Detection of and Powassan Virus Lineage II (Deer Tick Virus) from Harvested in Oklahoma.

(white-tailed deer) is the primary host of adult (deer tick). Most of the research into has been geographically restricted to the northeastern United States, with limited interest in Oklahoma until recently as the populations spread due to climate change. Ticks serve as a vector for pathogenic bacteria, protozoans, and viruses that pose a significant human health risk.

Blood Mononuclear Cell Mitochondrial Respiratory Chain Complex IV Activity Is Decreased in Multiple Sclerosis Patients: Effects of β-Interferon Treatment.

Objectives: Evidence of mitochondrial respiratory chain (MRC) dysfunction and oxidative stress has been implicated in the pathophysiology of multiple sclerosis (MS). However, at present, there is no reliable low invasive surrogate available to evaluate mitochondrial function in these patients. In view of the particular sensitivity of MRC complex IV to oxidative stress, the aim of this study was to assess blood mononuclear cell (BMNC) MRC complex IV activity in MS patients and compare these results to age matched controls and MS patients on β-interferon treatment.

Biochemical diagnosis of coenzyme q10 deficiency.

Coenzyme Q10 (CoQ10) deficiency appears to have a particularly heterogeneous clinical presentation. However, there appear to be 5 recognisable clinical phenotypes: encephalomyopathy, severe infantile multisystemic disease, nephropathy, cerebellar ataxia, and isolated myopathy. However, although useful, clinical symptoms alone are insufficient for the definitive diagnosis of CoQ10 deficiency which relies upon biochemical assessment of tissue CoQ10 status.

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood.

Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy.

Objective: Charcot-Marie Tooth disease (CMT) forms a clinically and genetically heterogeneous group of disorders. Although a number of disease genes have been identified for CMT, the gene discovery for some complex form of CMT has lagged behind. The association of neuropathy and optic atrophy (also known as CMT type 6) has been described with autosomaldominant, recessive and X-linked modes of inheritance.

Levels of 5-methyltetrahydrofolate and ascorbic acid in cerebrospinal fluid are correlated: implications for the accelerated degradation of folate by reactive oxygen species.

Deficiency of 5-methyltetrahydrofolate (5-MTHF) in cerebrospinal fluid (CSF) is associated with a number of neurometabolic conditions including mitochondrial electron transport chain defects. Whilst failure of the active transport of 5-methyltetrahydrofolate (5-MTHF) into the CSF compartment has been proposed as a potential mechanism responsible for the 5-MTHF deficiency seen in mitochondrial disorders, it is becoming increasingly clear that other mechanisms are involved. Here, we have considered the role of oxidative stress as a contributing mechanism.

COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.

Importance: Isolated cytochrome-c oxidase (COX) deficiency is one of the most frequent respiratory chain defects seen in human mitochondrial disease. Typically, patients present with severe neonatal multisystem disease and have an early fatal outcome. We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.

SURF1 deficiency: a multi-centre natural history study.

Background: SURF1 deficiency, a monogenic mitochondrial disorder, is the most frequent cause of cytochrome c oxidase (COX) deficient Leigh syndrome (LS). We report the first natural history study of SURF1 deficiency.

Methods: We conducted a multi-centre case notes review of 44 SURF1-deficient patients from ten different UK centres and two Australian centres.

Secondary coenzyme Q10 deficiency and oxidative stress in cultured fibroblasts from patients with riboflavin responsive multiple Acyl-CoA dehydrogenation deficiency.

Coenzyme Q10 (CoQ10) is essential for the energy production of the cells and as an electron transporter in the mitochondrial respiratory chain. CoQ10 links the mitochondrial fatty acid β-oxidation to the respiratory chain by accepting electrons from electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). Recently, it was shown that a group of patients with the riboflavin responsive form of multiple acyl-CoA dehydrogenation deficiency (RR-MADD) carrying inherited amino acid variations in ETF-QO also had secondary CoQ10 deficiency with beneficial effects of CoQ10 treatment, thus adding RR-MADD to an increasing number of diseases involving secondary CoQ10 deficiency.

Coenzyme Q10 quantification in muscle, fibroblasts and cerebrospinal fluid by liquid chromatography/tandem mass spectrometry using a novel deuterated internal standard.

Rationale: Neurological dysfunction is common in primary coenzyme Q10 (2,3-dimethoxy, 5-methyl, 6-polyisoprene parabenzoquinone; CoQ10 ; ubiquinone) deficiencies, the most readily treatable subgroup of mitochondrial disorders. Therapeutic benefit from CoQ10 supplementation has also been noted in other neurodegenerative diseases. CoQ10 can be measured by high-performance liquid chromatography (HPLC) in plasma, muscle or leucocytes; however, there is no reliable method to quantify CoQ10 in cerebrospinal fluid (CSF).

Coenzyme Q₁₀ deficiency in mitochondrial DNA depletion syndromes.

