Primary Coenzyme Q10 Deficiency

open4siCLINICAL CHARACTERISTICS: Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen. DIAGNOSIS/TESTING: The diagnosis of primary CoQ10 deficiency in a proband is established by identification of biallelic pathogenic variants in one of the nine genes encoding proteins directly involved in the synthesis of coenzyme Q10 or by detection of reduced levels of CoQ10 (ubiquinone) in skeletal muscle or reduced activities of complex I+III and II+III of the mitochondrial respiratory chain on frozen muscle homogenates. MANAGEMENT: Treatment of manifestations: In individuals with primary CoQ10 deficiency early treatment with high-dose oral CoQ10 supplementation (ranging from 5 to 50 mg/kg/day) can limit disease progression and reverse some manifestations; however, established severe neurologic and/or renal damage cannot be reversed. ACE inhibitors may be used in combination with CoQ10 supplementation in persons with proteinuria; renal transplantation is an option for those with ESRD. Treatment of hypertrophic cardiomyopathy, retinopathy, and sensorineural hearing loss is per usual practice. Prevention of primary manifestations: Supplementation with high-dose oral CoQ10 can prevent progression of the renal disease and onset of neurologic manifestations. Surveillance: Periodic neurologic evaluation, urine analysis (for proteinuria) and renal function tests, ophthalmologic evaluation, and audiometry. Evaluation of relatives at risk: Presymptomatic diagnosis for the purpose of early treatment with CoQ10 supplementation is warranted for relatives at risk. GENETIC COUNSELING: Primary coenzyme Q10 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible if the pathogenic variants in a family are known.openSalviati, L; Trevisson, E; Doimo, M; Navas, PSalviati, Leonardo; Trevisson, Eva; Doimo, Mara; Navas, P

Clinical syndromes associated with Coenzyme Q10 deficiency.

Primary Coenzyme Q deficiencies represent a group of rare conditions caused by mutations in one of the genes required in its biosynthetic pathway at the enzymatic or regulatory level. The associated clinical manifestations are highly heterogeneous and mainly affect central and peripheral nervous system, kidney, skeletal muscle and heart. Genotype-phenotype correlations are difficult to establish, mainly because of the reduced number of patients and the large variety of symptoms. In addition, mutations in the same COQ gene can cause different clinical pictures. Here, we present an updated and comprehensive review of the clinical manifestations associated with each of the pathogenic variants causing primary CoQ deficiencies

Teoría de conjuntos e introducción de funciones

El siguiente informe está elaborado en base a las prácticas educativas realizadas por Elina Fernández y Valeria Trevisson. Las mismas fueron realizadas en tercer año A y C de una institución de la ciudad de Córdoba. Además se desarrolla la siguiente problemática desde una perspectiva teórica: ¿cómo y para qué dirigir una discusión en clases de matemática en el marco de la enseñanza de teoría de conjuntos y funciones en las condiciones del "escenario" propuesto en nuestras práctica

Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency

Under a Creative Commons license.-- et al.Human COQ6 encodes a monooxygenase which is responsible for the C5-hydroxylation of the quinone ring of coenzyme Q (CoQ). Mutations in COQ6 cause primary CoQ deficiency, a condition responsive to oral CoQ10 supplementation. Treatment is however still problematic given the poor bioavailability of CoQ10. We employed S. cerevisiae lacking the orthologous gene to characterize the two different human COQ6 isoforms and the mutations found in patients. COQ6 isoform a can partially complement the defective yeast, while isoform b, which lacks part of the FAD-binding domain, is inactive but partially stable, and could have a regulatory/inhibitory function in CoQ10 biosynthesis. Most mutations identified in patients, including the frameshift Q461fs478X mutation, retain residual enzymatic activity, and all patients carry at least one hypomorphic allele, confirming that the complete block of CoQ biosynthesis is lethal. These mutants are also partially stable and allow the assembly of the CoQ biosynthetic complex. In fact treatment with two hydroxylated analogues of 4-hydroxybenzoic acid, namely, vanillic acid or 3-4-hydroxybenzoic acid, restored the respiratory growth of yeast δcoq6 cells expressing the mutant huCOQ6-isoa proteins. These compounds, and particularly vanillic acid, could therefore represent an interesting therapeutic option for COQ6 patients.This work has been supported by grants from Telethon Italy, Fondazione CARIPARO, and University of Padova (CPDA123573/12) (to L.S.), the Italian Ministry of Health (GR-2009-1578914) (to E.T.), Région Rhônes-Alpes CIBLE 2009 (to F.P.), Spanish FIS grant PI11-00078 (to P.N.) and Proyecto Excelencia P08-CTS-03988 (to P.N.).Open Access funded by Telethon (Italy).Peer Reviewe

Fine‐Sediment Erosion and Sediment‐Ribbon Morphodynamics in Coarse‐Grained Immobile Beds

