Molecular analysis of mucopolysaccharidosis type VI in Poland, Belarus, Lithuania and Estonia.

Mucopolysaccharidosis VI (MPS VI) is a rare autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-4-sulfatase (ARSB). Over 130 ARSB gene mutations have been identified thus far and most mutations are unique to individual families. We aimed to analyze the spectrum of mutations in the ARSB gene responsible for the disorder in Poland, Belarus and Baltic States.

Inhibition of development of Shiga toxin-converting bacteriophages by either treatment with citrate or amino acid starvation.

Objectives: Shiga toxin-producing Escherichia coli (STEC) are pathogenic strains, whose virulence depends on induction of Shiga toxin-converting prophages and their subsequent lytic development. We explored which factors or conditions could inhibit development of these phages, potentially decreasing virulence of STEC.

Materials And Methods: Lytic development of Shiga toxin-converting bacteriophages was monitored after mitomycin C-provoked prophage induction under various conditions.

Osteoprotegerin gene polymorphism in diabetic Charcot neuroarthropathy.

Aims: Recently, an association between two polymorphisms (1181G>C and 245T>G) of the osteoprotegerin (OPG) gene and diabetic Charcot neuroarthropathy was suggested on the basis of studies of a limited number of samples derived from subjects from one geographical region (Italy). The aim of this study was to assess the presence of various osteoprotegerin gene polymorphisms in patients with diabetes and Charcot neuroarthropathy compared with subjects with diabetic neuropathy but no Charcot foot and healthy controls from another geographical region (Poland).

Methods: DNA was isolated from 54 patients with Charcot neuroarthropathy, 35 subjects with diabetic neuropathy but no Charcot foot, and 95 healthy controls to evaluate OPG gene polymorphisms and their possible contribution to the development of Charcot neuroarthropathy.

[Mucopolysaccharidoses--biochemical mechanisms of diseases and therapeutic possibilities].

Mucopolysaccharidoses (MPS) are inherited metabolic diseases from the group of lysosomal storage disorders (LSD). They are caused by genetic defects resulting in the absence or severe deficiency in one of lysosmal hydrolases involved in degradation of glycosaminoglycans (GAG). Partially degraded GAGs are accumulated in lysosomes, causing dysfunction of cells, tissues and organs.

[Lysosomal storage diseases--an overview].

Lysosomal storage diseases (LSD) are a group of fifty or so metabolic disorders. They are caused by genetic defects causing a lack or severe deficiency in activity of one of proteins belonging to four functional groups: acid lysosomal hydorlases involved in degradation of various macromolecules, proteins involved in lysosomal transportation, proteins required to deliver enzymes into lysosomes or activators of lysosomal enzymes. Due to their deficiency, undegraded or partially degraded macromolecules accumulates in lysosomes, causing dysfunction of cells, tissues and organs.

Substrate reduction therapies for mucopolysaccharidoses.

Mucopolysaccharidoses (MPS) are inherited metabolic disorders, caused by mutations leading to dysfunction of one of enzymes involved in degradation of glycosaminoglycans (GAGs) in lysosomes. Due to their impaired degradation, GAGs accumulate in cells of patients, which results in dysfunction of tissues and organs, including the heart, respiratory system, bones, joints and central nervous system. Depending on the kind of deficient enzyme, 11 types and subtypes of MPS are currently recognized.

Mutagenicity of quaternary ammonium salts containing carbohydrate moieties.

Quaternary ammonium salts are widely used in industrial, agricultural, healthcare and domestic applications. They are believed to be safe compounds, with little or no health hazard to humans. However, in this report, we demonstrate that a series of newly synthesized quaternary ammonium salts containing carbohydrate moieties reveal potent mutagenic activities, as assessed by using the Vibrio harveyi bioluminescence mutagenicity test.

Bacteriophages carrying Shiga toxin genes: genomic variations, detection and potential treatment of pathogenic bacteria.

