Gas-Phase Production of Hydroxylated Silicon Oxide Cluster Cations: Structure, Infrared Spectroscopy, and Astronomical Relevance.

The interaction of free cationic silicon oxide clusters, Si x O y + (x = 2-5, y ≥ x), with dilute water vapor, was investigated in a flow tube reactor. Product mass distributions indicate cluster size-dependent dissociative water adsorption. To probe the structure and vibrational spectra of the resulting Si x O y H2 + (x = 2-4) clusters, we employed infrared multiple photon dissociation spectroscopy and density functional theory calculations. The planar rhombic cluster core of the disilicon oxides (x = 2) appears to be retained upon dissociative adsorption of one H2O unit, whereas a significant structural transformation of the tri- and tetra-silicon oxides (x = 3 and 4) is induced, resulting in an increased coordination of the Si atoms and more 3D cluster structures. In an astronomical context, we discuss the potential relevance of Si x O y H z + clusters as seeds for dust nucleation and catalysts for carbon-based chemistry in diffuse or translucent interstellar clouds, where all the necessary conditions for producing these species are found. In the produced clusters, the frequency of the isolated silanol Si-OH stretching vibrational mode is considerably blue-shifted compared to that in hydroxylated bulk silica and small inorganic compounds. This mode has a characteristic frequency range between 1200 cm-1 (8.3 µm) and 1090 cm-1 (9.2 µm) and is associated with the anomalously small Si-OH bond lengths in these ionised species. In infrared observations such high frequency Si-O stretching modes are usually associated with a pure bulk silica component of silicate cosmic dust. The presence of Si x O y H2 + clusters in low silica astrophysical environments could thus potentially be detected via their signature Si-O band using the James Webb space telescope.

Low aerobic capacity in McArdle disease: A role for mitochondrial network impairment?

BACKGROUND: McArdle disease is caused by myophosphorylase deficiency and results in complete inability for muscle glycogen breakdown. A hallmark of this condition is muscle oxidation impairment (e.g., low peak oxygen uptake (VO2peak)), a phenomenon traditionally attributed to reduced glycolytic flux and Krebs cycle anaplerosis. Here we hypothesized an additional role for muscle mitochondrial network alterations associated with massive intracellular glycogen accumulation. METHODS: We analyzed in depth mitochondrial characteristics-content, biogenesis, ultrastructure-and network integrity in skeletal-muscle from McArdle/control mice and two patients. We also determined VO2peak in patients (both sexes, N = 145) and healthy controls (N = 133). RESULTS: Besides corroborating very poor VO2peak values in patients and impairment in muscle glycolytic flux, we found that, in McArdle muscle: (a) damaged fibers are likely those with a higher mitochondrial and glycogen content, which show major disruption of the three main cytoskeleton components-actin microfilaments, microtubules and intermediate filaments-thereby contributing to mitochondrial network disruption in skeletal muscle fibers; (b) there was an altered subcellular localization of mitochondrial fission/fusion proteins and of the sarcoplasmic reticulum protein calsequestrin-with subsequent alteration in mitochondrial dynamics/function; impairment in mitochondrial content/biogenesis; and (c) several OXPHOS-related complex proteins/activities were also affected. CONCLUSIONS: In McArdle disease, severe muscle oxidative capacity impairment could also be explained by a disruption of the mitochondrial network, at least in those fibers with a higher capacity for glycogen accumulation. Our findings might pave the way for future research addressing the potential involvement of mitochondrial network alterations in the pathophysiology of other glycogenoses.

Status dissociatus: la expresión más extrema de los estados de disociación / Status dissociatus: The most extreme expression of state dissociation

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Hallazgos electroencefalográficos y polisomnográficos en un paciente con enfermedad de Creutzfeldt-Jakob familiar / Electroencephalographic and polysomnographic findings in a patient with familial Creutzfeldt-Jakob disease

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Influence of Mitochondrial Genetics on the Mitochondrial Toxicity of Linezolid in Blood Cells and Skin Nerve Fibers.