We evaluated coenzyme Q₁₀ (CoQ) levels in patients studied under suspicion of mitochondrial DNA depletion syndromes (MDS) (n=39). CoQ levels were quantified by HPLC, and the percentage of mtDNA depletion by quantitative real-time PCR. A high percentage of MDS patients presented with CoQ deficiency as compared to other mitochondrial patients (Mann-Whitney-U test: p=0.

Assessment of mitochondrial electron transport chain function in a primary astrocyte cell model of hyperhomocystinaemia.

Elevated plasma homocysteine (Hcy) has been detected in patients with various neurodegenerative conditions. Studies on neurones and cerebral tissue have revealed that hyperhomocystinaemia may inhibit mitochondrial electron transport chain (ETC) enzyme activity resulting in neuronal morbidity. As astrocytes convey a protective and supportive role towards neurones, we postulated that Hcy-induced astrocytic ETC inhibition may contribute to neurological dysfunction.

Dopamine but not l-dopa stimulates neural glutathione metabolism. Potential implications for Parkinson's and other dopamine deficiency states.

Dopamine is produced first by hydroxylalation of l-tyrosine to l-dihydroxyphenylalanine (l-dopa) and subsequently by the decarboxylation of l-dopa to dopamine catalysed by the enzymes tyrosine hydroxylase and aromatic l-amino acid decarboxylase (AADC) respectively. Reduced glutathione (GSH) acts as a major cellular antioxidant. We have investigated the role of dopamine in the control of GSH homeostasis in brain cells.

Poor maternal nutrition followed by accelerated postnatal growth leads to alterations in DNA damage and repair, oxidative and nitrosative stress, and oxidative defense capacity in rat heart.

Low birth weight and accelerated postnatal growth lead to increased risk of cardiovascular disease. We reported previously that rats exposed to a low-protein diet in utero and postnatal catch-up growth (recuperated) develop metabolic dysfunction and have reduced life span. Here we explored the hypothesis that cardiac oxidative and nitrosative stress leading to DNA damage and accelerated cellular aging could contribute to these phenotypes.

Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease.

Objective: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.

Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway.

The citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain to be determined. To augment cardiac fumarate levels and to assess fumarate's cardioprotective properties, we generated fumarate hydratase (Fh1) cardiac knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R).

Uncovering genomic causes of co-morbidity in epilepsy: gene-driven phenotypic characterization of rare microdeletions.

Background: Patients with epilepsy often suffer from other important conditions. The existence of such co-morbidities is frequently not recognized and their relationship with epilepsy usually remains unexplained.

Methodology/principal Findings: We describe three patients with common, sporadic, non-syndromic epilepsies in whom large genomic microdeletions were found during a study of genetic susceptibility to epilepsy.

Rosuvastatin lowers coenzyme Q10 levels, but not mitochondrial adenosine triphosphate synthesis, in children with familial hypercholesterolemia.

Objective: To investigate whether statin therapy affects coenzyme Q10 (CoQ10) status in children with heterozygous familial hypercholesterolemia (FH).

Study Design: Samples were obtained at baseline (treatment naïve) and after dose titration with rosuvastatin, aiming for a low-density lipoprotein cholesterol level of 110 mg/dL. Twenty-nine patients were treated with 5, 10, or 20 mg of rosuvastatin for a mean period of 29 weeks.

Bezafibrate induced increase in mitochondrial electron transport chain complex IV activity in human astrocytoma cells: Implications for mitochondrial cytopathies and neurodegenerative diseases.

Mitochondrial encephalomyopathies resulting from electron transport chain (ETC) dysfunction can present with a wide spectrum of clinical manifestations having significant neuropathology and a progressive nature. Despite advances in diagnosis of ETC disorders, treatment still remains inadequate. A recent study in fibroblasts and myoblasts revealed the ability of fibrate treatment to correct ETC enzyme deficiencies.

Fungal endophytes of native grasses decrease insect herbivore preference and performance.

Endophytic fungal symbionts of grasses are well known for their protective benefit of herbivory reduction. However, the majority of studies on endophyte-grass symbioses have been conducted on economically important, agricultural species-particularly tall fescue (Lolium arundinaceum) and perennial ryegrass (Lolium perenne)-raising the hypothesis that strong benefits are the product of artificial selection. We examined whether fungal endophytes found in natural populations of native grass species deterred insect herbivores.

A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy.

Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM). However, such mutations account for only a small proportion of the clinical cases emphasising the need for alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM.

Pyridoxal 5'-phosphate deficiency causes a loss of aromatic L-amino acid decarboxylase in patients and human neuroblastoma cells, implications for aromatic L-amino acid decarboxylase and vitamin B(6) deficiency states.

Pyridoxal 5'-phosphate, the active form of vitamin B(6), is an essential cofactor for multiple enzymes, including aromatic l-amino acid decarboxylase that catalyses the final stage in the production of the neurotransmitters dopamine and serotonin. In two patients with inherited disorders of vitamin B(6) metabolism, we observed reductions in plasma aromatic l-amino acid decarboxylase activity. In one patient, this change was related to an increase in K(m) for pyridoxal 5'-phosphate.