Although most Escherichia coli strains occur in the mammalian intestine as commensals, some of them, including enterohemorrhagic E. coli (EHEC), are capable of causing disease in humans. The most notorious virulence factors of EHEC are Shiga toxins, encoded by genes located on genomes of lambdoid prophages.

Improvement in the range of joint motion in seven patients with mucopolysaccharidosis type II during experimental gene expression-targeted isoflavone therapy (GET IT).

Mucopolysaccharidosis type II (MPS II, Hunter disease) is an X chromosome-linked inherited metabolic disease caused by mutations resulting in deficiency of activity of iduronate-2-sulfatase (IDS) and accumulation of undegraded glycosaminoglycans (GAGs), heparan sulfate, and dermatan sulfate. Previous experiments with cell cultures and studies on animal model of MPS II suggested that gene expression-targeted isoflavone therapy (GET IT), based on genistein-mediated reduction of efficiency of GAG synthesis, might be a suitable therapy for this disease. In this report, we demonstrate efficacy of GET IT in connective tissue elasticity, particularly in improving the range of joint motion in seven patients with MPS II after 26 weeks of treatment with an isoflavone extract at the dose corresponding to 5 mg/kg/day of genistein.

Hyperactive behaviour in the mouse model of mucopolysaccharidosis IIIB in the open field and home cage environments.

Mucopolysaccharidosis IIIB (MPS IIIB) is a lysosomal storage disorder characterized by severe behavioural disturbances and progressive loss of cognitive and motor function. There is no effective treatment, but behavioural testing is a valuable tool to assess neurodegeneration and the effect of novel therapies in mouse models of disease. Several groups have evaluated behaviour in this model, but the data are inconsistent, often conflicting with patient natural history.

Drug-resistant epilepsia and fulminant valproate liver toxicity. Alpers-Huttenlocher syndrome in two children confirmed post mortem by identification of p.W748S mutation in POLG gene.

Background: POLG (polymerase gamma) gene mutations lead to a variety of neurological disorders, including Alpers-Huttenlocher syndrome (AHS). The diagnostic triad of AHS is: resistant epilepsy, liver impairment triggered by sodium valproate (VA), and mitochondrial DNA depletion.

Material/methods: A cohort of 28 children with mitochondrial encephalopathy and liver failure was qualified for retrospective study of mitochondrial DNA depletion and POLG mutations.

Two-year follow-up of Sanfilippo Disease patients treated with a genistein-rich isoflavone extract: assessment of effects on cognitive functions and general status of patients.

Background: Mucopolysaccharidoses (MPS) are inherited metabolic disorders caused by deficiencies in enzymes involved in degradation of glycosaminoglycans. MPS type III (Sanfilippo disease) is clinically characterized mainly by progressive and severe behavioral disturbances and cognitive dysfunction. Recent 1-year experimental treatment of 10 patients with a genistein (4', 5, 7-trihydroxyisoflavone)-rich extract resulted in improvement of tested parameters, including cognitive and behavioral functions.

Genetic response to metabolic fluctuations: correlation between central carbon metabolism and DNA replication in Escherichia coli.

Background: Until now, the direct link between central carbon metabolism and DNA replication has been demonstrated only in Bacillus. subtilis. Therefore, we asked if this is a specific phenomenon, characteristic for this bacterium and perhaps for its close relatives, or a more general biological rule.

A single point mutation in ricin A-chain increases toxin degradation and inhibits EDEM1-dependent ER retrotranslocation.

Ricin is a potent plant cytotoxin composed of an A-chain [RTA (ricin A-chain)] connected by a disulfide bond to a cell binding lectin B-chain [RTB (ricin B-chain)]. After endocytic uptake, the toxin is transported retrogradely to the ER (endoplasmic reticulum) from where enzymatically active RTA is translocated to the cytosol. This transport is promoted by the EDEM1 (ER degradation-enhancing α-mannosidase I-like protein 1), which is also responsible for directing aberrant proteins for ERAD (ER-associated protein degradation).

Specific detection of Salmonella enterica and Escherichia coli strains by using ELISA with bacteriophages as recognition agents.