The antibiotic linezolid is a ribosomal inhibitor with excellent efficacy. Although the administration period has been reduced to 28 days, side effects, usually of hematologic or neuropathic origin, are still reported due to secondary inhibition of mitochondrial protein synthesis. Susceptibility to linezolid toxicity remains unknown. Therefore, the objective of this study was to gain an understanding of clinical heterogeneity in response to identical linezolid exposures through exhaustive examination of the molecular basis of tissue-dependent mitotoxicity, consequent cell dysfunction, and the association of mitochondrial genetics with adverse effects of linezolid administered for the recommended period. Peripheral blood mononuclear cells (PBMC) and skin nerve fibers from 19 and 6 patients, respectively, were evaluated before and after a 28-day linezolid treatment in order to assess toxic effects on mitochondria and cells. Mitochondrial DNA haplotypes and single nucleotide polymorphisms (SNPs) in ribosomal sequences where linezolid binds to mitochondrial ribosomes were also analyzed to investigate their genetic contributions. We found that linezolid reduced mitochondrial protein levels, complex IV activity, and mitochondrial mass in PBMC and was associated with a trend toward an increase in the rate of apoptosis. In skin tissue, mitochondrial mass increased within nerve fibers, accompanied by subclinical axonal swelling. Mitochondrial haplogroup U, mutations in 12S rRNA, and the m.2706A→G, m.3197T→C, and m.3010G→A polymorphisms in 16S rRNA showed a trend toward an association with increased mitochondrial and clinical adverse effects. We conclude that even when linezolid is administered for a shorter time than formerly, adverse effects are reported by 63% of patients. Linezolid exerts tissue-dependent mitotoxicity that is responsible for downstream cellular consequences (blood cell death and nerve fiber swelling), leading to adverse hematologic and peripheral nervous side effects. Multicentric studies should confirm genetic susceptibility in larger cohorts.

Differences in Neisseria gonorrhoeae population structure and antimicrobial resistance pattern between men who have sex with men and heterosexuals.

This study compared the antimicrobial susceptibility and genotypes of strains of Neisseria gonorrhoeae isolated from men who have sex with men (MSM) and from heterosexuals. One hundred and eleven strains were characterized from 107 patients, comprising 57 strains from 54 heterosexuals and 54 strains from 53 MSM. Antimicrobial resistance rates were higher in strains from heterosexual patients, with resistance to cefixime (P = 0·0159) and ciprofloxacin (P = 0·002) being significantly higher. Typing by N. gonorrhoeae multi-antigen sequence typing (NG-MAST) showed that the most prevalent sequence types (ST) and genogroups (G) respectively were ST2400, ST2992, and ST5793, and G1407, G2992, and G2400. A statistically significant association was observed for MSM and genogroups G2400 (P = 0·0005) and G2992 (P = 0·0488), and G1407 with heterosexuals (P = 0·0002). We conclude that in our region distinct populations of gonococci are circulating among subjects with different sexual practices, with their corresponding transmission patterns. Furthermore, the high prevalence of genotype G2400 in MSM, has not to our knowledge been previously described.

Neisseria gonorrhoeae antimicrobial susceptibility in Barcelona: penA, ponA, mtrR, and porB mutations and NG-MAST sequence types associated with decreased susceptibility to cephalosporins.

