele and genotype frequencies between cases and controls were identified, of which 12 remained significant after Benjamini-Hochberg adjustment. The minor allele of five SNPs was associated with an increased risk of PEXS development, while for nine SNPs, it showed a protective effect. Beyond the known LOXL1 variant rs2165241, nine other SNPs were located within gene regions, including in OR11L1, CD80, TNIK, CADM2, SORBS2, RNF180, FGF14, FMN1, and RBFOX1 genes. None of these associations with PEXS has previously been reported. Selected SNPs were found to explain nearly 69% of the total risk of PEXS development. The overall risk prediction accuracy for PEXS, expressed by the area under the ROC curve (AUC) value, increased by 0.218, from 0.672 for LOXL1 rs2165241 alone to 0.89 when seven additional SNPs were included in the proposed 8-SNP prediction model. In conclusion, several new susceptibility loci for PEXS without glaucoma suggested that neuronal development and actin remodeling are potentially involved in either PEXS onset or inhibition or delay of its conversion to glaucoma

Recurrence of Cryoglobulinemia Secondary to Hepatitis C in a Patient with HCV RNA (−) Negative in the Serum

Hepatitis C virus infection is associated with many extrahepatic manifestations such as mixed cryoglobulinemia (MC). Renal manifestation of HCV infection might present as cryo-positive membranoproliferative glomerulonephritis (MPGN). First-line therapy includes antiviral treatment as the underlying infection leads to formation of immune complexes. After introducing direct-acting antiviral agents (DAAs) cure rates of HCV infection increased. Sustained virologic response (SVR) is defined as the absence of HCV RNA in serum by a sensitive test performed 12 or 24 weeks after the end of antiviral treatment. Although HCV RNA is undetectable in the serum, it may be present in hepatocytes and peripheral blood mononuclear cells (occult HCV infection). However, the impact of DAA treatment on occult HCV infection is not clear. We report a case of recurrence of MC with MPGN and development of lymphoproliferative disorder 2 years after achieving SVR

Alfa-mannozydoza u 3,5-letniej dziewczynki z uszkodzeniem wątroby

Alfa-mannozydoza jest rzadką, dziedziczoną w sposób autosomalno-recesywny, postępującą chorobą metaboliczną, której istota polega na braku lub niedoborze aktywności enzymu α-mannozydazy. U dzieci dotkniętych tym schorzeniem stwierdza się zaburzenia immunologiczne, niepełnosprawność intelektualną wraz z opóźnionym rozwojem ruchowym, dysmorfię twarzy oraz zaburzenia szkieletowe i słuchu. W pracy przedstawiono przypadek 3,5-letniej dziewczynki hospitalizowanej w Klinice Pediatrii, Gastroenterologii, Hepatologii i Żywienia Dzieci z powodu uszkodzenia wątroby, nawracających infekcji dróg oddechowych i przewlekłej biegunki. Dziecko było opóźnione w rozwoju psychoruchowym, nadpobudliwe, stwierdzono dysmorfię twarzy, niedosłuch oraz nieznaczną splenomegalię. W badaniach dodatkowych stwierdzono liczne nieprawidłowości. Na podstawie nieprawidłowego wydalania oligosacharydów w moczu i badania aktywności enzymów lizosomalnych w leukocytach (deficyt aktywności α-mannozydazy) rozpoznano α-mannozydozę. Obecnie nie ma możliwości stosowania enzymatycznej terapii zastępczej u pacjentów z tym schorzeniem. Dziecko objęto wielospecjalistyczną opieką i wdrożono wielokierunkową rehabilitację. Forum Medycyny Rodzinnej 2011, tom 5, nr 6, 521–52

Atypical microbial infections of digestive tract may contribute to diarrhea in mucopolysaccharidosis patients: a MPS I case study