In rivers, fine sediments are often transported over immobile coarse grains. With low sediment supply, they tend to aggregate in longitudinal ribbons. Yet, the long-term evolution of such ribbons and the influence of immobile grains on the erosion of fine sediments are still not well understood. Flume experiments without sediment supply were therefore performed to investigate the erosion of an initially uniform fine-sediment bed covering an immobile bed of staggered spheres through topographic and flow measurements. The topographic measurements yielded the spheres\u27 protrusion above the fine sediment (P) and revealed long-lived ribbons with ridges and troughs. The ridges are the main long-term sediment source as the troughs are quickly eroded to a stable bed level resulting from the spheres\u27 sheltering. The ridges stabilize with a spacing of 1.3 effective water depths, their number resulting from the integer number of wavelengths fitting into the effective channel width which excludes side-wall accumulations. The ridges\u27 erosion is damped by the local upflow of secondary current cells, which displaces the strongest sweep events above the bed. The upflow intensity is controlled by the ridges\u27 height for low P, while for high P by the lateral roughness heterogeneity. The trends in erosion rates over ridges and troughs are similar and characterized by the following sequence of four regimes with increasing P: a drag sheltering, a turbulence-enhancement, a wake-interference sheltering, and a skimming-flow sheltering regime. The critical P levels at the transitions are independent of the flow above the canopy, depending only on the geometrical configuration of the immobile bed

Molecular characterization of the human COQ5 C-methyltransferase in coenzyme Q10 biosynthesis

Under a Creative Commons license.Coq5 catalyzes the only C-methylation involved in the biosynthesis of coenzyme Q (Q or ubiquinone) in humans and yeast Saccharomyces cerevisiae. As one of eleven polypeptides required for Q production in yeast, Coq5 has also been shown to assemble with the multi-subunit complex termed the CoQ-synthome. In humans, mutations in several COQ genes cause primary Q deficiency, and a decrease in Q biosynthesis is associated with mitochondrial, cardiovascular, kidney and neurodegenerative diseases. In this study, we characterize the human COQ5 polypeptide and examine its complementation of yeast coq5 point and null mutants. We show that human COQ5 RNA is expressed in all tissues and that the COQ5 polypeptide is associated with the mitochondrial inner membrane on the matrix side. Previous work in yeast has shown that point mutations within or adjacent to conserved COQ5 methyltransferase motifs result in a loss of Coq5 function but not Coq5 steady state levels. Here, we show that stabilization of the CoQ-synthome within coq5 point mutants or by over-expression of COQ8 in coq5 null mutants permits the human COQ5 homolog to partially restore coq5 mutant growth on respiratory media and Q6 content. Immunoblotting against the human COQ5 polypeptide in isolated yeast mitochondria shows that the human Coq5 polypeptide migrates in two-dimensional blue-native/SDS-PAGE at the same high molecular mass as other yeast Coq proteins. The results presented suggest that human and Escherichia coli Coq5 homologs expressed in yeast retain C-methyltransferase activity but are capable of rescuing the coq5 yeast mutants only when the CoQ-synthome is assembled.Open Access funded by Telethon (Italy).Peer Reviewe

Stereo-PIV measurements within the canopy in open-channel flows

Measuring the flow field not just above but also inside the canopy of rough beds in open-channel flows is challenging when optical access from below or the side is not possible. To this end, a new stereo-PIV arrangement was implemented and tested. To optically access the area in between the roughness elements, a top-viewing stereo-PIV system was installed at a steep viewing angle of 70◦ . Furthermore, a glass plate was installed at the water surface to avoid random image distortions from surface waves. Finally, in-house-produced low-cost fluorescent particles were used to filter out laser reflections on the canopy’s surface. To validate the stereo-PIV measurements with respect to the steep viewing angle of the stereo cameras, the instantaneous flow field above a bed of spheres was measured simultaneously with the stereo-PIV system and with a third side-looking camera for standard 2D-PIV processing. Two different water depths and two different Reynolds numbers were investigated under uniform flow conditions. Finally, to assess the influence of the glass plate on the flow, 2D-PIV measurements were performed with and without the glass plate. It is shown that the steep viewing stereo PIV can properly reconstruct the instantaneous, mean and turbulent statistics except for the vertical normal turbulent stresses, which are overestimated due to peak-locking errors. Also, the boundary layer developing below the glass plate induces a slight acceleration in the bulk flow, which can be considered negligible for higher water depths. In all instances, the flow acceleration does not affect the near-bed region

Estudio ex vivo de la eficacia de la autoinfusión de plasma rico en células blancas en úlceras infectadas