The aims of this study were to determine the antimicrobial susceptibility of Neisseria gonorrhoeae (NG) in our area, to analyze the molecular mechanisms involved in cephalosporins resistance, and to undertake molecular typing of our NG strains. Antimicrobial susceptibility was determined using the Etest. The genes penA, mtrR, penB, and ponA were studied. Molecular typing was performed by N. gonorrhoeae multiantigen sequence typing. Of 329 strains analyzed in 2013, none showed high-level cephalosporin resistance, but 8.2 % had resistance to cefixime [minimum inhibitory concentration (MIC) > 0.125 µg/mL] and 0.6 % to ceftriaxone (MIC > 0.125 µg/mL). Azithromycin resistance was documented in 4.3 % and ciprofloxacin resistance in 49.2 %. Among 48 strains with an MIC ≥ 0.125 µg/mL to cefixime, 58.3 % showed the penA mosaic pattern XXXIV, 98 % a Leu → Pro substitution at position 421 of the ponA gene, 100 % amino acid changes at positions 101 and 102 of the PorB1b porin, and 87.5 % of strains an adenine deletion in the promoter region of the MtrC-D-E efflux pump. A significant difference between strains with and without decreased cephalosporin susceptibility (MIC ≥ 0.125 µg/mL) was observed for these four genes. Of the 48 strains with an MIC ≥ 0.125 µg/mL to cefixime, 43.8 % belonged to the genogroup G1407 and 27.1 % belonged to the genogroup G2400. A significant association of G1407 with decreased susceptibility (MIC ≥ 0.125 µg/mL) and G2992 with susceptibility was found, and also between G1407 and mosaic pattern XXXIV and between G2400 and A501T substitution in penA. The NG resistance rate in our area is higher than the median of Europe. We have detected the emergence of G2400, which may be a source of antimicrobial resistance.

Comparison between conventional culture and NAATs for the microbiological diagnosis in gonococcal infection.

Gonorrhea is a public health problem. Fast diagnostics is necessary. The aim of this study was to compare the diagnostic yield of culture with that of polymerase chain reaction (PCR) in gonococcal infection. This is a study comparing the results of Neisseria gonorrhoeae detection by culture versus PCR from July to December 2012. Molecular diagnosis was performed by real-time PCR using the Versant CT/GC DNA 1.0 assay. In the 768 specimens, 96.9% the results were concordant. In 3.1%, the results were discordant, being PCR-positive and culture-negative in 21 cases and PCR-negative and culture-positive in 3. The sensitivity, specificity, positive predictive value, and negative predictive value for culture were 86.2%, 99.8%, 99.2%, and 96.7%, and for PCR, 98.7%, 100%, 100% and 99.7%, respectively. In laboratories where antimicrobial susceptibility is monitored, an effective approach would be to perform culture in addition to PCR in symptomatic patients.

Temporal trends in classical and alternative flame retardants in bird eggs from Doñana Natural Space and surrounding areas (south-western Spain) between 1999 and 2013.

Several halogenated flame retardants were detected in black kite, white stork and greater flamingo unborn eggs from Doñana Natural Space (Spain) collected in 1999, 2003, 2011 and 2013. The main components of Penta-BDE commercial mixture (BDE-47, -99 and -100) showed a decrease in the studied time interval, concurring with the ban of this mixture in the European Union (EU) in 2006. On the other hand, BDE-209, the main component of Deca-BDE mixture showed a clear trend in black kites but further monitoring is needed since its production ceased at the end of 2013. Besides, even if Dechlorane Plus (DP) was proposed by the EU as an alternative to BDE-209 no time trends were observed. Furthermore, total concentrations of PBDEs (classical FRs) are still higher than concentrations of hexabromocyclododecane (HBCD) and alternative FRs halogenated norbornenes (HNs), which are theoretically substitutes of the already banned PBDEs.

Bioaccumulation and biomagnification of emerging and classical flame retardants in bird eggs of 14 species from Doñana Natural Space and surrounding areas (South-western Spain).

The occurrence of classical (polybrominated diphenyl ethers, PBDEs) and emerging FRs (dechloranes, hexabromobenzene (HBB), pentabromoethyl benzene (PBEB) and decabromodiphenyl ethane (DBDPE)) in unborn eggs of 14 different species from Doñana Natural Space and surrounding areas was studied. PBDEs, Dec-602, Dec-603 and DP were detected in all the species, whereas HBB, PBEB, DBDPE and Dec-604 were not detected in any sample. ΣPBDE and ΣDechlorane levels ranged from 1.40 to 90.7, and from 0.77 to 260 ng/g lw, respectively. BDE-209 was the most abundant BDE congener in almost all the species, whereas Dec-602 was the predominant among dechloranes. In general, levels of PBDEs and dechloranes were similar and even higher for dechloranes, probably indicating the increasing use of dechloranes as a result of legal restrictions on PBDEs. In both cases, the most contaminated specie was the white stork. Using stable isotope characterization, differences among species and possible biomagnification processes were also evaluated. PBDE levels increased as the trophic position increased, showing biomagnification capacity. The same behavior was observed for Dec-602 and Dec-603; however, DP levels were not linearly correlated with trophic level. These results show that more attention should be given to emerging FRs such as dechloranes since they show similar environmental behavior as PBDEs.