The use of bacteriophages, instead of antibodies, in the ELISA-based detection of bacterial strains was tested. This procedure appeared to be efficient, and specific strains of Salmonella enterica and Escherichia coli could be detected. The sensitivity of the assay was about 10(5) bacterial cells/well (10(6)/ml), which is comparable with or outperforms other ELISA tests detecting intact bacterial cells without an enrichment step.

Effects of flavonoids on glycosaminoglycan synthesis: implications for substrate reduction therapy in Sanfilippo disease and other mucopolysaccharidoses.

Sanfilippo disease (mucopolysaccharidosis type III, MPS III) is a severe metabolic disorder caused by accumulation of heparan sulfate (HS), one of glycosaminoglycans (GAGs), due to a genetic defect resulting in a deficiency of GAG hydrolysis. This disorder is characterized as the most severe neurological form of MPS, revealing rapid deterioration of brain functions. Among therapeutic approaches for MPS III, one of the most promising appears to be the substrate reduction therapy (SRT).

A reliable method for storage of tailed phages.

A universal and effective method for long-term storage of bacteriophages has not yet been described. We show that randomly selected tailed phages could be stored inside the infected cells at -80°C without a major loss of phage and host viability. Our results suggest the suitability of this method as a standard for phage preservation.

Persistence of bacteriophage T4 in a starved Escherichia coli culture: evidence for the presence of phage subpopulations.

Bacteriophage T4 is able to adjust its development to the growth parameters of the host cell. Here, we present evidence for the production of two different subpopulations of phage particles, which differ in their ability to infect starved Escherichia coli cells. The ability of phage T4 to produce a fraction of virions unable to infect starved cells is linked to the functions of genes rI and rIII, as well as rIIA.

Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease.

Background: Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease) accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments.

Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure.

Deoxyguanosine kinase deficiency (dGK) is a frequent cause of the hepatocerebral form of mitochondrial depletion syndrome (MDS). A group of 28 infants with severe progressive liver failure of unknown cause was recruited for post mortem search for deoxyguanosine kinase (DGUOK) gene mutations. Four affected patients (14% of the studied group), two homozygotes, one compound heterozygote, and one heterozygote, with DGUOK mutation found on only one allele, were identified.

Female Hunter syndrome caused by a single mutation and familial XCI skewing: implications for other X-linked disorders.

Familial X-chromosome inactivation (XCI) skewing was investigated in a family in which a female mucopolysaccharidosis type II (MPS II) (Hunter syndrome, an X-linked genetic disease) occurred. Among eight related females aged under 60 years from three generations who were tested, four revealed a non-random pattern of XCI. Detailed genetic analysis failed to find mutations in genes that were previously reported as important for the XCI process.

A role for accessory genes rI.-1 and rI.1 in the regulation of lysis inhibition by bacteriophage T4.

Lysis inhibition (LIN) is a known feature of the T-even family of bacteriophages. Despite its historical role in the development of modern molecular genetics, many aspects of this phenomenon remain mostly unexplained. The key element of LIN is an interaction between two phage-encoded proteins, the T holin and the RI antiholin.

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.

Replication of plasmids derived from Shiga toxin-converting bacteriophages in starved Escherichia coli.

The pathogenicity of Shiga toxin-producing Escherichia coli (STEC) depends on the expression of stx genes that are located on lambdoid prophages. Effective toxin production occurs only after prophage induction, and one may presume that replication of the phage genome is important for an increase in the dosage of stx genes, positively influencing their expression. We investigated the replication of plasmids derived from Shiga toxin (Stx)-converting bacteriophages in starved E.

Why are behaviors of children suffering from various neuronopathic types of mucopolysaccharidoses different?

Mucopolysaccharidoses (MPS) are inherited metabolic disorders from the group of lysosomal storage diseases (LSD). They arise from mutations causing dysfunction of one of enzymes involved in degradation of glycosaminoglycans (GAGs) in lysosomes. Impaired degradation of these compounds results in their accumulation in cells and dysfunction of most tissues and organs of patients.