BACKGROUND: Mucopolysaccharidoses are heritable, metabolic diseases caused by deficiency in an activity of one of specific lysosomal enzymes involved in degradation of mucoplysaccharides (glycosaminoglycans). Among many medical problems of patients with mucopolysaccharidoses, there are frequent episodes of diarrhea of unknown etiology. CASE PRESENTATION: A girl, diagnosed enzymatically for mucopolysaccharidosis type I (deficiency of α-L-iduronidase) at the age of 3 years and 9 months, was investigated until the age of 5 years and 4 months. Frequent loose stools and episodes of diarrhea, often accompanied by vomiting, were encountered. Detailed microbiological analyses were performed and atypical microbial infections (most often enetropathogenic Escherichia coli, but also other species, like Pseudomonas aeruginosa or Staphylococcus aureus, as well as adenoviruses) of the digestive tract were found in most severe diarrhea episodes. Often, isolations of pathogenic bacterial strains from stools of the investigated patient suffering from diarrhea were not obvious during the first screening, and only detailed microbiological studies, including re-isolation of colonies, gave the results of isolation of particular pathogenic strains (especially in the case of enetropathogenic E. coli). CONCLUSION: We conclude that atypical microbial infections of digestive tract may contribute significantly to diarrhea in mucopolysaccaridosis patients. Since isolated strains were not typical and their isolation was often possible only after detailed investigation (not during a standard screening), such atypical microbial infections of digestive tract of mucopolysaccharidosis patients could be usually overlooked to date. Importantly, these atypical infections could be effectively treated with antimicrobial agents

The features of liver lesions in children at the time of diagnosis of inflammatory bowel disease. Observations from one medical center

Wstęp: W przebiegu nieswoistych zapaleń jelit stosunkowo często procesem chorobowym objęte są inne narządy, w tym wątroba.Cel pracy: Ocena częstości występowania biochemicznych cech uszkodzenia wątroby w momencie rozpoznania nieswoistego zapalenia jelit (NZJ) u dzieci.Materiał i metody: Analizą objęto 49 dzieci z NZJ w wieku 2–18 lat. U wszystkich chorych przeprowadzono badanie kliniczne oraz diagnostykę laboratoryjną [między innymi aktywność aminotransferazy alaninowej (ALT) i asparaginowej (AST), gammaglutamylotranspeptydazy (GGTP) i stężenie bilirubiny w surowicy krwi]. Rozpoznanie choroby podstawowej ustalono na podstawie badania endoskopowego przewodu pokarmowego oraz oceny histopatologicznej wycinków błony śluzowej jelita. Jako podstawowe kryterium uszkodzenia wątroby przyjęto wartości aktywności ALT powyżej 45 j./l.Wyniki: Podwyższoną aktywność ALT stwierdzono u 16 badanych dzieci (32%) z nieswoistymi zapaleniami jelit. Aktywność ALT mieściła się w granicach 45–157 j./l; średnio 75,8 ± 40 j./l.Wnioski: U pacjentów pediatrycznych z nieswoistymi zapaleniami jelit stosunkowo często, już w momencie rozpoznania, obserwuje się cechy uszkodzenia wątroby. U wszystkich chorych z nieswoistymi zapaleniami jelit należy monitorować parametry funkcji wątroby w celu wczesnego rozpoznania współistniejących powikłań hepatologicznych. Obserwacje poczynione w niniejszym badaniu mają jedynie charakter wstępny i zobowiązują do pogłębienia diagnostyki „hepatologicznej” w celu ustalenia szczegółowego rozpoznania i wdrożenia właściwego leczenia. Konieczne są dalsze badania obejmujące liczniejsze grupy dzieci chorych na nieswoiste zapalenia jelit.Introduction: Patients with inflammatory bowel diseases (IBD) often develop complications involving other organs, including the liver.Aim of study: To assess the prevalence of elevated liver enzymes in children suffering from inflammatory bowel disease (IBD).Material and methods: We analyzed a group of 49 patients with IBD from 2 to 18 years old. Each patient had physical examination done, medical history taken and laboratory tests performed [alanine transaminase (ALT), aspartate transaminase (AST), gamma gluthamylotranspeptydase (GGTP), bilirubin]. The diagnosis of IBD was based on endoscopic and histopathological criteria.The liver damage was recognized when activity of ALT was above 45 U/l.Results: Increased liver enzymes activity was found in a group of 32% of patients with IBD. The activity of ALT ranged from 54 to 157 U/l.Conclusions: 1. In pediatric population with inflammatory bowel diseases the liver damage might be present at the very beginning of the IBD. 2. In all the patients with IBD liver enzymes activity ought to be monitored in order to recognize hepatic complications. 3. Observations of this study oblige to extend diagnostic procedures enabling accurate recognition and appropriate treatment