Identification and biochemical characterization of the novel mutation m.8839G>C in the mitochondrial ATP6 gene associated with NARP syndrome.

Mutations in the ATP6 gene are reported to be associated with Leber hereditary optic neuropathy, bilateral striatal necrosis, coronary atherosclerosis risk and neuropathy, ataxia and retinitis pigmentosa (NARP)/maternally inherited Leigh syndromes. Here, we present a patient with NARP syndrome, in whom a previously undescribed mutation was detected in the ATP6 gene: m.8839G>C. Several observations support the concept that m.8839G>C is pathogenically involved in the clinical phenotype of this patient: (1) the mutation was heteroplasmic in muscle; (2) mutation load was higher in the symptomatic patient than in the asymptomatic carriers; (3) cybrids carrying this mutation presented lower cell proliferation, increased mitochondrial DNA (mtDNA) copy number, increased steady-state OxPhos protein levels and decreased mitochondrial membrane potential with respect to isogenic wild-type cybrids; (4) this change was not observed in 2959 human mtDNAs from different mitochondrial haplogroups; (5) the affected amino acid was conserved in all the ATP6 sequences analyzed; and (6) using in silico prediction, the mutation was classified as 'probably damaging'. However, measurement of ATP synthesis showed no differences between wild-type and mutated cybrids. Thus, we suggest that m.8839G>C may lower the efficiency between proton translocation within F0 and F1 rotation, required for ATP synthesis. Further experiments are needed to fully characterize the molecular mechanisms involved in m.8839G>C pathogenicity.

Economic benefits of inactivated influenza vaccines in the prevention of seasonal influenza in children.

The aim of this study was to systematically review published studies that evaluated the efficiency of inactivated influenza vaccination in preventing seasonal influenza in children. The vaccine evaluated was the influenza-inactivated vaccine in 10 studies and the virosomal inactivated vaccine in 3 studies. The results show that yearly vaccination of children with the inactivated influenza vaccine saves money from the societal and family perspectives but not from the public or private provider perspective. When vaccination does not save money, the cost-effectiveness ratios were very acceptable. It can be concluded, that inactivated influenza vaccination of children is a very efficient intervention.

Distribution of pilus islands in Streptococcus agalactiae that cause human infections: insights into evolution and implication for vaccine development.

At least one pilus island, PI-1 (70%), PI-2a (79%), or PI-2b (21%), was found among 898 Streptococcus agalactiae (group B streptococcus [GBS]) isolates recovered from humans, supporting the use of pilus proteins in vaccines. The stability and dominance of PI-1 and PI-2a in multiple serotypes and founder multilocus sequence types disseminated worldwide suggest it could be the PI combination present in ancestral GBS human pathogens.

Lymphogranuloma venereum: a hidden emerging problem, Barcelona, 2011.

From the beginning of 2007 until the end of 2011, 146 cases of lymphogranuloma venereum (LGV) were notified to the Barcelona Public Health Agency. Some 49% of them were diagnosed and reported in 2011, mainly in men who have sex with men. Almost half of them, 32 cases, were reported between July and September. This cluster represents the largest since 2004. This article presents the ongoing outbreak of LGV in Barcelona.

Effect of an ambulatory diagnostic and treatment programme in patients with sleep apnoea.