Programa Oficial de Doutoramento en Saúde e Motricidade Humana. 5002V01[Resumo] Introdución: as úlceras do pé diabético infectadas (UPDI) son enfermidades recalcitrantes que son difíciles de controlar. A infiltración de plasma rico en plaquetas (PRP) é beneficiosa para promover a cicatrización natural das feridas, pero a súa composición depende do dispositivo concentrador e do hemograma do suxeito. O papel dos leucocitos é fundamental, controlan a infección e restablecen a curación natural e non se examinou. Obxectivos: determinar a eficacia da PRP rica en leucocitos (LRPRP) en UPDIs e optimizar a terapia; actividade antimicrobiana, variabilidade LRPRP entre sistemas e suxeitos. Probabilidade de éxito. Material e métodos: desenvolvéronse ensaios clínicos e ex vivo para determinar a eficacia antimicrobiana de LRPRP en organismos prevalentes de UPDIs e a variación na composición entre sistemas e suxeitos. Resultados: as concentracións alcanzables de plaquetas e neutrófilos en LRPRP reducen ou conteñen carga orgánica (> 2log CFU/ml, plaquetas) (neutrófilos). O sistema Easy Kit é máis óptimo para obter densidades efectivas, aínda que a calidade celular do PRP-L depende do sistema, do sexo e da idade do suxeito. Conclusións: LRPRP restauraría o proceso de curación natural reducindo a carga de microorganismos. Despois de optimizar a terapia, calquera suxeito independentemente do sexo e a idade beneficiaríase do tratamento.[Resumen] Introducción: Las úlceras de pie diabético infectadas (UPDI) son afecciones recalcitrantes de difícil manejo. La infiltración de plasma rico en plaquetas (PRP) es beneficiosa por fomentar la cicatrización natural de heridas, pero su composición es dependiente del dispositivo concentrador y hemograma del sujeto. El papel de los leucocitos es determinante, controlan la infección y restauran la cicatrización natural, y no ha sido examinado. Objetivos: Determinar la efectividad del PRP rico en leucocitos (LRPRP) en UPDIs y optimizar la terapia; actividad antimicrobiana, variabilidad del LRPRP entre sistemas y sujetos. Probabilidad de éxito. Material y Métodos: Se desarrollaron ensayos clínicos y ex vivo para determinar la eficacia antimicrobiana del PRP-L en organismos prevalentes de UPDIs y la variación de composición entre sistemas y sujetos. Resultados: Concentraciones de plaquetas y neutrófilos alcanzables en LRPRP-reducen la biocarga (>2log UFC/ml, plaquetas) o la contienen (neutrófilos). El sistema Easy Kit es más óptimo para obtener densidades efectivas aunque la calidad celular del PRP-L depende del sistema y del sexo y edad del sujeto. Conclusiones: El LRPRP restauraría el proceso natural de cicatrización por reducción de la biocarga de microrganismos. Tras optimizar la terapia, cualquier sujeto con independencia del sexo y edad, se beneficiaría del tratamiento.[Abstract] Introduction: Infected diabetic foot ulcers (IDFUs) are recalcitrant ulcers with complicated clinical management. Platelet-rich plasma (PRP) infiltration is beneficial by promoting natural wound healing, but its composition is highly dependent on the concentration device and blood count of the subject. The role of leukocytes is decisive, they control infection and restore natural healing but it has not been examined. Objectives: To determine the effectiveness of the PRP rich in leukocytes (LRPRP) in DFIs and to optimize the therapy; antimicrobial activity, LRPRP variability between systems and subjects. Probability of clínical success. Material and Methods: Clinical and ex vivo trials were developed to determine the antimicrobial efficacy of LRPRP in prevalent organisms of DFIsand the compositional variation accordint to systems and subjects. Results: Achievable platelet and neutrophil concentrations in LRPRP reduce (> 2log CFU/ml, platelets) or contain (neutrophils) bioburden. The Easy Kit system is more optimal to obtain effective densities, although the cellular quality of LRPRP depends on the system and the sex and age of the subject. Conclusions: LRPRP would restore the natural healing process by reducing the bioburden of microorganisms. After optimizing therapy, any subject regardless of gender and age would benefit from treatment

Effect of a canopy patch made of streamwise-oriented plates on turbulence in an open-channel flow

The paper examines the flow through a highly porous canopy patch made of streamwise-oriented thin plates arranged in a staggered configuration and placed in a rough-bed open channel. This patch geometry contrasts with the patches made of bluff bodies, which are nearly exclusively used in the literature. Particle Image Velocimetry was used to measure the flow upstream, within and downstream of the patch. The canopy patch has the effect of drastically reducing the turbulence level of the incoming flow, especially the turbulence shear stress, which is reduced by 85%. Spectral analysis of the velocity shows that the reduction in turbulent kinetic energy occurs at all length scales. Yet, at the entrance of the patch, the energy from the smallest scales up to the scale of the water surface increases. This suggests a spectral shortcut mechanism by which the large-scale structures of the incoming flow are disintegrated by the group of plates instead of decaying through the energy cascade. The increased small-scale turbulent energy then dissipates through the patch