Coupling of transcription and replication machineries in λ DNA replication initiation: evidence for direct interaction of Escherichia coli RNA polymerase and the λO protein

Transcription proceeding downstream of the λ phage replication origin was previously shown to support initial steps of the λ primosome assembly in vitro and to regulate frequency and directionality of λ DNA replication in vivo. In this report, the data are presented indicating that the RNA polymerase β subunit makes a direct contact with the λO protein, a replication initiator of λ phage. These results suggest that the role of RNA polymerase during the initiation of λ phage DNA replication may be more complex than solely influencing DNA topology. Results demonstrated in this study also show that gyrase supercoiling activity stimulates the formation of a complex between λO and RNA polymerase, suggesting that the introduction of negative supercoils by DNA gyrase, besides lowering the energy required for DNA strand separation, may play an additional role in modeling protein–protein interactions at early steps of DNA replication initiation

Annales Academiae Medicae Gedanensis, 2008, supl. 1 : Rola transformującego czynnika wzrostu β1 (TGF - β1) i jego polimorfizmu genowego w etiopatogenezie i przebiegu klinicznym przewlekłych stanów zapalnych układu pokarmowego u dzieci

Praca wykonana w: Katedra i Klinika Pediatrii, Gastroenterologii, Hepatologii i Żywienia Dzieci

Genistin-rich soy isoflavone extract in substrate reduction therapy for Sanfilippo syndrome: An open-label, pilot study in 10 pediatric patients

Background: Mucopolysaccharidoses (MPSs) are a group of severe metabolic disorders caused by deficiencies in enzymes involved in the degradation of glycosaminoglycans (GAGs)—long chains of sugar carbohydrates in cells that help build bone, cartilage, tendons, corneas, skin, and connective tissue. Although enzyme replacement therapy has become available for the treatment of some types of MPS, effective treatment of neurodegenerative forms of MPS has yet to be determined. Recently, genistein (4',5,7-trihydroxyisoflavone), a specific inhibitor of protein tyrosine kinase, has been found to inhibit GAG synthesis and to reduce GAG concentrations in cultures of fibroblasts of MPS patients. Therefore, a potential substrate reduction therapy has been proposed. Objective: The aim of this study was to examine urinary GAG concentration, hair morphology, and cognitive function in patients receiving genistin treatment for Sanfilippo syndrome (MPS type III). Methods:Patients aged 3 to 14 years with a biochemically confirmed diagnosis of MPS IIIA or MPS IIIB were eligible to enroll in this open-label, pilot study. Genistin-rich soy isoflavone extract 5 mg/kg/d was administered PO for 12 months. Urinary GAG concentration, hair morphology,and cognitive function (measured using a modified version of the Brief Assessment Examination [BAE] and parent observations)were measured at baseline and after 12 months of treatment. Results: Ten patients (6 girls, 4 boys; mean age, 8 years [range,3\2-14 years];mean weight, 28 kg [range, 17\2-43 kg]) were included in the study. All patients had Sanfilippo syndrome; 5 patients had MPS IIIA and 5 had MPS IIIB. After 1 year, statistically significant improvement was found in urinary GAG concentration, hair morphology, and cognitive function. Urinary GAG concentration decreased significantly in all 5 patients with MPS IIIA and in 2 patients with MPS IIIB (P = 0.028). Hair morphology improved significantly in all 5 MPS IIIA patients and in 3 MPS IIIB patients (P = 0.012). A significant increase in the BAE score (by 2-6 points) was noted in 8 patients, while the scores of 2 patients did not change after 12 months of treatment (P = 0.012). No adverse events (AEs) considered related to treatment were reported. Moreover, no AEs not related to the treatment (apart from classical symptoms of MPS III) were noted. Conclusions: This pilot study found some improvements in GAG concentration, hair morphology, and cognitive function in these pediatric patients with Sanfilippo syndrome treated with genistin-rich soy isoflavone extract for 1 year. Clinical trials are needed to evaluate the efficacy and safety of this potential treatment