The aim of this study to evaluate the efficacy of a home-based programme on clinical response, continuous positive airway pressure (CPAP) compliance and cost in a population of high pre-test probability of suffering obstructive sleep apnoea syndrome (OSAS). Patients were randomised into the following three groups. Group A: home respiratory polygraphy (RP) and home follow-up; group B: hospital polysomnography and hospital follow-up; and group C: home RP and hospital follow-up. Evaluation during 6 months included Epworth Sleepiness Scale (ESS), Functional Outcomes Sleep Questionnaire (FOSQ), and daily activity and symptom questionnaires. Compliance was assessed by memory cards (group A) and using an hourly counter (groups B and C). 66 patients were included (22 per branch), 83% were males, aged mean±sd 52±10 yrs, body mass index 34±7kg·m(-2), apnoea/hypopnoea index 43±20 h(-1), CPAP pressure 8±2 cmH(2)O, with no between-group differences. Clinical response showed an ESS of mean±sd 15±3 to 6±4, a FOSQ of 16±3 to 18±2, symptoms of 43±7 to 25±7, and activity of 37±11 to 25±8. At the end of the study, compliance was: group A 73%, group B 68% and group C 57%. The cost per patient was: group A €590±43, group B €894±11 and group C €644±93 (p<0.001). In conclusion, patients with a high initial probability of having OSAS can be diagnosed and treated in a home setting, with a high level of CPAP compliance and lower cost than using either a hospital-based approach or home RP/hospital follow-up.

Group B streptococci causing neonatal infections in barcelona are a stable clonal population: 18-year surveillance.

We analyzed 212 group B streptococci (GBS) from newborns with invasive infections in the area of Barcelona, Spain, between 1992 and 2009, with the aim of documenting changes in the prevalences of serotypes, antimicrobial resistance, and genetic lineages and evaluating their associations with either early-onset disease (EOD) or late-onset disease (LOD). Serotypes III (n = 118) and Ia (n = 47) together accounted for nearly 78% of the isolates. All isolates carried an alpha or alpha-like protein gene, and specific associations between genes and serotypes, such as serotype Ib and bca, serotype II and bca, serotype III and rib, and serotype V and alp3, reflected the presence of particular genetic lineages. Macrolide resistance (14.2%) was significantly associated with serotype V. Pulsed-field gel electrophoresis (PFGE) clustering was an excellent predictor of serotype and antibiotic resistance. The combination of PFGE and multilocus sequence typing revealed a large number of genetically distinct lineages. Still, specific lineages were dominant in our collection, particularly the serotype III/ST17/rib lineage, which had enhanced potential to cause LOD. Serotype Ia was concentrated in a single PFGE cluster composed of two genetic lineages: ST23/eps and ST24/bca. The ST24/bca sublineage of serotype Ia, which is found infrequently elsewhere, may be emerging as an important cause of neonatal invasive infections in the Mediterranean region. In spite of the introduction of prophylaxis, resulting in a pronounced decline in the frequency of EOD, the study revealed a remarkably stable clonal structure of GBS causing neonatal infections in Barcelona over a period of 18 years.

Hematopoietic gene therapy restores thymidine phosphorylase activity in a cell culture and a murine model of MNGIE.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the TYMP gene, which encodes thymidine phosphorylase (TP). TP dysfunction results in systemic thymidine (dThd) and deoxyuridine (dUrd) overload, which selectively impair mitochondrial DNA replication. Allogeneic hematopoietic transplantation has been used to treat MNGIE patients; however, this approach has serious adverse effects, including the toxicity of myeloablative conditioning, graft rejection and graft-versus-host disease. With the aim of testing the feasibility of gene therapy for MNGIE, we transduced TP-deficient B-lymphoblastoid cells from two MNGIE patients, with lentiviral vectors carrying a functional copy of the human TYMP DNA coding sequence. This restored TP activity in the cells, which reduced the excretion of dThd and dUrd and their concentrations when added in excess. Additionally, lentiviral-mediated hematopoietic gene therapy was used in partially myeloablated double Tymp/Upp1 knockout mice. In spite of the relatively low levels of molecular chimerism achieved, high levels of TP activity were observed in the peripheral blood of the transplanted mice, with a concomitant reduction of nucleoside concentrations. Our results suggest that hematopoietic gene therapy could be an alternative treatment for this devastating disorder in the future.